TGF-β1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets

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Abstract
Although forkhead box p3 (Foxp3) expression is restricted to naturally occurring CD4+ regulatory T cells (TREG), little is known about the various signals that regulate it in T cells. As TGF-β has been reported to modulate Foxp3 expression in T cells, we investigated its effects on the induction or maintenance of regulatory functions in different CD4+ T cell subsets. TGF-β1 priming was able to promote differentiation of TREG cells from nonregulatory CD4+CD25– T cells in a concentration-dependent manner through Foxp3 induction. As CD4+CD25– T cells remain a highly heterogeneous population with variable degrees of antigen experience, we then examined the effect of TGF-β1 on naive CD4+CD25–CD45RBHIGH T cells. Freshly isolated or TGF-β1-treated CD4+CD25–CD45RBHIGH T cells never displayed any regulatory functions or significant Foxp3 expression following TCR activation. In stark contrast, freshly isolated CD4+CD25–CD45RBLOW cells, albeit expressing low levels of Foxp3 mRNA and protein, were unable to suppress CD4+ effector T cell proliferation but acquired regulatory activity and de novo Foxp3 expression following TGF-β1 exposure. Furthermore, suppression was IL-10-dependent, as anti-IL-10 receptor antibody treatment abrogated this suppression completely, consistent with the ability of TGF-β1-treated CD4+CD25–CD45RBLOW to synthesize IL-10 upon restimulation in vitro. Last, we show that TGF-β1 treatment or blockade did not lead to enhanced expansion or function of naturally occurring CD4+CD25+ TREG cells, although it maintained Foxp3 mRNA and protein expression. Altogether, TGF-β1 promotes the induction of IL-10-secreting CD4+ TREG cells from CD4+CD25–CD45RBLOW precursors through de novo Foxp3 production and maintains natural TREG cell peripheral homeostasis by sustaining Foxp3 expression.
Funding Information
  • Canadian Institutes for Health Research (MOP 67211)
  • Canadian Foundation for Innovation
  • Canadian Diabetes Association

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