title: Cytotoxic NKG2C+ CD4 T cells target oligodendrocytes in multiple sclerosis.
abstract: The mechanisms whereby immune cells infiltrating the CNS in multiple sclerosis patients contribute to tissue injury remain to be defined. CD4 T cells are key players of this inflammatory response. Myelin-specific CD4 T cells expressing CD56, a surrogate marker of NK cells, were shown to be cytotoxic to human oligodendrocytes. Our aim was to identify NK-associated molecules expressed by human CD4 T cells that confer this oligodendrocyte-directed cytotoxicity. We observed that myelin-reactive CD4 T cell lines, as well as short-term PHA-activated CD4 T cells, can express NKG2C, the activating receptor interacting with HLA-E, a nonclassical MHC class I molecule. These cells coexpress CD56 and NKG2D, have elevated levels of cytotoxic molecules FasL, granzyme B, and perforin compared with their NKG2C-negative counterparts, and mediate significant in vitro cytotoxicity toward human oligodendrocytes, which upregulated HLA-E upon inflammatory cytokine treatment. A significantly elevated proportion of ex vivo peripheral blood CD4 T cells, but not CD8 T cells or NK cells, from multiple sclerosis patients express NKG2C compared with controls. In addition, immunohistochemical analyses showed that multiple sclerosis brain tissues display HLA-E(+) oligodendrocytes and NKG2C(+) CD4 T cells. Our results implicate a novel mechanism through which infiltrating CD4 T cells contribute to tissue injury in multiple sclerosis.
authors: Department of Medicine, Research Center of the Hospital Center of the University of Montreal-Notre-Dame Hospital, Montreal, Quebec H2L 4M1, Canada;
authors: Fatma
authors: F
authors: Zaguia
authors: Philippe
authors: P
authors: Saikali
authors: Samuel
authors: S
authors: Ludwin
authors: Jia
authors: J
authors: Newcombe
authors: Diane
authors: D
authors: Beauseigle
authors: Ellie
authors: E
authors: McCrea
authors: Pierre
authors: P
authors: Duquette
authors: Alexandre
authors: A
authors: Prat
authors: Jack P
authors: JP
authors: Antel
authors: Nathalie
authors: N
authors: Arbour
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019002:CD56 Antigen / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009836:Oligodendroglia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D000097625:HLA-E Antigens
chemical_list: D019002:CD56 Antigen; D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; D000097625:HLA-E Antigens; C527059:KLRC2 protein, human; C522918:NCAM1 protein, human