A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis.
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 tolerance. 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+CD45RB(high) splenic 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.
Groux
H
H
DNAX Research Institute of Molecular and Cellular Biology, Inc., Human Immunology Department, Palo Alto, California 94304-1104, USA.
O'Garra
A
A
Bigler
M
M
Rouleau
M
M
Antonenko
S
S
de Vries
J E
JE
Roncarolo
M G
MG
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002999:Clone Cells; D003092:Colitis / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation
D016207:Cytokines; D016753:Interleukin-10; D010047:Ovalbumin