title: Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors.
abstract: 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.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine, University of Southern California, 2211 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.forename: J Dixon
authors.initials: JD
authors.lastname: Gray
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohtsuka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamagiwa
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004768:Enterotoxins / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013211:Staphylococcus aureus / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018089:Superantigens / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D004768:Enterotoxins; D007074:Immunoglobulin G; D015375:Receptors, Interleukin-2; D018089:Superantigens; D016212:Transforming Growth Factor beta; C031818:enterotoxin B, staphylococcal