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The Journal of Immunology, 2002, 169: 4183-4189.
Copyright © 2002 by The American Association of Immunologists

Generation Ex Vivo of TGF-{beta}-Producing Regulatory T Cells from CD4+CD25- Precursors1

Song Guo Zheng, J. Dixon Gray, Kazuo Ohtsuka, Satoshi Yamagiwa and David A. Horwitz2

Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033

Previously we reported that TGF-{beta} has an important role in the generation and expansion of human "professional" CD4+CD25+ regulatory T cells in the periphery that have a cytokine-independent mechanism of action. In this study we used low-dose staphylococcal enterotoxin to induce T cell-dependent Ab production. We report that TGF-{beta} induces activated CD4+CD25- T cells to become Th3 suppressor cells. While stimulating CD4+ cells with TGF-{beta} modestly increased expression of CD25 and intracellular CTLA-4 in primary cultures, upon secondary stimulation without TGF-{beta} the total number and those expressing these markers dramatically increased. This expansion was due to both increased proliferation and protection of these cells from activation-induced apoptosis. Moreover, adding as few as 1% of these TGF-{beta}-primed CD4+ T cells to fresh CD4+ cells and B cells markedly suppressed IgG production. The inhibitory effect was mediated by TGF-{beta} and was also partially contact dependent. Increased TGF-{beta} production was associated with a decreased production of IFN-{gamma} and IL-10. Depletion studies revealed that the precursors of these TGF-{beta}-producing CD4+ suppressor cells were CD25 negative. These studies provide evidence that CD4+CD25+ regulatory cells in human blood consist of at least two subsets that have TGF-{beta}-dependent and independent mechanisms of action. TGF-{beta} has an essential role in the generation of both of these T suppressor cell subsets from peripheral T cells. The ability to induce CD4+ and CD8+ cells to become regulatory cells ex vivo has the potential to be useful in the treatment of autoimmune diseases and to prevent transplant rejection.




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