IL-10 Is Required for Regulatory T Cells to Mediate Tolerance to Alloantigens In Vivo

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Abstract
We present evidence that donor-reactive CD4+ T cells present in mice tolerant to donor alloantigens are phenotypically and functionally heterogeneous. CD4+ T cells contained within the CD45RBhigh fraction remained capable of mediating graft rejection when transferred to donor alloantigen-grafted T cell-depleted mice. In contrast, the CD45RBlow CD4+ and CD25+CD4+ populations failed to induce rejection, but rather, were able to inhibit rejection initiated by naive CD45RBhigh CD4+ T cells. Analysis of the mechanism of immunoregulation transferred by CD45RBlow CD4+ T cells in vivo revealed that it was donor Ag specific and could be inhibited by neutralizing Abs reactive with IL-10, but not IL-4. CD45RBlow CD4+ T cells from tolerant mice were also immune suppressive in vitro, as coculture of these cells with naive CD45RBhigh CD4+ T cells inhibited proliferation and Th1 cytokine production in response to donor alloantigens presented via the indirect pathway. These results demonstrate that alloantigen-specific regulatory T cells contained within the CD45RBlow CD4+ T cell population are responsible for the maintenance of tolerance to donor alloantigens in vivo and require IL-10 for functional activity.