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,1
*Department of Neurology and
Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany
Calcium (Ca2+) signaling in T lymphocytes is essential for a variety of functions, including the regulation of differentiation, gene transcription, and effector functions. A major Ca2+ entry pathway in nonexcitable cells, including T cells, is store-operated Ca2+ entry (SOCE), wherein depletion of intracellular Ca2+ stores upon receptor stimulation causes subsequent influx of extracellular Ca2+ across the plasma membrane. Stromal interaction molecule (STIM) 1 is the Ca2+ sensor in the endoplasmic reticulum, which controls this process, whereas the other STIM isoform, STIM2, coregulates SOCE. Although the contribution of STIM molecules and SOCE to T lymphocyte function is well studied in vitro, their significance for immune processes in vivo has remained largely elusive. In this study, we studied T cell function in mice lacking STIM1 or STIM2 in a model of myelin-oligodendrocyte glycoprotein (MOG35–55)-induced experimental autoimmune encephalomyelitis (EAE). We found that STIM1 deficiency significantly impaired the generation of neuroantigen-specific T cell responses in vivo with reduced Th1/Th17 responses, resulting in complete protection from EAE. Mice lacking STIM2 developed EAE, but the disease course was ameliorated. This was associated with a reduced clinical peak of disease. Deficiency of STIM2 was associated with an overall reduced proliferative capacity of lymphocytes and a reduction of IFN-
/IL-17 production by neuroantigen-specific T cells. Neither STIM1 nor STIM2 deficiency altered the phenotype or function of APCs. These findings reveal a crucial role of STIM-dependent pathways for T cell function and activation under autoimmune inflammatory conditions, establishing them as attractive new molecular therapeutic targets for the treatment of inflammatory and autoimmune disorders.
Address correspondence and reprint requests to Dr. Sven G. Meuth, Department of Neurology, Josef-Schneider-Straße 11, 97080 Würzburg, Germany, or Dr. Bernhard Nieswandt, Rudolf-Virchow Zentrum, Josef-Schneider-Straße 2, 97080 Würzburg Germany. E-mail addresses: meuth_s{at}klinik.uni-wuerzburg.de and bernhard.nieswandt{at}virchow.uni-wuerzburg.de
1 M.K.S. and D.S. contributed equally to this work.
This work was supported by the Rudolf Virchow Center and the Deutsche Forschungsgemeinschaft (Sonderforschungsbereiche Grants 487 and 688 to B.N. and Grant 581 to S.G.M.). D.S. was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Würzburg.
The online version of this paper contains supplemental material.
Abbreviations used in this paper:
aGVHD, acute graft-versus-host disease; bd, below detection level; BM, bone marrow; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; LFB, Luxol fast blue; MOG, myelin-oligodendrocyte glycoprotein; SOCE, store-operated Ca2+ entry; STIM, stromal interaction molecule; wt, wild-type.
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