Juan Jose Lafaille, Ph.D.

It takes two to tango
Bilate, Angelina B; Lafaille, Juan J
2011 Jul 22;35(1):6-8, Immunity
Regulatory T (Treg) cells are essential for maintaining immune tolerance. In this issue of Immunity, Haribhai et al. (2011) demonstrate that both subsets of Treg cells, natural and induced, are necessary to achieve tolerance, probably because of their nonoverlapping T cell receptor repertoires
— id: 135577, year: 2011, vol: 35, page: 6, stat: Journal Article,

Lipid phosphate phosphatase 3 enables efficient thymic egress
Breart, Beatrice; Ramos-Perez, Willy D; Mendoza, Alejandra; Salous, Abdelghaffar K; Gobert, Michael; Huang, Yong; Adams, Ralf H; Lafaille, Juan J; Escalante-Alcalde, Diana; Morris, Andrew J; Schwab, Susan R
2011 Jun 6;208(6):1267-1278, Journal of experimental medicine
The signaling lipid sphingosine-1-phosphate (S1P) stabilizes the vasculature, directs lymphocyte egress from lymphoid organs, and shapes inflammatory responses. However, little is known about how S1P distribution is controlled in vivo, and it is not clear how a ubiquitously made lipid functions as a signal that requires precise spatial and temporal control. We have found that lipid phosphate phosphatase 3 (LPP3) enables efficient export of mature T cells from the thymus into circulation, and several lines of evidence suggest that LPP3 promotes exit by destroying thymic S1P. Although five additional S1P-degrading enzymes are expressed in the thymus, they cannot compensate for the loss of LPP3. Moreover, conditional deletion of LPP3 in either epithelial cells or endothelial cells is sufficient to inhibit egress. These results suggest that S1P generation and destruction are tightly regulated and that LPP3 is essential to establish the balance
— id: 134311, year: 2011, vol: 208, page: 1267, stat: Journal Article,

Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity
Huh, Jun R; Leung, Monica W L; Huang, Pengxiang; Ryan, Daniel A; Krout, Michael R; Malapaka, Raghu R V; Chow, Jonathan; Manel, Nicolas; Ciofani, Maria; Kim, Sangwon V; Cuesta, Adolfo; Santori, Fabio R; Lafaille, Juan J; Xu, H Eric; Gin, David Y; Rastinejad, Fraydoon; Littman, Dan R
2011 Apr 28;472(7344):486-490, Nature
CD4(+) T helper lymphocytes that express interleukin-17 (T(H)17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in T(H)17 cell differentiation and function with susceptibility to Crohn's disease, rheumatoid arthritis and psoriasis. Thus, the pathway towards differentiation of T(H)17 cells and, perhaps, of related innate lymphoid cells with similar effector functions, is an attractive target for therapeutic applications. Mouse and human T(H)17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORgammat, which is required for induction of IL-17 transcription and for the manifestation of T(H)17-dependent autoimmune disease in mice. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORgammat transcriptional activity. Digoxin inhibited murine T(H)17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin-21-salicylidene specifically inhibited induction of IL-17 in human CD4(+) T cells. Using these small-molecule compounds, we demonstrate that RORgammat is important for the maintenance of IL-17 expression in mouse and human effector T cells. These data indicate that derivatives of digoxin can be used as chemical templates for the development of RORgammat-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease
— id: 131813, year: 2011, vol: 472, page: 486, stat: Journal Article,

Can TNF-alpha boost regulatory T cells?
Bilate, Angelina M; Lafaille, Juan J
2010 Dec 1;120(12):4190-4192, Journal of clinical investigation
Deleterious immune responses that cause autoimmune diseases such as type 1 diabetes are normally kept in check by a myriad of mechanisms. Among these, protection mediated by CD4+Foxp3+ Tregs constitutes an essential pathway. Much work over the past decade aimed to understand how Tregs affect immune responses triggered by effector T cells (Teffs), but less is known about how Teffs affect Tregs. In this issue of the JCI, Grinberg-Bleyer et al. report the clearest example thus far regarding this important aspect of Treg biology. They find that in mice, sustained protection from diabetes by Tregs is dependent on Teffs and partially dependent on TNF-alpha, a cytokine traditionally considered proinflammatory
— id: 115425, year: 2010, vol: 120, page: 4190, stat: Journal Article,

Mechanisms of tolerance and allergic sensitization in the airways and the lungs
Curotto de Lafaille, Maria A; Lafaille, Juan J; Graca, Luis
2010 Oct;22(5):616-622, Current opinion in immunology
The respiratory mucosa is constantly exposed to non-infectious substances that have the potential of triggering inflammation. While many particles are excluded, soluble molecules can reach the epithelium surface, where they can be uptaken by dendritic cells and stimulate an adaptive immune response. Most mucosal responses result in tolerance to subsequent antigen encounters, which is mediated by Foxp3(+) regulatory T cells. Genetic and environmental factors, added to the ability of certain allergens to induce innate responses, can predispose to allergic sensitization. In this review we discuss recent advances in the understanding of the mechanisms of tolerance and allergic sensitization to airborne allergens
— id: 133816, year: 2010, vol: 22, page: 616, stat: Journal Article,

Two-photon laser scanning microscopy imaging of intact spinal cord and cerebral cortex reveals requirement for CXCR6 and neuroinflammation in immune cell infiltration of cortical injury sites
Kim, Jiyun V; Jiang, Ning; Tadokoro, Carlos E; Liu, Liping; Ransohoff, Richard M; Lafaille, Juan J; Dustin, Michael L
2010 Jan 31;352(1-2):89-100, Journal of immunological methods
The mouse spinal cord is an important site for autoimmune and injury models. Skull thinning surgery provides a minimally invasive window for microscopy of the mouse cerebral cortex, but there are no parallel methods for the spinal cord. We introduce a novel, facile and inexpensive method for two-photon laser scanning microscopy of the intact spinal cord in the mouse by taking advantage of the naturally accessible intervertebral space. These are powerful methods when combined with gene-targeted mice in which endogenous immune cells are labeled with green fluorescent protein (GFP). We first demonstrate that generation of the intervertebral window does not elicit a reaction of GFP(+) microglial cells in CX3CR1(gfp/+) mice. We next demonstrate a distinct rostrocaudal migration of GFP(+) immune cells in the spinal cord of CXCR6(gfp/+) mice during active experimental autoimmune encephalomyelitis (EAE). Interestingly, infiltration of the cerebral cortex by GFP(+) cells in these mice required three conditions: EAE induction, cortical injury and expression of CXCR6 on immune cells
— id: 106273, year: 2010, vol: 352, page: 89, stat: Journal Article,

Protein kinase C-theta mediates negative feedback on regulatory T cell function
Zanin-Zhorov, Alexandra; Ding, Yi; Kumari, Sudha; Attur, Mukundan; Hippen, Keli L; Brown, Maryanne; Blazar, Bruce R; Abramson, Steven B; Lafaille, Juan J; Dustin, Michael L
2010 Apr 16;328(5976):372-376, Science
T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Protein kinase C-theta (PKC-theta) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-theta was sequestered away from the Treg immunological synapse. Furthermore, PKC-theta blockade enhanced Treg function, demonstrating PKC-theta inhibits Treg-mediated suppression. Inhibition of PKC-theta protected Treg from inactivation by TNF-alpha, restored activity of defective Treg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-theta-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases
— id: 109214, year: 2010, vol: 328, page: 372, stat: Journal Article,

Cutting Edge: Intrathymic Differentiation of Adaptive Foxp3(+) Regulatory T Cells upon Peripheral Proinflammatory Immunization
Zelenay, Santiago; Bergman, Marie-Louise; Paiva, Ricardo Sousa; Lino, Andreia C.; Martins, Ana C.; Duarte, Joao H.; Moraes-Fontes, Maria F.; Bilate, Angelina M.; Lafaille, Juan J.; Demengeot, Jocelyne
2010 OCT 1 ;185(7):3829-3833, Journal of immunology
Thymocytes differentiate into CD4(+) Foxp3(+) regulatory T cells (TR) upon interaction between their TCR and peptide-MHC II complexes locally expressed in the thymus. Conversion of naive CD4(+) T cells into TR can additionally take place in the periphery under noninflammatory conditions of Ag encounter. In this study, making use of TCR transgenic models naturally devoid of Foxp3(+) cells, we report de novo generation of TR upon a single footpad injection of Ag mixed with a classic proinflammatory adjuvant. Abrupt TR differentiation upon immunization occurred intrathymically and was essential for robust tolerance induction in a mouse model of spontaneous encephalomyelitis. This phenomenon could be attributed to a specific feature of thymocytes, which, in contrast to mature peripheral CD4(+) T cells, were insensitive to the inhibitory effects of IL-6 on the induction of Foxp3 expression. Our findings uncover a pathway for TR generation with major implications for immunity and tolerance induction. The Journal of Immunology, 2010, 185: 3829-3833
— id: 113733, year: 2010, vol: 185, page: 3829, stat: Journal Article,

Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?
Curotto de Lafaille, Maria A; Lafaille, Juan J
2009 May;30(5):626-635, Immunity
Adaptive Foxp3(+)CD4(+) regulatory T (iTreg) cells develop outside the thymus under subimmunogenic antigen presentation, during chronic inflammation, and during normal homeostasis of the gut. iTreg cells are essential in mucosal immune tolerance and in the control of severe chronic allergic inflammation, and most likely are one of the main barriers to the eradication of tumors. The Foxp3(+) iTreg cell repertoire is drawn from naive conventional CD4(+) T cells, whereas natural Treg (nTreg) cells are selected by high-avidity interactions in the thymus. The full extent of differences and similarities between iTreg and nTreg cells is yet to be defined. We speculate that iTreg cell development is driven by the need to maintain a noninflammatory environment in the gut, to suppress immune responses to environmental and food allergens, and to decrease chronic inflammation, whereas nTreg cells prevent autoimmunity and raise the activation threshold for all immune responses
— id: 99220, year: 2009, vol: 30, page: 626, stat: Journal Article,

TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes
Leung, Monica W L; Shen, Shiqian; Lafaille, Juan J
2009 Sep 28;206(10):2121-2130, Journal of experimental medicine
Numerous studies have highlighted the importance of high-affinity interactions between T cell receptors (TCRs) and their ligands in the selection of Foxp3(+) regulatory T cells (T reg cells). To determine the role of the TCR in directing T cells into the Foxp3(+) lineage, we generated transgenic (Tg) mice expressing TCRs from Foxp3(+) cells. Initial analyses of the TCR Tg mice crossed with RAG-deficient mice showed that the percentage of Foxp3(+) cells was very low. However, intrathymic injection and bone marrow chimera experiments showed a saturable increase of the Foxp3(+) population when T reg TCR Tg cells were present in low numbers. Furthermore, when analyzing whole thymi of T reg TCR Tg RAG-deficient mice, we found significantly more Foxp3(+) cells than in conventional T cell TCR Tg mice. Our results indicate that although the TCR has an instructive role in determining Foxp3 expression, selection of Foxp3(+) individual clones in the thymus is limited by a very small niche
— id: 103153, year: 2009, vol: 206, page: 2121, stat: Journal Article,

In vitro generated Th17 cells maintain cytolkine profile in wild type but not in lymphopenic hosts in experimental autoimmune encephalomyelitis
Leung, MWL; Bilate, AM; Tadokoro, CE; Lafaille, JJ
2009 OCT-NOV ;48(1-2):71-71, Cytokine
— id: 105956, year: 2009, vol: 48, page: 71, stat: Journal Article,

Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation
Curotto de Lafaille, Maria A; Kutchukhidze, Nino; Shen, Shiqian; Ding, Yi; Yee, Herman; Lafaille, Juan J
2008 Jul;29(1):114-126, Immunity
Adaptive Foxp3(+) regulatory T (Treg) cells develop during induction of mucosal tolerance and after immunization. Large numbers of Foxp3(+) T cells have been found in inflamed tissues. We investigated the role of adaptive Foxp3(+) Treg cells in mucosal tolerance and in chronic allergic lung inflammation. We used two strains of mice that are devoid of naturally occurring Treg cells; one is capable of generating adaptive Foxp3(+) Treg cells upon exposure to antigen, whereas the other is deficient in both naturally occurring and adaptive Foxp3(+) Treg cells. We found that adaptive Foxp3(+) Treg cells were essential for establishing mucosal tolerance and for suppressing IL-4 production and lymphoid neogenesis in chronic inflammation, whereas IL-5 production and eosinophilia could be controlled by Foxp3-independent, IFN-gamma-dependent mechanisms. Thus, whereas adaptive Foxp3(+) Treg cells regulate sensitization to allergens and the severity of chronic inflammation, IFN-gamma-producing cells can play a beneficial role in inflammatory conditions involving eosinophils
— id: 80819, year: 2008, vol: 29, page: 114, stat: Journal Article,

Adaptive Foxp3+regulatory T cells
de Lafaille, MAC; Ding, Y; Lafaille, LJ
2008 SEP ;43(3):305-305, Cytokine
— id: 91473, year: 2008, vol: 43, page: 305, stat: Journal Article,

Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells
Ding, Yi; Shen, Shiqian; Lino, Andreia C; Curotto de Lafaille, Maria A; Lafaille, Juan J
2008 Feb;14(2):162-169, Nature medicine
Beta-catenin is a central molecule in the Wnt pathway. Expression of a stable form of beta-catenin on CD4+CD25+ regulatory T (T(reg)) cells resulted in a marked enhancement of survival of these cells in vitro. Furthermore, stable beta-catenin-expressing CD4+CD25+ T(reg) cells outcompeted control T(reg) cells in vivo, and the number of T(reg) cells necessary for protection against inflammatory bowel disease could be substantially reduced when stable beta-catenin-expressing CD4+CD25+ T(reg) cells were used instead of control T(reg) cells. Expression of stable beta-catenin on potentially pathogenic CD4+CD25- T cells rendered these cells anergic, and the beta-catenin-mediated induction of anergy occurred even in Foxp3-deficient T cells. Thus, through enhanced survival of existing regulatory T cells, and through induction of unresponsiveness in precursors of T effector cells, beta-catenin stabilization has a powerful effect on the prevention of inflammatory disease
— id: 76116, year: 2008, vol: 14, page: 162, stat: Journal Article,

Swift entry of myelin-specific T lymphocytes into the central nervous system in spontaneous autoimmune encephalomyelitis
Furtado, Glaucia C; Marcondes, Maria Cecilia G; Latkowski, Jo-Ann; Tsai, Julia; Wensky, Allen; Lafaille, Juan J
2008 Oct 1;181(7):4648-4655, Journal of immunology
Strong evidence supports that CNS-specific CD4(+) T cells are central to the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Using a model of spontaneous EAE, we demonstrated that myelin basic protein (MBP)-specific CD4(+) T cells up-regulate activation markers in the CNS-draining cervical lymph nodes at a time when there is no T cell activation anywhere else, including the CNS, and before the appearance of clinical signs. In spontaneous EAE, the number of MBP-specific T cell numbers does not build up gradually in the CNS; instead, a swift migration of IFN-gamma-producing T cells into the CNS takes place approximately 24 h before the onset of neurological signs of EAE. Surgical excision of the cervical lymph nodes in healthy pre-EAE transgenic mice delayed the onset of EAE and resulted in a less severe disease. In EAE induced by immunization with MBP/CFA, a similar activation of T cells in the draining lymph nodes of the injection site precedes the disease. Taken together, our results suggest that peripheral activation of T cells in draining lymph nodes is an early event in the development of EAE, which paves the way for the initial burst of IFN-gamma-producing CD4(+) T cell into the CNS
— id: 91439, year: 2008, vol: 181, page: 4648, stat: Journal Article,

CXCR6 is required for T cell recruitment into injured gray matter in the context of experimental autoimmune encephalomyelitis
Kim, JY; Tadokoro, C; Shen, SQ; Ning, J; Lafaille, J; Dustin, M
2008 OCT 25 ;203(2):165-166, Journal of neuroimmunology
— id: 91493, year: 2008, vol: 203, page: 165, stat: Journal Article,

Peripherally-induced allergen-specific Foxp3+regulatory T cells are essential for the control of chronic allergic lung inflammation
de Lafaille, MAC; Kutchukhidze, N; Ding, Y; Shen, S; Lafaille, JJ
2007 JAN ;119(1):S47-S47, Journal of allergy & clinical immunology
— id: 75696, year: 2007, vol: 119, page: S47, stat: Journal Article,

Unique maturation program of the IgE response in vivo
Erazo, Agustin; Kutchukhidze, Nino; Leung, Monica; Christ, Ana P Guarnieri; Urban, Joseph F Jr; Curotto de Lafaille, Maria A; Lafaille, Juan J
2007 Feb;26(2):191-203, Immunity
A key event in the pathogenesis of asthma and allergies is the production of IgE antibodies. We show here that IgE(+) cells were exceptional because they were largely found outside germinal centers and expressed, from very early on, a genetic program of plasma cells. In spite of their extragerminal center localization, IgE(+) cells showed signs of somatic hypermutation and affinity maturation. We demonstrated that high-affinity IgE(+) cells could be generated through a unique differentiation program that involved two phases: a pre-IgE phase in which somatic hypermutation and affinity maturation take place in IgG1(+) cells, and a post-IgE-switching phase in which IgE cells differentiate swiftly into plasma cells. Our results have implications for the understanding of IgE memory responses in allergy
— id: 71927, year: 2007, vol: 26, page: 191, stat: Journal Article,

Effect of presenilins in the apoptosis of thymocytes and homeostasis of CD8+ T cells
Maraver, Antonio; Tadokoro, Carlos E; Badura, Michelle L; Shen, Jie; Serrano, Manuel; Lafaille, Juan J
2007 Nov 1;110(9):3218-3225, Blood
Many studies have positioned Notch signaling at various critical junctions during T-cell development. There is, however, debate regarding the role of Notch in the CD4 versus CD8 lineage commitment. Because there are 4 Notch receptors and RBP-Jkappa-independent Notch signaling has been reported, we decided to eliminate gamma-secretase activity once its activity is required for all forms of Notch signaling. T-cell-specific elimination of gamma-secretase was carried out by crossing presenilin-1 (PS1) floxed mice with CD4-Cre mice and PS2 KO mice, generating PS KO mice. Thymic CD4+CD8+ double-positive (DP) cells from these mice were strikingly resistant to apoptosis by anti-CD3 treatment in vivo and expressed more Bcl-X(L) than control thymocytes, and deletion of only one allele of Bcl-X(L) gene restored wild-type levels of sensitivity to apoptosis. In addition, these PS KO animals displayed a significant decrease in the number of CD8+ T cells in the periphery, and these cells had higher level of phosphorylated p38 than cells from control littermates. Our results show that ablation of presenilins results in deficiency of CD8 cells in the periphery and a dramatic change in the physiology of thymocytes, bringing to our attention the potential side effects of presenilin inhibitors in ongoing clinical trials
— id: 75363, year: 2007, vol: 110, page: 3218, stat: Journal Article,

The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells
Ivanov, Ivaylo I; McKenzie, Brent S; Zhou, Liang; Tadokoro, Carlos E; Lepelley, Alice; Lafaille, Juan J; Cua, Daniel J; Littman, Dan R
2006 Sep 22;126(6):1121-1133, Cell
IL-17-producing T lymphocytes have been recently shown to comprise a distinct lineage of proinflammatory T helper cells, termed Th17 cells, that are major contributors to autoimmune disease. We show here that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage. RORgammat induces transcription of the genes encoding IL-17 and the related cytokine IL-17F in naive CD4(+) T helper cells and is required for their expression in response to IL-6 and TGF-beta, the cytokines known to induce IL-17. Th17 cells are constitutively present throughout the intestinal lamina propria, express RORgammat, and are absent in mice deficient for RORgammat or IL-6. Mice with RORgammat-deficient T cells have attenuated autoimmune disease and lack tissue-infiltrating Th17 cells. Together, these studies suggest that RORgammat is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases
— id: 69079, year: 2006, vol: 126, page: 1121, stat: Journal Article,

Latent TGF-{beta}1-transduced CD4+ T cells suppress the progression of allergic encephalomyelitis
Murano, Mitsuyuki; Xiong, Xiaozhong; Murano, Naoko; Salzer, James L; Lafaille, Juan J; Tsiagbe, Vincent K
2006 Jan;79(1):140-146, Journal of leukocyte biology
Systemic injection of small amounts of transforming growth factor-beta (TGF-beta), a cytokine produced by lymphoid and other cells, has a profound effect in protecting mice from the inflammatory demyelinating lesions of experimental allergic encephalomyelitis (EAE; an animal model for multiple sclerosis). However, TGF-beta has side-effects, which might be avoided if the cells producing TGF-beta can be delivered to the affected site in the nervous system to insure its local release in small amounts. Myelin basic protein (MBP)-specific, cloned CD4(+) T cells were engineered by retroviral transduction to produce latent TGF-beta. Studies about the spontaneous form of EAE in T cell receptor (TCR)-transgenic recombination-activating gene (RAG)-1(-/-) mice showed that essentially all of the MBP-specific, TCR-transgenic RAG-1(-/-) (BALB/cxB10.PL)F1 mice develop spontaneous EAE by the age of 11 weeks. By 12 weeks, 25-50% of the mice have died from disease. A single injection of TGF-beta1-transduced T helper cell type 1 (Th1) cells significantly protected the mice from EAE, and untransduced Th1 cells did not protect. MBP-specific BALB/c Th2 clones, transduced with TGF-beta1-internal ribosome entry site-green fluorescent protein (GFP) significantly reduced EAE induction by untransduced Th1 cells in RAG-1(-/-) B10.PL mice. Furthermore, the GFP(+) TGF-beta1-producing Th2 cells were detectable in the spinal cords of the injected mice
— id: 61318, year: 2006, vol: 79, page: 140, stat: Journal Article,

Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo
Tadokoro, Carlos E; Shakhar, Guy; Shen, Shiqian; Ding, Yi; Lino, Andreia C; Maraver, Antonio; Lafaille, Juan J; Dustin, Michael L
2006 Mar 20;203(3):505-511, Journal of experimental medicine
Regulatory T (T reg) cells exert powerful down-modulatory effects on immune responses, but it is not known how they act in vivo. Using intravital two-photon laser scanning microscopy we determined that, in the absence of T reg cells, the locomotion of autoantigen-specific T cells inside lymph nodes is decreased, and the contacts between T cells and antigen-loaded dendritic cells (DCs) are of longer duration. Thus, T reg cells can exert an early effect on immune responses by attenuating the establishment of stable contacts during priming of naive T cells by DCs
— id: 64138, year: 2006, vol: 203, page: 505, stat: Journal Article,

Do regulatory T cells play a role in the control of homeostatic proliferation?
Curotto de Lafaille, Maria A; Shen, Shiqian; Olivares-Villagomez, Danyvid; Camps-Ramirez, Marlin; Lafaille, Juan J
2005 May-Aug;24(3-4):269-284, International reviews of immunology
The control of peripheral lymphocyte numbers is a fundamental aspect of the immune system. Regulatory T cells are involved in the suppression of autoimmune, antitumor, allergic, and other inflammatory responses, as well as in facilitating graft acceptance. In this paper, we discuss whether the control of homeostatic proliferation is another facet of the immune system that is controlled by regulatory T cells. A review of the published data connecting regulatory T cells with the control of homeostatic proliferation indicates that several key questions remain open. One of these relates to the stage at which regulatory T cells could play a role (i.e., T-cell proliferation vs. survival)
— id: 58702, year: 2005, vol: 24, page: 269, stat: Journal Article,

Immune regulatory mechanisms influence early pathology in spinal cord injury and in spontaneous autoimmune encephalomyelitis
Marcondes, Maria Cecilia G; Furtado, Glaucia C; Wensky, Allen; Curotto de Lafaille, Maria A; Fox, Howard S; Lafaille, Juan J
2005 Jun;166(6):1749-1760, American journal of pathology
Injuries to the central nervous system (CNS) trigger an inflammatory reaction with potentially devastating consequences. In this report we compared the characteristics of the inflammatory response on spinal cord injury (SCI) caused by a stab wound between the T7 and T9 vertebrae and spontaneous experimental autoimmune encephalomyelitis (EAE). SCI and EAE were compared in two types of myelin basic protein Ac1-11-specific T-cell receptor transgenic mice: T/R+ mice harbor regulatory T cells, and T/R- mice lack regulatory T cells. Our results show that 8 days after SCI, T/R- mice developed a strong T-cell infiltrate in the spinal cord, with remarkable down-modulation of CD4 expression that was accompanied by a local increase in Mac-3+ and F4/80+ reactivity and diffuse local and distal astrogliosis. In contrast, T/R+ mice exhibited a modest increase in CD4+ cells localized to the site of injury, without CD4 down-modulation; focal astrogliosis was restricted to the site of the lesion, although Mac-3+ and F4/80+ cells were also present. Similarly to T/R- mice that underwent SCI, T cells displaying down-modulated CD4 expression were found in the CNS of older T/R- mice afflicted by spontaneous EAE. Overall, our results suggest that common mechanisms regulate T-cell accumulation in CNS lesions of different causes, such as mechanic lesion or autoimmune-mediated damage
— id: 56086, year: 2005, vol: 166, page: 1749, stat: Journal Article,

Oral tolerance in the absence of naturally occurring Tregs
Mucida, Daniel; Kutchukhidze, Nino; Erazo, Agustin; Russo, Momtchilo; Lafaille, Juan J; Curotto de Lafaille, Maria A
2005 Jul;115(7):1923-1933, Journal of clinical investigation
Mucosal tolerance prevents pathological reactions against environmental and food antigens, and its failure results in exacerbated inflammation typical of allergies and asthma. One of the proposed mechanisms of oral tolerance is the induction of Tregs. Using a mouse model of hyper-IgE and asthma, we found that oral tolerance could be effectively induced in the absence of naturally occurring thymus-derived Tregs. Oral antigen administration prior to i.p. immunization prevented effector/memory Th2 cell development, germinal center formation, class switching to IgE, and lung inflammation. Oral exposure to antigen induced development of antigen-specific CD4(+)CD25(+)Foxp3(+)CD45RB(low) cells that were anergic and displayed suppressive activity in vivo and in vitro. Oral tolerance to the Th2 allergic response was in large part dependent on TGF-beta and independent of IL-10. Interestingly, Tregs were also induced by single i.p. immunization with antigen and adjuvant. However, unlike oral administration of antigen, which induced Tregs but not effector T cells, i.p. immunization led to the simultaneous induction of Tregs and effector Th2 cells displaying the same antigen specificity
— id: 56085, year: 2005, vol: 115, page: 1923, stat: Journal Article,

Control of homeostatic proliferation by regulatory T cells
Shen, Shiqian; Ding, Yi; Tadokoro, Carlos E; Olivares-Villagomez, Danyvid; Camps-Ramirez, Marlin; Curotto de Lafaille, Maria A; Lafaille, Juan J
2005 Dec;115(12):3517-3526, Journal of clinical investigation
Homeostatic proliferation of T cells leads to the generation of effector/memory cells, which have the potential to cause harm to the host. The role of Tregs in the control of homeostatic proliferation is unclear. In this study we utilized mice that either harbor or lack Tregs as recipients of monoclonal or polyclonal T cells. We observed that while Tregs completely prevented cell division of T cells displaying low affinity for self ligands, they had a less marked, albeit significant, effect on cell cycle entry of T cells displaying higher affinity. The presence of Tregs resulted in a lower accumulation of T cells, enhanced apoptosis, and impaired differentiation to a cytokine-producing state. We conclude that Tregs play a major role in the control of homeostatic proliferation
— id: 62396, year: 2005, vol: 115, page: 3517, stat: Journal Article,

IFN-gamma determines distinct clinical outcomes in autoimmune encephalomyelitis
Wensky, Allen K; Furtado, Glaucia C; Marcondes, Maria Cecilia Garibaldi; Chen, Shaohua; Manfra, Denise; Lira, Sergio A; Zagzag, David; Lafaille, Juan J
2005 Feb 1;174(3):1416-1423, Journal of immunology
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the CNS initiated by autoreactive CD4(+) T cells. EAE classically presents with a progressive ascending paralysis and is a model of multiple sclerosis that recapitulates some aspects of the disease. In this report we describe a mouse strain that spontaneously develops a severe, nonclassical form of EAE with 100% incidence. The distinct clinical phenotype is marked initially by a slight head tilt, progressing to a severe head tilt, spinning, or a rotatory motion. Classical EAE spontaneously occurs in myelin basic protein (MBP)-specific TCR transgenic RAG-1(-/-) mice (referred to as T/R(-)), whereas nonclassical EAE spontaneously occurs in T/R(-) IFN-gamma(-/-) mice (T/R(-)gamma(-)). Thus, the TCR recognizes the same Ag (MBP) and uses identical TCR in both cases. The cellular infiltrate in nonclassical EAE is predominantly found in the brainstem and cerebellum, with very little inflammation in the spinal cord, which is primarily affected in classical disease. Importantly, depending on the genetic makeup and priming conditions of the MBP-specific T cells, nonclassical disease can occur in the presence of an inflammatory infiltrate with eosinophilic, neutrophilic, or monocytic characteristics. Finally, we believe that nonclassical spontaneous EAE could be a useful model for the study of some characteristics of multiple sclerosis not observed in classical EAE, such as the inflammatory responses in the brainstem and cerebellum that can cause vertigo
— id: 49302, year: 2005, vol: 174, page: 1416, stat: Journal Article,

The role of regulatory T cells in allergy
Curotto de Lafaille, Maria A; Lafaille, Juan J
2004 Feb;25(3-4):295-310, Springer seminars in immunopathology
Atopic diseases are characterized by Th2 and IgE responses to common environmental and food antigens. In vivo, IgE production depends on interactions between allergen-specific B lymphocytes and Th2 lymphocytes. IgE levels are extremely low in normal individuals, suggesting that IgE production is under strong regulation. One of the reasons behind the lack of atopy in healthy individuals is the activity of regulatory T cells, which prevent naive T helper cell precursors from acquiring a differentiated Th2 phenotype. In addition to naturally occurring regulatory T cells, atopy can be prevented by allergen-specific tolerant/regulatory cells induced through mucosal stimulation, and by mechanisms that directly suppress Iepsilon sterile transcript production on activated B lymphocytes. This article reviews the recent progress on thymic-derived as well as peripherally induced regulatory T cells as they relate to atopy. The latter discussion also includes regulatory T cells that arise through immunotherapy
— id: 44895, year: 2004, vol: 25, page: 295, stat: Journal Article,

CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion
Curotto de Lafaille, Maria A; Lino, Andreia C; Kutchukhidze, Nino; Lafaille, Juan J
2004 Dec 15;173(12):7259-7268, Journal of immunology
Naturally occurring CD4(+) regulatory T cells are generally identified through their expression of CD25. However, in several experimental systems considerable T(reg) activity has been observed in the CD4(+)CD25(-) fraction. Upon adoptive transfer, the expression of CD25 in donor-derived cells is not stable, with CD4(+)CD25(+) cells appearing in CD4(+)CD25(-) T cell-injected animals and vice versa. We show in this study that CD25(+) cells arising from donor CD25(-) cells upon homeostatic proliferation in recipient mice express markers of freshly isolated T(reg) cells, display an anergic state, and suppress the proliferation of other cells in vitro. The maintenance of CD25 expression by CD4(+)CD25(+) cells depends on IL-2 secreted by cotransferred CD4(+)CD25(-) or by Ag-stimulated T cells in peripheral lymphoid organs
— id: 48108, year: 2004, vol: 173, page: 7259, stat: Journal Article,

T-cell receptor transgenic mice in the study of autoimmune diseases
Lafaille, Juan J
2004 Mar;22(2):95-106, Journal of autoimmunity
T cell receptor transgenic mice have been a valuable tool in the study of the immune system, from development to selection to tolerance or pathogenesis. In this manuscript we review the T cell receptor transgenic mouse lines with specificity for self antigens that have been reported before August 2003. Many such lines have been generated, which have been instrumental in our understanding of, among other aspects, the role regulatory T cells in preventing autoimmunity, the role of microbes in modifying its outcome, the influence of the genetic background, the importance of regional differences in self-antigen concentration, and the importance of differences in antigen deposition between different tissues
— id: 44896, year: 2004, vol: 22, page: 95, stat: Journal Article,

Delta-like 4 in T cell lymphoma
Latkowski, JM; Lafaille, J
2004 MAR ;122(3):A20-A20, Journal of investigative dermatology
— id: 46572, year: 2004, vol: 122, page: A20, stat: Journal Article,

Early self-regulatory mechanisms control the magnitude of CD8+ T cell responses against liver stages of murine malaria
Hafalla, Julius C R; Morrot, Alexandre; Sano, Gen-Ichiro; Milon, Genevieve; Lafaille, Juan J; Zavala, Fidel
2003 Jul 15;171(2):964-970, Journal of immunology
Following immunization with Plasmodium yoelii sporozoites, the CD8(+) T cell population specific for the SYVPSAEQI epitope expressed in sporozoite and liver stages of this malaria parasite revealed the existence of a short term Ag presentation process that translated into a single clonal burst. Further expansion of this CD8(+) T cell population in conditions of sustained Ag exposure and additional supply of naive cells was inhibited by regulatory mechanisms that were developed as early as 24-48 h after priming. Studies using mouse models for Plasmodium or influenza virus infections revealed that this mechanism is Ag specific and is mediated by activated CD8(+) T cells that inhibit the priming of naive cells. This interference of the priming of naive cells appeared to result from limited access to Ag-presenting dendritic cells, which become disabled or are eliminated after contact with activated cells. Thus, concomitantly with the development of their effector antimicrobial capacity, CD8(+) T cells also acquire a self-regulatory role that is likely to represent one of the earliest mechanisms induced in the course of an immune response and that limits the magnitude of the early expansion of CD8(+) T lymphocytes reactive to microorganisms
— id: 39159, year: 2003, vol: 171, page: 964, stat: Journal Article,

Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system
Yan, Shirley ShiDu; Wu, Zhi-Ying; Zhang, Hui Ping; Furtado, Glaucia; Chen, Xi; Yan, Shi Fang; Schmidt, Ann Marie; Brown, Chris; Stern, Alan; LaFaille, Juan; Chess, Leonard; Stern, David M; Jiang, Hong
2003 Mar;9(3):287-293, Nature medicine
Multiple sclerosis (MS) is a devastating neuroinflammatory disorder of the central nervous system (CNS) in which T cells that are reactive with major components of myelin sheaths have a central role. The receptor for advanced glycation end products (RAGE) is present on T cells, mononuclear phagocytes and endothelium. Its pro-inflammatory ligands, S100-calgranulins, are upregulated in MS and in the related rodent model, experimental autoimmune encephalomyelitis (EAE). Blockade of RAGE suppressed EAE when disease was induced by myelin basic protein (MBP) peptide or encephalitogenic T cells, or when EAE occurred spontaneously in T-cell receptor (TCR)-transgenic mice devoid of endogenous TCR-alpha and TCR-beta chains. Inhibition of RAGE markedly decreased infiltration of the CNS by immune and inflammatory cells. Transgenic mice with targeted overexpression of dominant-negative RAGE in CD4+ T cells were resistant to MBP-induced EAE. These data reinforce the importance of RAGE-ligand interactions in modulating properties of CD4+ T cells that infiltrate the CNS
— id: 44897, year: 2003, vol: 9, page: 287, stat: Journal Article,

CD4(+) regulatory T cells in autoimmunity and allergy
Curotto de Lafaille, Maria A; Lafaille, Juan J
2002 Dec;14(6):771-778, Current opinion in immunology
Regulatory T cells (also referred to as suppressor T cells) are important components of the homeostasis of the immune system, as impaired regulatory T cell activity can cause autoimmune diseases and atopy. It is now clear that the phrase 'regulatory T cells' encompasses more than one cell type. For instance, CD4(+)CD25(+) regulatory T cells have received attention due to their immunosuppressive properties in vitro and in vivo, but in several instances it has been shown that CD4(+)CD25(-) T cell populations also contain potent regulatory activity. Recent progress in the field of regulatory T cells includes the discovery of the role of two tumor necrosis factor receptor (TNFR) family members (GITR and TRANCE-R/RANK) in Treg biology, the improved understanding of the role of co-stimulatory molecules and cytokines IL-10 and IL-2 in the induction and function of Tregs, and the generation of CD25(+) and CD25(-) regulatory T cells in vivo through high-avidity T cell receptor interactions
— id: 34996, year: 2002, vol: 14, page: 771, stat: Journal Article,

Removal of the deep cervical lymph nodes decreases the severity of EAE
Furtado, GC; Marcondes, MCG; Tsai, J; Latkowski, JA; Lafaille, JJ
2002 Mar 20;16(4):A715-A715, FASEB journal
— id: 27503, year: 2002, vol: 16, page: A715, stat: Journal Article,

Interleukin 2 signaling is required for CD4(+) regulatory T cell function
Furtado, Glaucia C; Curotto de Lafaille, Maria A; Kutchukhidze, Nino; Lafaille, Juan J
2002 Sep 16;196(6):851-857, Journal of experimental medicine
Mice deficient in interleukin (IL)-2 production or the IL-2 receptor alpha or beta chains develop a lethal autoimmune syndrome. CD4(+) regulatory T cells have been shown to prevent autoimmune diseases, allograft rejection, and to down-regulate antibody responses against foreign antigens. To assess the role of IL-2 in the generation and function of regulatory T cells, we transferred CD4(+) T cells from mice genetically deficient in IL-2 or IL-2R(alpha) (CD25) expression. A small number of splenic or thymic CD4(+) T cells from IL-2 knockout mice can protect mice from spontaneous experimental autoimmune encephalomyelitis (EAE). In contrast, splenic or thymic CD4(+) T cells from CD25 knockout donor mice conferred little or no protection. We conclude that T cells with regulatory potential can develop, undergo thymic selection, and migrate to the peripheral lymphoid organs in the absence of IL-2, and do not protect from disease by means of IL-2 secretion. However, IL-2 signaling in regulatory T cells is essential for their protective function. Altogether, our results favor a model whereby IL-2 induces regulatory T cell activity
— id: 34997, year: 2002, vol: 196, page: 851, stat: Journal Article,

Receptor protein tyrosine phosphatase (RPTP)-beta is involved in functional recovery from demyelinating lesions of the spinal cord
Harroch, S; Casaccia-Bonnefil, P; Furtado, G; Rosenbluth, J; Chao, M; Lafaille, J; Buxbaum, J; Schlessinger, J
2002 May;(Suppl 1):S84-S84 #P328, Glia
— id: 28182, year: 2002, vol: , page: S84, stat: Journal Article,

A critical role for the protein tyrosine phosphatase receptor type Z in functional recovery from demyelinating lesions
Harroch, Sheila; Furtado, Glaucia C; Brueck, Wolfgang; Rosenbluth, Jack; Lafaille, Juan; Chao, Moses; Buxbaum, Joseph D; Schlessinger, Joseph
2002 Nov;32(3):411-414, Nature genetics
Several lines of evidence suggest that tyrosine phosphorylation is a key element in myelin formation, differentiation of oligodendrocytes and Schwann cells, and recovery from demyelinating lesions. Multiple sclerosis is a demyelinating disease of the human central nervous system, and studies of experimental demyelination indicate that remyelination in vivo requires the local generation, migration or maturation of new oligodendrocytes, or some combination of these. Failure of remyelination in multiple sclerosis could result from the failure of any of these processes or from the death of oligodendrocytes. Ptprz encodes protein tyrosine phosphatase receptor type Z (Ptpz, also designated Rptpbeta), which is expressed primarily in the nervous system but also in oligodendrocytes, astrocytes and neurons. Here we examine the susceptibility of mice deficient in Ptprz to experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We observe that mice deficient in Ptprz show impaired recovery from EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide. This sustained paralysis is associated with increased apoptosis of mature oligodendrocytes in the spinal cords of mutant mice at the peak of inflammation. We further demonstrate that expression of PTPRZ1, the human homolog of Ptprz, is induced in multiple sclerosis lesions and that the gene is specifically expressed in remyelinating oligodendrocytes in these lesions. These results support a role for Ptprz in oligodendrocyte survival and in recovery from demyelinating disease
— id: 66616, year: 2002, vol: 32, page: 411, stat: Journal Article,

Peripheral expansion of thymus-derived regulatory cells in anti-myelin basic protein T cell receptor transgenic mice
Hori, Shohei; Haury, Matthias; Lafaille, Juan J; Demengeot, Jocelyne; Coutinho, Antonio
2002 Dec;32(12):3729-3735, European journal of immunology
CD4+ regulatory T cells (Treg) play an indispensable role in tolerance to peripheral antigens, but the origin of the Treg pool in the adult remains unclear. Thus, while thymic commitment of Treg has been demonstrated, evidence also exists for the peripheral recruitment of naive tissue-specific T cells into Treg functions. Anti-myelin basic protein TCR transgenic mice spontaneously develop autoimmune encephalomyelitis when 'monoclonal', but are protected by adoptive transfer of CD4+ cells from wild-type donors. We have now used this transfer system to investigate whether previously infused Treg can recruit transgenic T cells to regulatory functions. The results show that transgenic T cells from protected animals did not transfer tolerance to secondary recipients, and that elimination of donor Treg in protected recipients resulted in rapid onset of disease. In addition, Treg-containing T cell susbsets were highly enriched for proliferating cells in vivo, which was also the case for CD4+CD25+ T cells in normal animals. These observations thus exclude peripheral differentiation of Treg in this particular system, and indicate that expansion of thymically committed cells ensures the maintenance of the peripheral Treg pool in the adult
— id: 34995, year: 2002, vol: 32, page: 3729, stat: Journal Article,

Autoimmunity - Immunological Yin-Yang
Lafaille, JJ; Mathis, D
2002 DEC ;14(6):741-743, Current opinion in immunology
Research in Juan's laboratory focuses on the pathogenesis of T cell mediated diseases, investigating in particular the role of regulatory T cells in spontaneous experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, and the control of exacerbated IgE responses, such as the ones that occur in atopic individuals
— id: 33051, year: 2002, vol: 14, page: 741, stat: Journal Article,

Hyper immunoglobulin E response in mice with monoclonal populations of B and T lymphocytes
de Lafaille MA; Muriglan S; Sunshine MJ; Lei Y; Kutchukhidze N; Furtado GC; Wensky AK; Olivares-Villagomez D; Lafaille JJ
2001 Nov 5;194(9):1349-1359, Journal of experimental medicine
A key event in the pathogenesis of allergies is the production of antibodies of the immunoglobulin (Ig)E class. In normal individuals the levels of IgE are tightly regulated, as illustrated by the low serum IgE concentration. In addition, multiple immunizations are usually required to generate detectable IgE responses in normal experimental animals. To define the parameters that regulate IgE production in vivo, we generated mice bearing monoclonal populations of B and T lymphocytes specific for influenza virus hemagglutinin (HA) and chicken ovalbumin (OVA), respectively. A single immunization of the monoclonal mice with the cross-linked OVA-HA antigen led to serum IgE levels that reached 30-200 microg/ml. This unusually high IgE response was prevented by the infusion of regulatory alpha/beta CD4(+) T cells belonging to both CD25(+) and CD25(-) subpopulations. The regulation by the infused T cells impeded the development of fully competent OVA-specific effector/memory Th2 lymphocytes without inhibiting the initial proliferative response of T cells or promoting activation-induced cell death. Our results indicate that hyper IgE responses do not occur in normal individuals due to the presence of regulatory T cells, and imply that the induction of regulatory CD4(+) T cells could be used for the prevention of atopy
— id: 26571, year: 2001, vol: 194, page: 1349, stat: Journal Article,

Regulatory T cells in spontaneous autoimmune encephalomyelitis
Furtado GC; Olivares-Villagomez D; Curotto de Lafaille MA; Wensky AK; Latkowski JA; Lafaille JJ
2001 Aug;182(2):122-134, Immunological reviews
Spontaneous experimental autoimmune encephalomyelitis (EAE) develops in 100% of mice harboring a monoclonal myelin basic protein (MBP)-specific CD4+ alphabeta T-cell repertoire. Monoclonality of the alphabeta T-cell repertoire can be achieved by crossing MBP-specific T-cell receptor (TCR) transgenic mice with either RAG-/- mice or TCR alpha-/-/TCR beta-/- double knockout mice. Spontaneous EAE can be prevented by a single administration of purified CD4+ splenocytes or thymocytes obtained from wild-type syngeneic mice. The regulatory T cells (T-reg) that protect from spontaneous EAE need not express the CD25 marker, as effective protection can be attained with populations depleted of CD25+ T cells. Although the specificity of the regulatory T cells is important for their generation or regulatory function, T cells that protect from spontaneous EAE can have a diverse TCR alpha and beta chain composition. T-reg cells expand poorly in vivo, and appear to be long lived. Finally, precursors for T-reg are present in fetal liver as well as in the bone marrow of aging mice. We propose that protection of healthy individuals from autoimmune diseases involves several layers of regulation, which consist of CD4+CD25+ regulatory T cells, CD4+CD25- T-reg cells, and anti-TCR T cells, with each layer potentially operating at different stages of T-helper cell-mediated immune responses
— id: 32232, year: 2001, vol: 182, page: 122, stat: Journal Article,

Regulatory V[beta]14+CD4+T cells are part of the naive repertoire and their expansion results in the loss of activated V[beta]8.2+encephalitogenic T cells in vivo
Madakamutil, LT; Maricie, I; Lafaille, JJ; Sercarz, E; Kumar, V
2001 MAR 7 ;15(4):A350-A350, FASEB journal
— id: 55133, year: 2001, vol: 15, page: A350, stat: Journal Article,

Swift development of protective effector functions in naive cd8(+) t cells against malaria liver stages
Sano Gi; Hafalla JC; Morrot A; Abe R; Lafaille JJ; Zavala F
2001 Jul 16;194(2):173-180, Journal of experimental medicine
We generated T cell receptor transgenic mice specific for the liver stages of the rodent malaria parasite Plasmodium yoelii and studied the early events in the development of in vivo effector functions in antigen-specific CD8(+) T cells. Differently to activated/memory cells, naive CD8(+) T cells are not capable of exerting antiparasitic activity unless previously primed by parasite immunization. While naive cells need to differentiate before achieving effector status, the time required for this process is very short. Indeed, interferon (IFN)-gamma and perforin mRNA are detectable 24 h after immunization and IFN-gamma secretion and cytotoxic activity are detected ex vivo 24 and 48 h after immunization, respectively. In contrast, the proliferation of CD8(+) T cells begins after 24 h and an increase in the total number of antigen-specific cells is detected only after 48 h. Remarkably, a strong CD8(+) T cell-mediated inhibition of parasite development is observed in mice challenged with viable parasites only 24 h after immunization with attenuated parasites. These results indicate that differentiation of naive CD8(+) T cells does not begin only after extensive cell division, rather this process precedes or occurs simultaneously with proliferation
— id: 21116, year: 2001, vol: 194, page: 173, stat: Journal Article,

The role of IFN-gamma in the production of Th2 subpopulations: implications for variable Th2-mediated pathologies in autoimmunity
Wensky A; Garibaldi Marcondes MC; Lafaille JJ
2001 Sep 15;167(6):3074-3081, Journal of immunology
It has become increasingly apparent in studies of mutant mice and observations of disease that cytokine production by fully committed effector T cells within the Th1 and Th2 phenotype can vary within each group. This can potentially influence the type and effectiveness of a given immune response. The factors responsible for inducing variable Th1 and Th2 subtype responses have not been well established. Using transgenic mice expressing the myelin basic protein-specific TCR, we demonstrate here that two distinct populations of Th2 cells that are characterized primarily by differential IL-4 and IL-5 expression levels can be generated depending upon the levels of IFN-gamma present at the time of priming. We also demonstrate that populations expressing high levels of IL-4 relative to IL-5 vs those with intermediate levels of IL-4 relative to IL-5 are stable and possess distinct effector functions in an experimental autoimmune encephalomyelitis model
— id: 26621, year: 2001, vol: 167, page: 3074, stat: Journal Article,

Biological role of nervous system specific receptor tyrosine phosphatase revealed by analysis of RPTPbeta knockout mice
Harroch, S; Casaccia-Bonnefil, P; Lafaille, J; Chao, M; Custer, A; Shrager, P; Rosenbluth, J; Schlessinger, J
2000 Nov 04-09;26(1-2):?-? Abstract #4018, Abstracts (Society for Neuroscience)
Cell survival, differentiation and migration relies heavily on protein tyrosine phosphorylation of intracellular proteins and is regulated by the activity of kinases and phosphatases. RPTPbeta is a receptor-like protein tyrosine phosphatases composed of an extracellular domain, a single transmembrane domain and a cytoplasmic portion that contains two tyrosine phosphatase domains. Three different isoforms of RPTPbeta are expressed as a result of alternative splicing: a short and a long form that differ by the presence of the spacer region of the extracellular domain and a secreted form lacking phosphatase activity, also known as 3F8 proteoglycan or phosphacan. The pattern of RPTPbeta expression in the developing nervous system, is highly suggestive of its potential role in glial cell differentiation and survival. RPTPbeta is expressed in oligodendrocytes, Schwann cells and astrocytes. Both full-length RPTPbeta phosphatase and phosphacan isoforms are predominantly expressed as chondroitin sulfate proteoglycans in the subventricular zone and in glial cells from E8 throughout development and in the adult nervous system. RPTPbeta forms a ternary complex with contactin and Caspr, localized to the paranodal junctions. It has been suggested that the interaction between RPTPbeta and contactin may mediate bi-directional cellular signals between neurons and glial cells implicating a potential role of RPTPbeta in paranode formation. To investigate RPTPbeta functions, we have generated animals lacking RPTPbeta and demonstrate that these animals lack the three forms of RPTPbeta. Our results provide indications of a role of RPTPbeta in oligodendrocyte survival/differentiation and also an increased axonal sensitivity in disease states. We will discuss the role of RPTPbeta in oligodendrocyte differentiation and axonal growth and its implication for repair after injury
— id: 16057, year: 2000, vol: 26, page: ?, stat: Journal Article,

Biological role of nervous system specific receptor tyrosine phosphatase revealed by analysis of R
Harroch, S; Casaccia-Bonnefil, P; Lafaille, J; Chao, M; Rosenbluth, J; Verdugo-Garcia, JM; Schlessinger, J
2000 DEC ;11(2):401A-401A, Molecular biology of the cell
— id: 55212, year: 2000, vol: 11, page: 401A, stat: Journal Article,

Repertoire requirements of CD4+ T cells that prevent spontaneous autoimmune encephalomyelitis
Olivares-Villagomez D; Wensky AK; Wang Y; Lafaille JJ
2000 May 15;164(10):5499-5507, Journal of immunology
Spontaneous experimental autoimmune encephalomyelitis arises in 100% of mice exclusively harboring myelin basic protein-specific T cells, and can be prevented by a single injection of CD4+ T cells obtained from normal donors. Given the powerful regulatory effect of the transferred T cells, we further investigated their properties, and, in particular, their repertoire requirements. Transfer of monoclonal OVA-specific CD4+ T cells did not confer protection from disease even when present at very high proportions (about 80% of total lymphocytes). Lack of protection was also evident after immunization of these animals with OVA, indicating that not just any postthymic CD4+ T cells has the potential to become regulatory. However, protection was conferred by cells bearing limited TCR diversity, including cells expressing a single Valpha4 TCR chain or cells lacking N nucleotides. We also investigated whether coexpression of the myelin basic protein-specific TCR with another TCR in a single cell would alter either pathogenesis or regulation. This was not the case, as myelin basic protein-specific/OVA-specific recombinase activating gene-1-/- double TCR transgenic mice still developed experimental autoimmune encephalomyelitis spontaneously even after immunization with OVA. Based on this evidence, we conclude that CD4+ T regulatory cells do not express canonical TCRs and that the altered signaling properties brought about by coexpression of two TCRs are not sufficient for the generation of regulatory T cells. Instead, our results indicate that regulatory T cells belong to a population displaying wide TCR diversity, but in which TCR specificity is central to their protective function
— id: 11715, year: 2000, vol: 164, page: 5499, stat: Journal Article,

Distinct T-helper type 2 populations: Implications for variable TH2-mediated pathologies in autoimmunity, disease, and infection
Wensky, A K; Marcondes, M C; Lafaille, J J
2000 May 12-16;14(6):A1217-A1217, FASEB journal
— id: 15770, year: 2000, vol: 14, page: A1217, stat: Journal Article,

CD28 costimulation is crucial for the development of spontaneous autoimmune encephalomyelitis
Oliveira-dos-Santos AJ; Ho A; Tada Y; Lafaille JJ; Tonegawa S; Mak TW; Penninger JM
1999 Apr 15;162(8):4490-4495, Journal of immunology
Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE
— id: 18699, year: 1999, vol: 162, page: 4490, stat: Journal Article,

The role of helper T cell subsets in autoimmune diseases
Lafaille JJ
1998 Jun;9(2):139-151, Cytokine & growth factor reviews
CD4 helper T cells can be divided into Th1 and Th2 subsets based upon the cytokines they produce. Th1 and Th2 cells have been found to be mutually antagonistic, leading to either Th1- or Th2-dominated responses upon immunization. In recent years, several authors have suggested that in chronic inflammatory autoimmune diseases such as diabetes, multiple sclerosis and rheumatoid arthritis, Th1 cells are pathogenic and Th2 cells are protective. Therefore, a successful deviation from a Th1-dominated to a Th2-dominated response could have clinical benefits for individuals suffering from these diseases. Unfortunately, data accumulated over recent years have not supported this approach, in particular regarding the protective role of Th2 cells. In this review we discuss these data and conclude that, at least using currently available tools, immune deviation from Th1 to Th2-dominated responses is ineffective unless started at very early (subclinical) stages of the disease. In addition, we examine some recent data suggesting that, under some circumstances, Th2 cells can be pathogenic
— id: 57047, year: 1998, vol: 9, page: 139, stat: Journal Article,

Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis
Olivares-Villagomez D; Wang Y; Lafaille JJ
1998 Nov 16;188(10):1883-1894, Journal of experimental medicine
The development of T cell-mediated autoimmune diseases hinges on the balance between effector and regulatory mechanisms. Using two transgenic mouse lines expressing identical myelin basic protein (MBP)-specific T cell receptor (TCR) genes, we have previously shown that mice bearing exclusively MBP-specific T cells (designated T/R-) spontaneously develop experimental autoimmune encephalomyelitis (EAE), whereas mice bearing MBP-specific T cells as well as other lymphocytes (designated T/R+) did not. Here we demonstrate that T/R- mice can be protected from EAE by the early transfer of total splenocytes or purified CD4(+) T cells from normal donors. Moreover, whereas T/R+ mice crossed with B cell-deficient, gamma/delta T cell-deficient, or major histocompatibility complex class I-deficient mice did not develop EAE spontaneously, T/R+ mice crossed with TCR-alpha and -beta knockout mice developed EAE with the same incidence and severity as T/R- mice. In addition, MBP-specific transgenic mice that lack only endogenous TCR-alpha chains developed EAE with high incidence but reduced severity. Surprisingly, two-thirds of MBP-specific transgenic mice lacking only endogenous TCR-beta chains also developed EAE, suggesting that in T/R+ mice, cells with high protective activity escape TCR-beta chain allelic exclusion. Our study identifies CD4(+) T cells bearing endogenous alpha and beta TCR chains as the lymphocytes that prevent spontaneous EAE in T/R+ mice
— id: 7724, year: 1998, vol: 188, page: 1883, stat: Journal Article,

Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease
Lafaille JJ; Keere FV; Hsu AL; Baron JL; Haas W; Raine CS; Tonegawa S
1997 Jul 21;186(2):307-312, Journal of experimental medicine
Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4(+) Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in alphabeta T cell-deficient mice, albeit after a longer preclinical phase. Normal or gammadelta T cell-deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells
— id: 18700, year: 1997, vol: 186, page: 307, stat: Journal Article,

The T cell receptor repertoire of intestinal intraepithelial gammadelta T lymphocytes is influenced by genes linked to the major histocompatibility complex and to the T cell receptor loci
Pereira P; Lafaille JJ; Gerber D; Tonegawa S
1997 May 27;94(11):5761-5766, Proceedings of the National Academy of Sciences of the United States of America
Most of the gammadelta T cells in the intestinal epithelium of normal mice use the Vgamma1 or the Vgamma7 gene segments. However, the relative proportions of gammadelta intraepithelial lymphocytes expressing either the Vgamma1 or the Vgamma7 chain vary among different strains of mice whereas they are quite constant between different individuals of the same strain, suggesting that genetic factors, rather than environmental factors, are responsible for the observed differences. To analyze the genetic factors influencing the representation of different gammadelta T cell subsets in the intestinal epithelium, we used available anti-T cell antigen receptor (TCR) V region-specific mAbs against Vgamma1, Vgamma4, Vgamma7, and Vdelta4 to examine the TCR repertoire of intraepithelial gammadelta lymphocytes in a set of (C57BL/6 x DBA/2) recombinant inbred strains. Our results show that the representation of different Vgamma and Vdelta gene products among gammadelta intestinal intraepithelial lymphocytes is under a complex genetic control with a marked influence by genes closely linked to the TCRgamma, TCRdelta, and major histocompatibility complex loci
— id: 18701, year: 1997, vol: 94, page: 5761, stat: Journal Article,

High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice
Lafaille JJ; Nagashima K; Katsuki M; Tonegawa S
1994 Aug 12;78(3):399-408, Cell
We have generated TCR transgenic mice (T/R+) specific for myelin basic protein (MBP) and crossed them to RAG-1-deficient mice to obtain mice (T/R-) that have T cells expressing the transgenic TCR but no other lymphocytes. Both T/R+ and T/R- mice carry, in the lymph nodes and spleen, large numbers of the potentially encephalitogenic CD4+ anti-MBP T cells. These cells respond to MBP in vitro but show no signs of activation in vivo. Nevertheless, approximately 14% of H-2u T/R+ and 100% of H-2u T/R- mice developed spontaneous experimental autoimmune encephalomyelitis (EAE) within 12 months. These data indicate that EAE can be mediated by CD4+ anti-MBP T cells in the absence of any other lymphocytes and that nontransgenic lymphocytes that are present in T/R+ but absent in T/R- mice have a protective effect. The data also suggest that spontaneous EAE may be triggered by an in situ activation of CD4+ anti-MBP cells in the nervous system
— id: 18702, year: 1994, vol: 78, page: 399, stat: Journal Article,

T cell receptor delta gene mutant mice: independent generation of alpha beta T cells and programmed rearrangements of gamma delta TCR genes
Itohara S; Mombaerts P; Lafaille J; Iacomini J; Nelson A; Clarke AR; Hooper ML; Farr A; Tonegawa S
1993 Feb 12;72(3):337-348, Cell
T cells bearing T cell receptor (TCR) gamma and delta chain heterodimers are first generated early in ontogeny. They form distinct subsets that differ in their TCR repertoires and tissue distribution. Disruption of the mouse TCR C delta gene segment by a gene targeting method caused the complete loss of T cells bearing TCR gamma delta chains, but had little or no effect on the development of T cells bearing TCR alpha beta chains. The analyses of TCR gamma and delta genes in the mutant mice suggest that intracellular mechanisms acting at the level of DNA rearrangement play key roles in the differential gamma and delta gene rearrangements and in the generation of the highly restricted junctional sequences during fetal thymic development
— id: 18710, year: 1993, vol: 72, page: 337, stat: Journal Article,

Trypanosoma cruzi flagellar repetitive antigen expression by recombinant baculovirus: towards an improved diagnostic reagent for Chagas' disease
dos Santos CN; Krieger MA; Almeida E; Lafaille JJ; Goldenberg S; Galler R
1992 Nov;10(11):1474-1477, Bio/technology (NY)
We constructed a recombinant baculovirus that expressed part of a Trypanosoma cruzi flagellar repetitive antigen (FRA). Both cell- associated and secreted forms of recombinant FRA were detected in cultures of virus-infected Spodoptera frugiperda (Sf9) cells. These forms show a complex pattern after polyacrylamide gel electrophoresis and Western blot analysis using either an anti-FRA rabbit serum or human Chagasic sera. Competitive Western-blot experiments revealed that all bands react with the same antibodies as a bacterially-derived FRA. Polymerase chain reaction and Southern blots of the recombinant viral DNA also showed a complex pattern, suggesting the presence of more than one repeat unit in the viral genome. When tested against a panel of human sera from an endemic area for Chagas' disease, FRA recombinant-Sf9 culture supernatant showed the same reactivity as purified FRA produced in bacteria
— id: 18704, year: 1992, vol: 10, page: 1474, stat: Journal Article,

Use of recombinant antigens for the accurate immunodiagnosis of Chagas' disease
Krieger MA; Almeida E; Oelemann W; Lafaille JJ; Pereira JB; Krieger H; Carvalho MR; Goldenberg S
1992 Apr;46(4):427-434, American journal of tropical medicine & hygiene
We tested two Trypanosoma cruzi recombinant antigens in a diagnostic test for Chagas' disease. These antigens were a cytoplasmic repetitive antigen (CRA) and a flagellar repetitive antigen (FRA). The results indicate that the recombinant antigens give better results when used in combination than when used separately, and that the removal of the beta-galactosidase portion of the recombinant fusion proteins increases the specificity of the diagnostic test for Chagas' disease. In addition, a direct enzyme-linked immunosorbent assay (ELISA), which involves the use of peroxidase-labeled antigens to detect the immune-complexes, was developed and compared with a conventional ELISA. The results indicate that the recombinant (CRA+FRA) ELISA is better than the conventional ELISA in the diagnosis of Chagas' disease, providing 100% specificity and sensitivity in all sera tested to date. The recombinant ELISA was compared with conventional serologic tests (hemagglutination and immunofluorescence) for Chagas' disease diagnosis, and the results show that the recombinant ELISA does not give rise to false-positive results that are observed with the two other tests. The use of the recombinant ELISA should be useful in the prevention of transmission of Chagas' disease by blood transfusions
— id: 18705, year: 1992, vol: 46, page: 427, stat: Journal Article,

Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages
Mombaerts P; Clarke AR; Rudnicki MA; Iacomini J; Itohara S; Lafaille JJ; Wang L; Ichikawa Y; Jaenisch R; Hooper ML; et al.
1992 Nov 19;360(6401):225-231, Nature
Analysis of mice carrying mutant T-cell antigen receptor (TCR) genes indicates that TCR-beta gene rearrangement or expression is critical for the differentiation of CD4-CD8- thymocytes to CD4+CD8+ thymocytes, as well as for the expansion of the pool of CD4+CD8+ cells. TCR-alpha is irrelevant in these developmental processes. The development of gamma delta T cells does not depend on either TCR-alpha or TCR-beta
— id: 18703, year: 1992, vol: 360, page: 225, stat: Journal Article,

Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia
Itohara S; Farr AG; Lafaille JJ; Bonneville M; Takagaki Y; Haas W; Tonegawa S
1990 Feb 22;343(6260):754-757, Nature
In mice gamma delta T-cell populations with distinct T-cell receptor (TCR) repertoires and homing properties have been identified. Diversified populations are found in lymphoid organs and intestinal epithelia. By contrast, the gamma delta T-cells that have been found in the murine skin are homogeneous. They express a TCR consisting of one particular V gamma 5 and one particular V delta 1 chain and seem to originate from early fetal thymocytes. We have now systematically analysed many tissues by immunohistochemistry and TCR gene sequencing aided by the polymerase chain reaction. These studies revealed a second homogeneous gamma delta T-cell subset in epithelia not of the intestine and skin, but of the vagina, uterus and tongue. The TCR expressed by this gamma delta T-cell subset consists of the same V delta 1 chain. Cells that express this particular TCR have previously been shown to be positively selected in the late fetal thymus
— id: 57520, year: 1990, vol: 343, page: 754, stat: Journal Article,

Positive selection of gamma delta T cells
Lafaille JJ; Haas W; Coutinho A; Tonegawa S
1990 Mar;11(3):75-78, Immunology today
The issue of T-cell repertoire selection has been addressed recently by several laboratories. While evidence has been provided for both negative and positive selection of CD4+ and CD8+ alpha beta T cells, the molecular basis of positive selection remains unclear. In this article Juan Lafaille and colleagues describe molecular features of gamma delta T-cell selection in the fetal thymus. These features were deduced from extensive junctional sequence data of gamma delta T-cell receptor genes in fetal thymocytes. Their data suggest the active participation of a self peptide in the positive selection of gamma delta T cells
— id: 18706, year: 1990, vol: 11, page: 75, stat: Journal Article,

Junctional sequences of T cell receptor gamma delta genes: implications for gamma delta T cell lineages and for a novel intermediate of V-(D)-J joining
Lafaille JJ; DeCloux A; Bonneville M; Takagaki Y; Tonegawa S
1989 Dec 1;59(5):859-870, Cell
Nucleotide sequences of a large number of V-(D)-J junctions of T cell receptor (TCR) gamma and delta genes show that most fetal thymocytes express on their surface one of just two gamma delta TCRs known to be expressed by epidermal gamma delta T cells (s-IEL) or intraepithelial gamma delta T cells associated with female reproductive organs (r-IEL). In contrast, gamma delta TCRs expressed on adult thymocytes are highly diverse as a result of multiple combinations of gene segments as well as junctional deletions and insertions, indicating that developmental time-and cell lineage-dependent mechanisms exist that control the extent of gamma delta TCR diversity. In addition, this study revealed a new type of junctional insertion (P nucleotides), which led to a new model of V-(D)-J joining generally applicable to immunoglobulin and TCR genes
— id: 18707, year: 1989, vol: 59, page: 859, stat: Journal Article,

Structure and expression of two Trypanosoma cruzi genes encoding antigenic proteins bearing repetitive epitopes
Lafaille JJ; Linss J; Krieger MA; Souto-Padron T; de Souza W; Goldenberg S
1989 Jun 15;35(2):127-136, Molecular & biochemical parasitology
Trypanosoma cruzi genes were cloned in lambda gt11 and screened with an anti-trypomastigote antiserum. Two out of twelve clones were selected in view of their reactivity with human chagasic sera. One clone encodes a flagellar antigen (FRA) of more than 300 kDa, whereas the other corresponds to a roughly 225-kDa cytoplasmic antigen (CRA). The flagellar antigen is present in both epimastigotes and trypomastigotes, but the cytoplasmic antigen is not found in trypomastigotes. The CRA clone is entirely composed of at least 23 copies of a 42-bp repeat and the FRA gene contains at least 14 copies of a 204-bp motif. The FRA gene hybridizes to a RNA of about 10 kb, while the CRA gene detects a transcript of 5.2 kb
— id: 18708, year: 1989, vol: 35, page: 127, stat: Journal Article,

Strain specific protective immunity against Trypanosoma cruzi
Kloetzel JK; Lafaille JJ
1983 Apr;69(2):267-270, Journal of parasitology
Swiss albino, C57BL/10J, and B10.A mice previously inoculated with an LD50 dose of T. cruzi Y strain were protected against subsequent challenge with the homologous strain, but had a parasitemia comparable to that of control mice when challenged with F strain trypomastigotes, although they were protected against mortality. In contrast, animals previously inoculated with an LD50 of T. cruzi F strain were protected both against a subsequent challenge with the homologous strain and the Y strain
— id: 18709, year: 1983, vol: 69, page: 267, stat: Journal Article,