Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors

• Published in: The Journal of immunology (1950) 2002-10, Vol.169 (8), p.4183-4189
• Main Authors: Zheng, Song Guo, Gray, J Dixon, Ohtsuka, Kazuo, Yamagiwa, Satoshi, Horwitz, David A
• Format: Article
• Language: English
• Subjects: Adult; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Communication - immunology; Cells, Cultured; Culture Media, Conditioned - pharmacology; Cytokines - biosynthesis; Enterotoxins - pharmacology; Humans; Immunoglobulin G - biosynthesis; Immunophenotyping; Lymphocyte Activation; Receptors, Interleukin-2 - biosynthesis; Staphylococcus aureus - immunology; Stem Cells - cytology; Stem Cells - immunology; Stem Cells - metabolism; Superantigens - pharmacology; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.8.4183

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.