Store operated Ca2+ entry (SOCE) as a critical regulator of Th17 cells in autoimmune and anti fungal immune responses
Final Report Abstract
With the help of this postdoctoral fellowship I demonstrated that store-operated calcium entry (SOCE) is a critical regulator of Thl7 cell differentiation and their function in inflammatory immune responses. Thl7 cell-mediated diseases, such as experimental autoimmune encephalomyelitis, a model for multiple sclerosis, and Thl7 cell-mediated airway inflammation, a model for chronic obstructive pulmonary disease (COPD), are strongly dependent on SOCE and disease progression is attenuated when SOCE is lacking in Thl7 cells. I investigated the role of SOCE in Thl7 cell-mediated autoimmunity on the basis of experimental autoimmune encephalomyelitis (EAE). I demonstrated that genetic deletion of the Orail gene in T cells and pharmacological inhibition of Orail inhibits Ca2+ influx and the function of pro-inflammatory Thl and Thl7 cells but not induced regulatory T cells (iTreg). Orai1 gene deletion in T cells ameliorated the severity of EAE and the pharmacological inhibition of calcium release activated calcium (CRAC) channels halted EAE disease progression. The CRAC channel inhibitor AMG1 also suppressed Ca2+ influx and cytokine expression in human T cells. My findings support the conclusion that Th1 and Th17 cells require CRAC channels for their proper function, whereas iTreg cells are less dependent on this pathway, thus providing a rationale for exploring CRAC channel inhibition as a therapeutic approach in Th1/Th17 cell-mediated autoimmune diseases. Further studies investigating the quantitative requirement for SOCE in different T helper cell subsets confirmed that Th17 cells show the strongest dependency on SOCE, while iTreg cells need only low levels of SOCE for their differentiation and function. To investigate the molecular mechanism of Th17 cell differentiation and function, I used an animal model for Th17-cell mediated airway inflammation that is mediated by hyperactive expression of STAT3 in Th17 cells. I demonstrated that SOCE is crucial for the spontaneous differentiation of T cells expressing hyperactive STAT3 into Th17 cells, pathogenic Th17 cell gene expression signature and the resulting severe airway inflammation. Depletion of Stim1 led to reduced IL-17 expression, blocked differentiation of pathogenic Th17 cells and rather favored a non-pathogenic Th17 cell signature. Gene expression analysis revealed reduced expression of genes associated with cell cycle and mitochondrial metabolism, which I confirmed by functional testing. In addition, I contributed to studies revealing the role of ORAI2 in T cells function and T cell-mediated immunity as well as the role of SOCE in lipolysis and lipid metabolism. Collectively, my data demonstrate the importance of SOCE for pathogenic Th17 cell differentiation and function in inflammatory diseases.
Publications
- Selective ORAI1 Inhibition Ameliorates Autoimmune Central Nervous System Inflammation by Suppressing Effector but Not Regulatory T Cell Function. J Immunol. 2016 Jan 15;196(2):573-85
Kaufmann U, Shaw PJ, Kozhaya L, Subramanian R, Gaida K, Unutmaz D, McBride HJ, Feske S
(See online at https://doi.org/10.4049/jimmunol.1501406) - ORAI2 modulates store-operated calcium entry and T cell-mediated immunity. Nat Commun. 2017 Mar 15;8:14714
Vaeth M, Yang J, Yamashita M, Zee I, Eckstein M, Knosp C, Kaufmann U, Karoly Jani P, Lacruz RS, Flockerzi V, Kacskovics I, Prakriya M, Feske S
(See online at https://doi.org/10.1038/ncomms14714) - Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism. Cell Metab. 2017 Mar 7;25(3):698-712
Maus M, Cuk M, Patel B, Lian J, Ouimet M, Kaufmann U, Yang J, Horvath R, Hornig-Do HT, Chrzanowska-Lightowlers ZM, Moore KJ, Cuervo AM, Feske S
(See online at https://doi.org/10.1016/j.cmet.2016.12.021)
