Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis

Anne L Astier, Gregory Meiffren, Samuel Freeman, David A Hafler

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)3252-7
Number of pages6
JournalJournal of Clinical Investigation
Volume116
Issue number12
DOIs
Publication statusPublished - 2006

Keywords

  • Adult
  • Antigens, CD28
  • Antigens, CD46
  • CD4-Positive T-Lymphocytes
  • Female
  • Flow Cytometry
  • Humans
  • Interleukin-10
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Multiple Sclerosis
  • Protein Isoforms
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Regulatory

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