Store operated Ca2+ entry (SOCE) as a critical regulator of Th17 cells in autoimmune and anti fungal immune responses

• Applicant: Dr. Ulrike Kaufmann
• Subject Area: Immunology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 273673641

Th17 cells are important mediators of pathologic (autoimmunity) and protective (antifungal) immune responses. Store-operated Ca2+ entry (SOCE) mediated by ORAI1 channels and its activators STIM1 and STIM2 is critical for Th17 effector functions and potentially the differentiation and lineage stability of Th17 cells. Data from the Feske lab including my own preliminary data show that interfering with SOCE by genetic deletion of Orai1, Stim1 or Stim2 genes attenuates the severity of autoimmune diseases in which Th17 cells mediate disease pathology. How SOCE regulates Th17 cell differentiation and maintenance and its role in vivo in the context of autoimmune diseases still remains elusive. Furthermore, the role of SOCE in protective immune responses against pathogens controlled by Th17 cells is not known. To characterize the mechanisms by which SOCE regulates Th17 cell differentiation and function, and the role of SOCE in Th17-dependent immune responses in vivo, we propose the following two aims: Aim 1: Identify the molecular mechanisms by which SOCE regulates Th17 cell differentiation and function. Our preliminary data show that expression of cytokines and cytokine receptors required for terminal Th17 cell differentiation is dependent on SOCE and that a number of novel SOCE-dependent genes are differentially expressed in STIM1-deficient vs. wild-type Th17 cells. We will analyze (A) the role of SOCE in cytokine dependent Th17 cell differentiation and (B) novel STIM1-regulated genes in Th17 cell differentiation and function. Aim 2: Determine the role of SOCE in Th17-mediated autoimmunity (IBD) and antifungal immunity. (A) We will analyze the role of SOCE in the differentiation and plasticity of pathogenic Th17 cells and chronic, Th17-dependent autoimmune inflammation in an animal model of inflammatory bowel disease (IBD). (B) Since Th17 cells play an important role in controlling fungal infections as well as patients with mutations in ORAI1 and STIM1 are susceptible to fungal infections, we will investigate if SOCE in Th17 cells is required to provide adaptive immunity to mucosal and systemic infection with Candida albicans. The results of the proposed studies will provide a detailed understanding of the molecular mechanisms by which SOCE regulates Th17 cell differentiation, lineage stability and function, and elucidate the role of SOCE in Th17 cells in autoimmunity and immune responses to fungal infection in vivo. From a translational perspective, our results will provide important information if SOCE inhibition would be a suitable approach for the treatment of autoimmune and inflammatory diseases in which Th17 cells play an important pathophysiological role.

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