Immunoregulatory T Cells

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Abstract

Autoreactive T cells that are capable of inducing autoimmune diseases exist in normal adult animals, but are maintained in a dormant or inactive state due to the suppressive functions of regulatory T cells. We have demonstrated that the regulatory T cells can be easily identified in normal lymphoid tissues by co- expression of CD4 and the interleukin-2 receptor alpha chain (CD25). Transfer of CD4+ CD25- T cells to immunoincompetent mice results in the development of autoimmune disease that can be prevented by co-transfer of CD4+CD25+ cells. Our recent studies have focused on defining the mechanism of action of the CD4+CD25+ in vitro. CD4+CD25+ T cells are completely non-responsive to stimulation via their T cell receptor due to an inability to produce IL-2. When mixed with CD4+CD25- cells, they suppress proliferation by blocking transcription of the IL-2 gene in the CD25- population. Suppression is mediated by a T-T interaction. Addition of IL-2 or anti-CD28 abrogates CD4+CD25+-mediated suppression of proliferation and has been assumed to break suppression. We examined IL-2 mRNA by quantitative PCR in cocultures of mouse CD4+CD25+ and CD4+CD25- T cells. Although IL-2 gene transcription was inhibited in the presence or absence of IL-2, the addition of anti-CD28 stimulated endogenous IL-2 production. Surprisingly, transcription of IL-2 mRNA was also restored in the cocultures in the presence of anti-IL-2. These results are most compatible with a model in which CD4+CD25+ T cells do not suppress the initial activation of CD4+CD25- T cells, but mediate their suppressive effects following production of IL-2 by the responder cells resulting in both the expansion of the CD4+CD25+ T cells and induction of their suppressor function. We have employed microarray technology to identify several genes that encode factors that may be related to the suppressive function of CD4+CD25+ cells. Resting CD25+ T cells selectively express the glucocorticoid induced TNF receptor (GITR, TNFRSF18) and engagement of this molecule by antibody or by its ligand (GITR-L) abrogates suppression mediated by CD4+CD25+ T cells. We have generated monoclonal antibodies to the GITR-L and shown that it has a unique tissue distribution with expression being limited to resting B cells and dendritic cells. Expression of GITR-L on antigen presenting cells is down-regulated following TLR signaling in vitro. Using combinations of CD4+CD25+ T cells from wild type and GITR deficient mice in coculture experiments, we found that ligation of GITR on CD25- responder T cells, not on CD25+ suppressor cells, was required to abrogate suppression. In the absence of CD4+CD25+ T cells, GITR deficient T cells mounted proliferative responses similar to those of wild-type animals, although they were totally suppressed in the presence of physiological numbers of CD25+ T cells. Our results suggest that GITR/GITR-L interactions provide a previously undefined signal that renders effector T cells resistant to the inhibitory effects of CD4+CD25+ T cells. Thus, the downregulation of GITR-L expression subsequent to secondary inflammatory signals may facilitate CD25-mediated suppression and prevent the deleterious consequences of an exuberant effector cell response. In addition to autoimmune disease, our studies have demonstrated that CD4+CD25+ T cells also play an important role in the control of the immune response to infectious agents and in the immune response to tumors. Thus, CD4+CD25+ T cells have pleiotropic effects on immune responses in autoimmunity, tumor immunity, and infectious disease. Manipulation of regulatory T cell function should represent a novel adjunct to the therapy of several diseases.