期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 116, 期 12, 页码 3252-3257出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI29251
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资金
- NIAID NIH HHS [P01AI39671, P01 AI039671] Funding Source: Medline
- NIDDK NIH HHS [U01DK6192601] Funding Source: Medline
- NINDS NIH HHS [P01NS38037, P01 NS038037, R01NS2424710] Funding Source: Medline
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 ofTr1 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 ofTrl cells with CD46 costimulation as measured by IL-10 but not IFN-gamma secretion in patients with MS compared with healthy subjects. This loss ofTrl 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.
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