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* Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;
Department of Functional Anatomy and Neuroscience, Asahikawa Medical College, Asahikawa, Japan; and
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
CD4+CD25+ regulatory T cells (Tregs) are essential for maintaining self-tolerance and immune homeostasis. Here we characterize a novel subset of CD4+CD25+ Tregs that express latency-associated peptide (LAP) on their cell surface (CD4+CD25+LAP+ cells). CD4+CD25+LAP+ cells express elevated levels of Foxp3 and Treg-associated molecules (CTLA4, glucocorticoid-induced TNFR-related gene), secrete TGFβ, and express both cell surface TGFβ and surface receptors for TGFβ. In vitro, the suppressive function of CD4+CD25+LAP+ cells is both cell contact and soluble factor dependent; this contrasts with CD4+CD25+LAP– cells, which are mainly cell contact dependent. In a model of experimental autoimmune encephalomyelitis, CD4+CD25+LAP+ cells exhibit more potent suppressive activity than CD4+CD25+LAP– cells, and the suppression is TGFβ dependent. We further show that CD4+CD25+LAP+ cells suppress myelin oligodendrocyte glycoprotein-specific immune responses by inducing Foxp3 and by inhibiting IL-17 production. Our findings demonstrate that CD4+CD25+ Tregs are a heterogeneous population and that the CD4+CD25+ subset that expresses LAP functions in a TGFβ-dependent manner and has greater in vivo suppressive properties. Our work helps elucidate the ambiguity concerning the role of TGFβ in CD4+CD25+ Treg-mediated suppression and indicates that LAP is an authentic marker able to identify a TGFβ-expressing CD4+CD25+ Treg subset.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI435801 and NS38037 (to H.L.W.).
2 Address correspondence and reprint requests to Dr. Howard L. Weiner, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115. E-mail address: hweiner{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: Treg, regulatory T cell; Foxp3, forkhead box P3; EAE, experimental autoimmune encephalomyelitis; LAP, latency-associated peptide; GITR, glucocorticoid-induced TNFR-related gene (TNFRSF18); MFI, mean fluorescence intensity; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; Tg, transgenic; SiRNA, small interfering RNA; TNFRSF, TNFR superfamily; mTGFβ, cell surface TGFβ1.
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