My lab's research is focused on signaling pathways in T cells, particularly store-operated calcium entry (SOCE) and calcium channel function and how these affect immune function in vitro and in vivo.

Ca2+ ions are important "second messengers" for the activation of cells of the immune system, for instance T and B lymphocytes. Antigen binding to immunoreceptors such as the T or B cell receptor will lead to an influx of Ca2+ across the plasma membrane, which is mediated by specialized Ca2+ channels. The genetic nature of the Ca2+ channel in lymphocytes remained elusive more than 2 decades, although patch-clamp analysis has allowed for the biophysical characterization of Ca2+ release activated Ca2+ (CRAC) channels at a functional level.

In recent years, we have described patients who lack Ca2+ influx in their lymphocytes and who suffer from Severe Combined Immunodeficiency (SCID), a rare but lethal defect impairing the patients? immune responses and rendering them susceptible to life-threatening opportunistic infections. In vitro T cells from these patients can be activated only poorly due to a lack of functional CRAC Ca2+ channels. *********** Through genetic analysis of the defect in these patients and with the help of a genome-wide RNAi screen we have recently cloned a crucial component of the CRAC channel, which was termed Orai1. Orai1 is a member of a novel class of putative ion channels, which also comprises the structurally related proteins Orai2 and Orai3.

Through mutagenesis of critical amino acid residues in Orai1 and patch-clamp analysis we were able to show that Orai1 is a pore-forming subunit of the CRAC channel responsible for Ca2+ binding and the high Ca2+ selectivity of the channel. CRAC channels are activated through depletion of Ca2+ from intracellular ER Ca2+ stores. The mechanism of this activation remained, like the nature of the CRAC channel itself, mysterious for almost 2 decades.

Recently stromal interaction molecule 1 (STIM1) was identified to be crucially important for the CRAC channel opening following store depletion, putatively through interaction with Orai1 and the CRAC channel. In collaboration with the lab of Dr. Anjana Rao at Harvard Medical School we have now developed several mouse models to study the role of STIM1, as well as its homologue STIM2, for in vivo immune responses.

In the future, my lab will be interested to understand the regulation of the STIM1/ Orai1/ CRAC pathway in greater detail and to explore the role of store-operated Ca2+ signals for immune function in vitro and in vivo using several animal models. We are also interested in the role of this pathway in diseases of the immune system, such as immunodeficiencies and autoimmune diseases, and in the function of other cell types.

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