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A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis

Abstract

Induction and maintenance of peripheral tolerance are important mechanisms to maintain the balance of the immune system. In addition to the deletion of T cells and their failure to respond in certain circumstances, active suppression mediated by T cells or T-cell factors has been proposed as a mechanism for maintaining peripheral tolerance1. However, the inability to isolate and clone regulatory T cells involved in antigen-specific inhibition of immune responses has made it difficult to understand the mechanisms underlying such active suppression. Here we show that chronic activation of both human and murine CD4+T cells in the presence of interleukin (IL)-10 gives rise to CD4+T-cell clones with low proliferative capacity, producing high levels of IL-10, low levels of IL-2 and no IL-4. These antigen-specific T-cell clones suppress the proliferation of CD4+T cells in response to antigen, and prevent colitis induced in SCID mice by pathogenic CD4+CD45RBhighsplenic T cells. Thus IL-10 drives the generation of a CD4+T-cell subset, designated T regulatory cells 1 (Tr1), which suppresses antigen-specific immune responses and actively downregulates a pathological immune response in vivo .

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Figure 1: Generation of murine Tr1 cells in the presence of IL-10.
Figure 2: Proliferative responses of Tr1 cells.
Figure 3: Tr1 cells inhibit the antigen-specific proliferative responses of naive CD4+T cells.
Figure 4: Co-transfer of Tr1 clones prevents colitis.

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Acknowledgements

We thank E. Murphy, E. Callas and D. Polakoff for technical assistance; R. L. Coffman and L. L. Lanier for reviewing the manuscript; and J. A. Katheiser for secretarial help. DNAX Research Institute of Molecular and Cellular Biology, Inc. is supported by Schering-Plough Corporation.

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Groux, H., O'Garra, A., Bigler, M. et al. A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997). https://doi.org/10.1038/39614

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