TGF-beta1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets.

Although forkhead box p3 (Foxp3) expression is restricted to naturally occurring CD4(+) regulatory T cells (T(REG)), little is known about the various signals that regulate it in T cells. As TGF-beta 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-beta1 priming was able to promote differentiation of T(REG) 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-beta1 on naive CD4(+)CD25(-)CD45RB(HIGH) T cells. Freshly isolated or TGF-beta1-treated CD4(+)CD25(-)CD45RB(HIGH) T cells never displayed any regulatory functions or significant Foxp3 expression following TCR activation. In stark contrast, freshly isolated CD4(+)CD25(-)CD45RB(LOW) 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-beta1 exposure. Furthermore, suppression was IL-10-dependent, as anti-IL-10 receptor antibody treatment abrogated this suppression completely, consistent with the ability of TGF-beta1-treated CD4(+)CD25(-)CD45RB(LOW) to synthesize IL-10 upon restimulation in vitro. Last, we show that TGF-beta1 treatment or blockade did not lead to enhanced expansion or function of naturally occurring CD4(+)CD25(+) T(REG) cells, although it maintained Foxp3 mRNA and protein expression. Altogether, TGF-beta1 promotes the induction of IL-10-secreting CD4(+) T(REG) cells from CD4(+)CD25(-)CD45RB(LOW) precursors through de novo Foxp3 production and maintains natural T(REG) cell peripheral homeostasis by sustaining Foxp3 expression.