title: Stromal interaction molecules 1 and 2 are key regulators of autoreactive T cell activation in murine autoimmune central nervous system inflammation.
abstract: Calcium (Ca(2+)) signaling in T lymphocytes is essential for a variety of functions, including the regulation of differentiation, gene transcription, and effector functions. A major Ca(2+) entry pathway in nonexcitable cells, including T cells, is store-operated Ca(2+) entry (SOCE), wherein depletion of intracellular Ca(2+) stores upon receptor stimulation causes subsequent influx of extracellular Ca(2+) across the plasma membrane. Stromal interaction molecule (STIM) 1 is the Ca(2+) 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 (MOG(35-55))-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-gamma/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.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.forename: Alejandro
authors.initials: A
authors.lastname: Berna-Erro
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.forename: Attila
authors.initials: A
authors.lastname: Braun
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
mesh_terms: D000818:Animals; D015220:Calcium Channels; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D016503:Drug Delivery Systems; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000633:toxicity; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D015220:Calcium Channels; D006023:Glycoproteins; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D020033:Protein Isoforms; C100757:Stim1 protein, mouse; C525024:Stim2 protein, mouse; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; C445081:myelin oligodendrocyte glycoprotein (35-55)