A T helper cell type 1–mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RBhigh CD4+ T cells and can be prevented by cotransfer of the CD45RBlow subset. The immune-suppressive activities of the CD45RBlow T cell population can be reversed in vivo by administration of an anti-transforming growth factor β antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RBlow population. This population isolated from IL-10–deficient (IL-10−/−) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti–murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RBlow CD4+ cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RBhigh CD4+ cells, as CD45RBlow CD4+ cells from WT mice were able to inhibit colitis induced by IL-10−/− CD45RBhigh CD4+ cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

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CD4+ T cells in the mouse can be subdivided into two fractions based on the level of expression of the CD45RB determinant. Previous studies have shown that these subsets are functionally distinct. We have further characterized the properties of these subpopulations in vivo by injecting them into C. B-17 scid mice. The animals restored with the CD45RBhighCD4+ T cell population developed a lethal wasting disease with severe mononuclear cell infiltrates into the colon and elevated levels of IFN-gamma mRNA. In contrast, animals restored with the reciprocal CD45RBlow subset or with unfractionated CD4+ T cells did not develop the wasting or colitis. Importantly, the co-transfer of the CD45RBlow population with the CD45RBhigh population prevented the wasting disease and colitis. These data indicate that important regulatory interactions occur between the CD45RBhigh and CD45RBlowCD4+ T cell subsets and that disruption of this mechanism has fatal consequences.

SummaryA T helper type 1 (Thl)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45R_B high CD4 + splenic T ceils and could be prevented by cotransfer ofCD45RB l~ CD4 + T cells. Inhibition of this Thl response by the CD45ILB l~ T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) 13 antibody. Interleukin (IL) 4 was not required for either the differentiation or function of protective cells as CD45RB l~ CD4 + cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4 + cells and TGF-13 as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Thl responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.

SummaryBALB/c mice infected with the intracellular protozoan Leishmania major mount a T hdper cell 2 (Th2) response that fails to control growth of the parasite and results in the development of visceral leishmaniasis. Separation of CD4 + T cells into CD45RB hgh and CD45KB l~ subsets showed that the L. major-specific Th2 cells were contained within the CD45RB I~ population as these cells produced high levels of antigen-specific interleukin 4 (IL-4) in vitro and transferred a nonhealing response to L. major-infected C.B-17 scid mice. In contrast, the CD45RBh'ghCD4 + population contained L. major-reactive cells that produced interferon 3, (IFN-'y) in vitro and transferred a healing Thl response to L. major-infected C.B-17 scid mice. Transfer of the Thl response by the CD45R.B hSh population was inhibited by the CD45RB l~ population by a mechanism that was dependent on IL-4. These data indicate that L. major-specific Thl cells do develop in BALB/c mice, but their functional expression is acttvely inhibited by production of IL-4 by Th2 calls. In this response, the suppressed Thl cells can be phenotypically distinguished from the suppressive Th2 cells by the level of expression of CD45RB. Although the CD45R.B hxgh population mediated a protective response to L. major, C.B-17 scid mice restored with this population developed a severe inflammatory response in the colon that was independent of L. major infection, and was prevented by cotransfer of the CD45KB l~ population. The colitis appeared to be due to a dysregulated Thl response as anti-IFN-% but not anti-IL-4, prevented it. Taken together, the data show that the CD4 + T cell population identified by high level expression of the CD45RB antigen contains ceils that mediate both protective and pathogenic Thl responses and that the reciprocal CD45RB l~ population can suppress both of these responses. Whether suppression of cell-mediated immunity is beneficial or not depends on the nature of the stimulus, being deleterious during L. major infection but crucial for control of potentmlly pathogenic inflammatory responses developing m the gut.