The role of store-operated Ca2+ entry (SOCE) mediated by STIM1 and ORAI1 in T-helper cells during asthma
Immunology
Final Report Abstract
With the help of this postdoctoral fellowship I demonstrated that Orai1-mediated SOCE in T cells is critical for house-dust mite (HDM)-induced Th2 airway inflammation in mice. In vitro Th2 differentiation and cytokine production of murine CD4+ T cells lacking the pore forming subunit of the CRAC channel, Orai1, was strongly reduced. In line with this HDM-induced asthmatic airway inflammation in mice with a T cell–specific deletion of Orai1 (Orai1fl/flCd4Cre mice) was impaired. CD4+ T cells in the lungs of Orai1fl/flCd4Cre mice sensitized and rechallenged with HDM extract produced less Th2 (IL-4, IL13) and Th17 cytokines (IL-17A) compared to WT littermates. Furthermore, we observed abolished expansion and Th2 differentiation of HDM-specific T cells as well as significant reduced numbers of HDM-specific Tfh cells and less serum IgE in Orai1fl/flCd4Cre mice after HDM administration. In conclusion our data revealed that Orai1-mediated SOCE in T cells mediates Th2-mediated asthmatic airway inflammation which could be used for therapy at later stage. In this context yet unpublished results indicate different regulations and SOCE dependencies of Tfh cell-mediated humoral immune responses during asthmatic airway inflammation and in immunity against influenza A virus infection (Sascha Kahlfuss, unpublished observations). Besides Th2 cells also pathogenic Th17 cells play an important role in asthmatic airway inflammation. With the help of this postdoctoral fellowship I investigated the role of SOCE in pathogenic Th17 cell function and inflammation using mice expressing a hyperactive form of STAT3 (STAT3C) in CD4+ T cells driving Th17 cell-mediated diseases including airway inflammation as a model of steroid-resistant asthma. Conditional deletion of STIM1, and thus abrogation of SOCE, in STAT3C expressing T cells prevented the production of IL-17A and attenuated pulmonary inflammation. Deletion of STIM1 converted the pathogenic Th17 gene expression signature of STAT3C expressing cells into a non-pathogenic signature. Furthermore, mitochondrial respiration, gene expression and function were strongly impaired in the absence of STIM1. Besides diminished mitochondrial function, superoxide levels were increased in STIM1-deficient Th17 cells resulting in DNA damage and cell death. Consistent with an important role of mitochondrial function in pathogenic Th17 cells, inhibition of OXPHOS suppressed the pathogenic function and gene signature of STAT3C expressing Th17 cells. Our findings thus demonstrate that SOCE regulates the pathogenic function of Th17 cells in lung inflammation by controlling mitochondrial metabolism. During the time of this postdoctoral fellowship Dr. Feske furthermore gave me the unique opportunity to characterize patients suffering from anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) and autoimmunity due to mutations within the ORAI1 and STIM1 genes. Our investigations identified and described the molecular consequences of 3 novel yet undescribed mutations in ORAI1. In addition we detected a STIM1 mutation in patients from a family with recurrent fungal infections that is in particular important for the coupling of STIM1 to ORAI1 and thereby SOCE and antifungal immunity in humans and mice.
Publications
- ORAI1 mutations abolishing store-operated Ca2+ entry cause anhidrotic ectodermal dysplasia with immunodeficiency. Journal of Allergy and Clinical Immunology, Vol. 142. 2018, Issue 4, pp. 1297-1310.e11.
Lian J., Cuk M., Kahlfuss S., Kozhaya L., Vaeth M., Rieux-Laucat F., et al.
(See online at https://doi.org/10.1016/j.jaci.2017.10.031) - Calcium Signaling Controls Pathogenic Th17 Cell-Mediated Inflammation by Regulating Mitochondrial Function. Cell Metabolism, Vol. 29. 2019, Issue 5, pp. 1104-1118.e6.
. 2019 May 7;29(5):1104-1118.e6. doi: . Epub 2019 Feb 14. PMID: 30773462; PMCID: PMC6506368.
Kaufmann U., Kahlfuss S., Yang J., Ivanova E., Koralov S.B., Feske S.
(See online at https://doi.org/10.1016/j.cmet.2019.01.019) - CRAC Channels and Calcium Signaling in T Cell-Mediated Immunity. Trends in Immunology, Vol. 41. 2020, Issue 10, pp. 878-901.
Vaeth M., Kahlfuss S., Feske S.
(See online at https://doi.org/10.1016/j.it.2020.06.012) - STIM1-mediated calcium influx controls antifungal immunity and the metabolic function of non-pathogenic Th17 cells. EMBO Molecular Medicine, Vol. 12. 2020, Issue 8, e11592.
Kahlfuss S., Kaufmann U., Concepcion A.R., Noyer L., Raphael D., Vaeth M., Yang J., Pancholi P., Maus M., Muller J., Kozhaya L., Khodadadi-Jamayran A., et al.
(See online at https://doi.org/10.15252/emmm.201911592)
