T-cell-specific deletion of STIM1 and STIM2 protects mice from EAE by impairing the effector functions of Th1 and Th17 cells.
T-cell function is dependent on store-operated Ca(2+) influx that is activated by the stromal interaction molecules (STIM) 1 and 2. We show that mice with T-cell-specific deletion of STIM1 or STIM2 are protected from EAE, a mouse model of multiple sclerosis (MS). While STIM1- and STIM2-deficient T cells could be successfully primed by autoantigen, they failed to produce the proinflammatory cytokines IL-17 and IFN-γ. STIM1-deficient T cells showed reduced expression of IL-23R, required for Th17 cell homeostasis, and had impaired chemokine-dependent T-cell migration caused by a lack of chemokine-induced Ca(2+) influx. Autoantigen-specific STIM1- or STIM2-deficient T cells failed to expand and accumulate in the CNS and lymph nodes following adoptive transfer to passively induce EAE, suggesting that autoantigen-specific restimulation or homeostasis of STIM1- and STIM2-deficient T cells are impaired. Combined deletion of both STIM1 and STIM2, previously shown to impair Treg development and function, completely protected mice from EAE. This indicates that, in the absence of Ca(2+) influx, autoreactive T cells are severely dysfunctional rendering Treg dispensable for the prevention of CNS inflammation. Our findings demonstrate that both STIM1 and STIM2 are critical for T-cell function and autoimmunity in vivo.
Department of Pathology, New York University Langone Medical Center, New York, NY, USA.
Jian
J
Ma
Christie-Ann
CA
McCarl
Sara
S
Khalil
Kevin
K
Lüthy
Stefan
S
Feske
D000818:Animals; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D015220:Calcium Channels; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D015220:Calcium Channels; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; C100757:Stim1 protein, mouse; C525024:Stim2 protein, mouse; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; C528688:interleukin-23 receptor, mouse; D002118:Calcium