The role of store-operated Ca2+ entry (SOCE) mediated by STIM1 and ORAI1 in T-helper cells during asthma

• Applicant: Professor Dr. Sascha Kahlfuß
• Subject Area: Rheumatology ; Immunology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320729834

Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels is an essential signaling pathway in many immune cells. CRAC channels are encoded by ORAI1 proteins, activated by stromal interaction molecules 1 and 2 (STIM1 and STIM2) and are important for T cell-driven immunity to infection and regulation of immunological tolerance to self. CRAC channels are functional in many cells involved in allergic asthma including T cells, mast cells, airway epithelial and smooth muscle cells. However, although beneficial effects of CRAC channel inhibitors during animal airway inflammation models were reported, the role of CRAC channels in T cells during asthma was surprisingly not analyzed to date. Given the significant potential of CRAC channel inhibition for asthma treatment and the lack of studies analyzing the mechanisms how SOCE contributes to T cell-driven asthmatic disease, I here propose to investigate the role of SOCE in different T helper (Th) cell subsets during airway inflammation. Recently, the classical Th2-mast cell-eosinophil paradigm in asthma was reconsidered in that also Th17 cells and neutrophils were shown to be important regulators of steroid-resistant asthma. In addition, the role of T follicular helper (Tfh) cells during asthma is less understood, although Tfh cells mediate B cell differentiation into allergen-specific IgE producing plasma cells in secondary lymphatic organs and, thus, are assumed to be key elements in asthma pathogenesis. In my studies I will therefore investigate how SOCE controls Th2 cell, Th17 cell and Tfh cell differentiation and function in two different mouse asthma models that emphasize different aspects of human asthma. I propose the following two research aims: (1) Elucidate the function of SOCE in (A) Th2 cells and (B) Tfh cells during house dust mite (HDM)-induced Th2-mediated airway inflammation. (2) Investigate the role of SOCE in (A) Th17 cells and (B) Tfh cells in a model of STAT3-driven airway inflammation. In my experiments I will use conditionally gene-targeted mice lacking expression of Stim1 and Orai1 genes in T cells. To investigate how SOCE controls Th2-mediated asthma, I will use a mouse model of allergic asthma in which Stim1fl/flCd4-Cre and Orai1fl/flCd4-Cre mice undergo sensitization and challenge with HDM extract, which is a physiological allergen found in asthma patients. To investigate how SOCE controls Th17-mediated asthma, I will use STIM1-deficient mice that express a hyperactive form of the transcription factor STAT3 that induces spontaneous Th17 dominated airway inflammation with neutrophil infiltration of the lung.

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