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 anergic 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. The suppression was not cytokine mediated, required activation of the CD25+ T cells, and cell contact between suppressors and responders. CD4+CD25+ T cells require activation via their TCR to become suppressive, but once activated, their suppressor effector function is completely non-specific. We have demonstrated that CD4+CD25+ T cells also suppress both proliferation and IFN-g production by CD8+ T cells induced either by polyclonal or antigen-specific stimuli. CD4+ CD25+ inhibit the activation of CD8+ responders by inhibiting both IL-2 production and upregulation of CD25 expression. Suppression is mediated by a T-T interaction as activated CD25+ T cells suppress the responses of TCR-transgenic CD8+ T cells stimulated with soluble peptide MHC-class I tetramers in the complete absence of antigen presenting cells. These results broaden the immunoregulatory role played by CD4+CD25+ T cells in the prevention of autoimmune diseases, but also raise the possibility that they may hinder the induction of CD8+ effector cells responding to tumor antigens or antigens derived from pathogens. We have employed microarray technology to compare gene expression in CD4+CD25+ T cells. This technique allows a systematic analysis of gene expression differences between cell groups with a single hybridization. Our goals in the application of this technology were to identify genes differentially expressed by resting CD4+CD25+ T cells whose products might be used to develop more specific reagents for functional studies, to analyze differential gene expression at several time points following activation to search for molecules that may be involved in the effector phase of suppression, and to determine genes expressed by the CD25+ cells that may maintain their anergic phenotype. We find that only a small number of genes (29) are differentially expressed between the resting CD25-abnd CD25+ T cells and that a larger number (77) are differentially expressed following activation. None of these genes are shared between the resting and activated state making the total number of genes differentially expressed 97. Several genes encode factors that may be related to the anergic state 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. Manipulation of GITR/GITR-L interactions may result in enhancement or inhibition of regulatory T cell function. In addition to autoimmune disease, regulatory T cells also play an important role in the persistence of chronic infectious diseases. We have shown that the persistence of Leishmania major infection in resistant C57BL/6 mice is controlled by CD4+CD25+ T cells. In mice that lack regulatory T cells, L. major infection is completely cleared, but these mice fail to develop immunity to the parasite. 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.