title: Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis.
abstract: Loss of Treg function appears to be a critical factor in the pathogenesis of human autoimmune diseases. Attention has focused on defects of CD4(+)CD25(high) Tregs, and techniques have been developed to determine their function. In contrast, the role of Tr1 regulatory T cells, which secrete the antiinflammatory cytokine IL-10, in autoimmune disease has not been well assessed. CD46 is a newly defined costimulatory molecule for T cell activation, and CD46-costimulated human T cells induce a Tr1 Treg phenotype with considerable amounts of IL-10 secretion. Here, we examined the role of Tr1 cells in patients with multiple sclerosis (MS) by stimulating CD4(+) T cells with anti-CD3 and -CD46 mAbs and measuring IL-10 secretion. There were striking defects in the induction of Tr1 cells with CD46 costimulation as measured by IL-10 but not IFN-gamma secretion in patients with MS compared with healthy subjects. This loss of Tr1 cell-associated IL-10 secretion was specific to CD46 and not CD28 costimulation and was associated with an altered regulation of the CD46-Cy2 isoform that differentially regulates T cell function in a CD46-transgenic murine model. These data demonstrate a second major Treg defect in human autoimmune disease associated with the CD46 pathway.
authors.affiliation: Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. aastier@rics.bwh.harvard.edu
authors.forename: Anne L
authors.initials: AL
authors.lastname: Astier
authors.forename: Gregory
authors.initials: G
authors.lastname: Meiffren
authors.forename: Samuel
authors.initials: S
authors.lastname: Freeman
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000328:Adult; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D051916:Membrane Cofactor Protein; D020033:Protein Isoforms; D016753:Interleukin-10