Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors.
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.
Zheng
Song Guo
SG
Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine, University of Southern California, 2211 Zonal Avenue, Los Angeles, CA 90033, USA.
Gray
J Dixon
JD
Ohtsuka
Kazuo
K
Yamagiwa
Satoshi
S
Horwitz
David A
DA
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
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