Generation Ex Vivo of TGF-β-Producing Regulatory T Cells from CD4+CD25− Precursors

• DOI: 10.4049/jimmunol.169.8.4183
• Publication Date: 2014-04-21T00:03:53Z
• Authors: Song Guo Zheng; J. Dixon Gray; Kazuo Ohtsuka; Satoshi Yamagiwa; David A. Horwitz
• Keywords: Adult; CD4-Positive T-Lymphocytes; Staphylococcus aureus; Superantigens; Stem Cells; Receptors, Interleukin-2; Cell Communication; Lymphocyte Activation; T-Lymphocytes, Regulatory; Immunophenotyping; 3. Good health; Enterotoxins; 03 medical and health sciences; 0302 clinical medicine; T-Lymphocyte Subsets; Transforming Growth Factor beta; Culture Media, Conditioned; Immunoglobulin G; Cytokines; Humans; Cells, Cultured

AbstractPreviously 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.