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

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

Research output: Contribution to journalArticle

340 Citations (Scopus)

Abstract

Previously we reported that TGF-β 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-β induces activated CD4+CD25- T cells to become Th3 suppressor cells. While stimulating CD4+ cells with TGF-β modestly increased expression of CD25 and intracellular CTLA-4 in primary cultures, upon secondary stimulation without TGF-β 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-β-primed CD4+ T cells to fresh CD4+ cells and B cells markedly suppressed IgG production. The inhibitory effect was mediated by TGF-β and was also partially contact dependent. Increased TGF-β production was associated with a decreased production of IFN-γ and IL-10. Depletion studies revealed that the precursors of these TGF-β-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-β-dependent and independent mechanisms of action. TGF-β 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.

Original languageEnglish (US)
Pages (from-to)4183-4189
Number of pages7
JournalJournal of Immunology
Volume169
Issue number8
StatePublished - Oct 15 2002

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Regulatory T-Lymphocytes
T-Lymphocytes
Cytoprotection
Enterotoxins
Graft Rejection
T-Lymphocyte Subsets
Interleukin-10
Autoimmune Diseases
B-Lymphocytes
Immunoglobulin G
Cell Proliferation
Apoptosis
Cytokines

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Zheng, S. G., Gray, J. D., Ohtsuka, K., Yamagiwa, S., & Horwitz, D. A. (2002). Generation ex vivo of TGF-β-producing regulatory T cells from CD4+CD25- precursors. Journal of Immunology, 169(8), 4183-4189.
Zheng, Song Guo ; Gray, J. Dixon ; Ohtsuka, Kazuo ; Yamagiwa, Satoshi ; Horwitz, David A. / Generation ex vivo of TGF-β-producing regulatory T cells from CD4+CD25- precursors. In: Journal of Immunology. 2002 ; Vol. 169, No. 8. pp. 4183-4189.
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Zheng, SG, Gray, JD, Ohtsuka, K, Yamagiwa, S & Horwitz, DA 2002, 'Generation ex vivo of TGF-β-producing regulatory T cells from CD4+CD25- precursors', Journal of Immunology, vol. 169, no. 8, pp. 4183-4189.

Generation ex vivo of TGF-β-producing regulatory T cells from CD4+CD25- precursors. / Zheng, Song Guo; Gray, J. Dixon; Ohtsuka, Kazuo; Yamagiwa, Satoshi; Horwitz, David A.

In: Journal of Immunology, Vol. 169, No. 8, 15.10.2002, p. 4183-4189.

Research output: Contribution to journalArticle

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AU - Zheng, Song Guo

AU - Gray, J. Dixon

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AU - Yamagiwa, Satoshi

AU - Horwitz, David A.

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Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA. Generation ex vivo of TGF-β-producing regulatory T cells from CD4+CD25- precursors. Journal of Immunology. 2002 Oct 15;169(8):4183-4189.