Regulation of follicular T cells by ORAI and STIM proteins in protective immune responses and autoimmunity

• Applicant: Martin Väth, Ph.D.
• Subject Area: Immunology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 247992079

The generation of antibody-producing plasma cells and memory lymphocytes, essential for specific and efficient immune responses to infection, is precisely controlled in the germinal center (GC) reaction. Dysregulation of the GC reaction causes severe immune dysfunction ranging from immunodeficiency to autoimmunity. Specialized T lymphocytes localized in GCs, termed follicular T helper (Tfh) cells, are indispensable for adequate and effective humoral immune responses. By contrast, follicular regulatory T (Tfr) cells limit and terminate the GC reaction to prevent the production of autoantibodies and autoimmunity. Calcium (Ca2+) influx mediated by Ca2+ release-activated Ca2+ (CRAC) channels is a fundamental signaling pathway in T cells. CRAC channels are encoded by ORAI proteins, which are activated by stromal interaction molecules (STIM) 1 and STIM2. Mutations and/or deletions of Stim1 and Orai1 in genetically modified mice and human patients result in impaired T cell-mediated immunity to infection and severe immunodeficiency. The complex immunological phenotypes of CRAC channel-deficient patients and transgenic mice are only partially understood. Besides immunodeficiency, patients and mice develop autoimmune disease characterized by autoantibodies against red blood cells and platelets and an impaired development of regulatory T (Treg) cells. Given the important role of Tfh and Tfr cells in regulating humoral immunity and preliminary data indicating that both cell types are controlled by CRAC channel function, the goal of my proposal is to characterize the function of STIM- and ORAI-proteins in follicular T cells. To this end, we will study the GC reaction of mice with conditional inactivation of the CRAC channel genes Orai1, Stim1 and Stim2. We will investigate CRAC channel function in Tfh and Tfr cells in the context of protective immune responses (Aim 1) as well as in animal models of allergic asthma (Aim 2) and humoral autoimmunity, e.g. systemic lupus erythematosus (Aim 3). The detailed analysis of how CRAC channels control follicular T cells and the GC reaction promises a fundamental understanding of humoral immune regulation, which will thereby benefit the development of appropriate therapeutics to treat immunodeficiency and autoimmune diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Stefan Feske