Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.
It is now clear that functionally specialized regulatory T (Treg) cells exist as part of the normal immune repertoire, preventing the development of pathogenic responses to both self- and intestinal antigens. Here, we report that the Treg cells that control intestinal inflammation express the same phenotype (CD25(+)CD45RB(low)CD4(+)) as those that control autoimmunity. Previous studies have failed to identify how CD25(+) Treg cells function in vivo. Our studies reveal that the immune-suppressive function of these cells in vivo is dependent on signaling via the negative regulator of T cell activation cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as secretion of the immune-suppressive cytokine transforming growth factor beta. Strikingly, constitutive expression of CTLA-4 among CD4(+) cells was restricted primarily to Treg cells, suggesting that CTLA-4 expression by these cells is involved in their immune-suppressive function. These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling. Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.
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Oxford University, Nuffield Department of Surgery, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
Malmström
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Powrie
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D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D060908:CTLA-4 Antigen; D003092:Colitis / Q000517:prevention & control*; D018796:Immunoconjugates; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D000069594:Abatacept; D017493:Leukocyte Common Antigens