Th3 Cells in Peripheral Tolerance. I. Induction of Foxp3-Positive Regulatory T Cells by Th3 Cells Derived from TGF- T Cell-Transgenic Mice

TGFhas been shown to be critical in the generation of CD4 CD25 Foxp3 regulatory T cells (Tregs). Because Th3 cells produce large amounts of TGF, we asked whether induction of Th3 cells in the periphery was a mechanism by which CD4 CD25 Tregs were induced in the peripheral immune compartment. To address this issue, we generated a TGF1-transgenic (Tg) mouse in which TGFis linked to the IL-2 promoter and T cells transiently overexpress TGFupon TCR stimulation but produce little or no IL-2, IL-4, IL-10, IL-13, or IFN. Naive TGF-Tg mice are phenotypically normal with comparable numbers of lymphocytes and thymic-derived Tregs. We found that repeated antigenic stimulation of pathogenic myelin oligodendrocyte glycoprotein (MOG)-specific CD4 CD25 T cells from TGFTg mice crossed to MOG TCR-Tg mice induced Foxp3 expression in both CD25 and CD25 populations. Both CD25 subsets were anergic and had potent suppressive properties in vitro and in vivo. Furthermore, adoptive transfer of these induced regulatory CD25 / T cells suppressed experimental autoimmune encephalomyelitis when administrated before disease induction or during ongoing experimental autoimmune encephalomyelitis. The suppressive effect of TGFon T cell responses was due to the induction of Tregs and not to the direct inhibition of cell proliferation. The differentiation of Th3 cells in vitro was TGFdependent as anti-TGFabrogated their development. Thus, Ag-specific TGF-producing Th3 cells play a crucial role in inducing and maintaining peripheral tolerance by driving the differentiation of Ag-specific Foxp3 regulatory cells in the periphery. The Journal of Immunology, 2007, 178: 179–185.