title: Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol.
abstract: Most adaptive immune responses require the activation of specific T cells through the T cell antigen receptor (TCR)-CD3 complex. Here we show that cholesterol sulfate (CS), a naturally occurring analog of cholesterol, inhibits CD3 ITAM phosphorylation, a crucial first step in T cell activation. In biochemical studies, CS disrupted TCR multimers, apparently by displacing cholesterol, which is known to bind TCRβ. Moreover, CS-deficient mice showed heightened sensitivity to a self-antigen, whereas increasing CS content by intrathymic injection inhibited thymic selection, indicating that this molecule is an intrinsic regulator of thymocyte development. These results reveal a regulatory role for CS in TCR signaling and thymic selection, highlighting the importance of the membrane microenvironment in modulating cell surface receptor activation.
authors.affiliation: The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Center for Biological Signaling Studies (BIOSS) and Faculty of Biology, University of Freiburg, Freiburg, Germany.|Centre for Chronic Immunodeficiency (CCI), University of Freiburg, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Beck-García
authors.affiliation: Center for Biological Signaling Studies (BIOSS) and Faculty of Biology, University of Freiburg, Freiburg, Germany.|Centre for Chronic Immunodeficiency (CCI), University of Freiburg, Freiburg, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Zorzin
authors.affiliation: Center for Biological Signaling Studies (BIOSS) and Faculty of Biology, University of Freiburg, Freiburg, Germany.|Centre for Chronic Immunodeficiency (CCI), University of Freiburg, Freiburg, Germany.
authors.forename: Wolfgang W A
authors.initials: WW
authors.lastname: Schamel
authors.affiliation: The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.|Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D060966:Clonal Selection, Antigen-Mediated; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D055503:Protein Multimerization / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015398:Signal Transduction; D015238:Sulfotransferases / Q000235:genetics; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D002788:Cholesterol Esters; D016693:Receptors, Antigen, T-Cell, alpha-beta; D002784:Cholesterol; C554336:SULT2B1b protein, mouse; D015238:Sulfotransferases; C007045:cholesteryl sulfate