Regulation of murine inflammatory bowel disease by CD25+ and CD25- CD4+ glucocorticoid-induced TNF receptor family-related gene+ regulatory T cells

Koji Uraushihara, Takanori Kanai, Kwibeom Ko, Teruji Totsuka, Shin Makita, Ryoichi Iiyama, Tetsuya Nakamura, Mamoru Watanabe

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133 Citations (Scopus)


CD4+CD25+ regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance and prevention of autoimmune disease. However, accumulating evidence suggests that a fraction of the peripheral CD4+CD25- T cell population also possesses regulatory activity in vivo. Recently, it has been shown glucocorticoid-induced TNFR family-related gene (GITR) is predominantly expressed on CD4+CD25+ regulatory T cells. In this study, we show evidence that CD4+GITR+ T cells, regardless of the CD25 expression, regulate the mucosal immune responses and intestinal inflammation. SCID mice restored with the CD4+GITR- T cell population developed wasting disease and severe chronic colitis. Cotransfer of CD4+GITR+ population prevented the development of CD4+CD45RBhigh T cell-transferred colitis. Administration of anti-GITR mAb-induced chronic colitis in mice restored both CD45RBhigh and CD45RBlow CD4+ T cells. Interestingly, both CD4+CD25+ and CD4+CD25- GITR+ T cells prevented wasting disease and colitis. Furthermore, in vitro studies revealed that CD4+CD25-GITR+ T cells as well as CD4+CD25+GITR+ T cells expressed CTLA-4 intracellularly, showed anergic, suppressed T cell proliferation, and produced IL-10 and TGF-β. These data suggest that GITR can be used as a specific marker for regulatory T cells controlling mucosal inflammation and also as a target for treatment of inflammatory bowel disease.

Original languageEnglish
Pages (from-to)708-716
Number of pages9
JournalJournal of Immunology
Issue number2
Publication statusPublished - 2003 Jul 15
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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