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

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.

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…These results may be explained by the observation that TGF-b at higher concentrations generates and expands induced Treg in ex vivo cell cultures [39]. Thus, we propose that external TGF-b supplemented in our 5-day cell cultures may induce Treg arising from CD4 1 CD25 À T cells.…”

IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells

“…We reported previously that TCR stimulation of CD4 ϩ cells with TGF-␤ enhances expression of CD25, CD122, CTLA-4, and GITR (8,16,19,20). Fig.…”

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

“…Studies have reported that TGF-has the ability to induce CD4 + CD25 -cells to become CD4 + CD25 + Tregs in vitro [52,53], and TGF-can induce FoxP3 expression in iTregs [54,55]. Additionally, other studies have clearly demonstrated that the suppressive capacity of FoxP3 + Tregs in vivo is via a TGF--dependent mechanism [56,57].…”