Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice.
TGF-beta has been shown to be critical in the generation of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Because Th3 cells produce large amounts of TGF-beta, 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 TGF-beta1-transgenic (Tg) mouse in which TGF-beta is linked to the IL-2 promoter and T cells transiently overexpress TGF-beta upon TCR stimulation but produce little or no IL-2, IL-4, IL-10, IL-13, or IFN-gamma. Naive TGF-beta-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 TGF-beta Tg 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 TGF-beta on 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 TGF-beta dependent as anti-TGF-beta abrogated their development. Thus, Ag-specific TGF-beta-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.
Carrier
Yijun
Y
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Yuan
Jing
J
Kuchroo
Vijay K
VK
Weiner
Howard L
HL
D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D017635:Clonal Anergy; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000235:genetics; D063308:Myelin-Oligodendrocyte Glycoprotein; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000819:agonists; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D000941:Antigens; D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta