P38 MAP Kinase Signaling Is Required for the Conversion of CD4+CD25− T Cells into iTreg

Abstract

CD4+CD25+ regulatory T cells (Treg) are important mediators of immune tolerance. A subset of Treg can be generated in the periphery by TGF-beta dependent conversion of conventional CD4+CD25− T cells into induced Treg (iTreg). In chronic viral infection or malignancy, such induced iTreg, which limit the depletion of aberrant or infected cells, may be of pathogenic relevance. To identify potential targets for therapeutic intervention, we investigated the TGF-beta signaling in Treg. In contrast to conventional CD4+ T cells, Treg exhibited marked activation of the p38 MAP kinase pathway. Inhibition of p38 MAP kinase activity prevented the TGF-beta-dependent conversion of CD4+CD25− T cells into Foxp3+ iTreg in vitro. Of note, the suppressive capacity of nTreg was not affected by inhibiting p38 MAP kinase. Our findings indicate that signaling via p38 MAP kinase seems to be important for the peripheral generation of iTreg; p38 MAP kinase could thus be a therapeutic target to enhance immunity to chronic viral infection or cancer.

MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis

“…Transplanted mice were injected with pertussis toxin (PT) on the day of T cell transfer and 48 hours later and monitored for the development of EAE. We found that mice that received Th17 cells differentiated in the presence of control TGF-β signaling through SMAD-dependent and SMAD-independent pathways plays a role in Treg differentiation and function (56)(57)(58)(59)(60)(61). Although TGF-β signaling through the SMAD-2/3 pathway has been demonstrated to partially regulate iTreg differentiation, it has also been shown that a combination of SMAD-2 and SMAD-3 deficiency does not alter FOXP3 expression or the suppressive activity of iTregs in vivo (58).…”

“…In fact, the development, homeostasis, and function of Tregs remained intact in SMAD-2 and SMAD-3 doubledeficient mice, suggesting a role for a SMAD-independent pathway in Treg differentiation and function (60). Among the SMAD-independent TGF-β signaling pathways, p38 MAPK signaling has been shown to be required for the conversion of naive CD4 + T cells into iTregs (61). Furthermore, IL-2 has been shown to stabilize TGF-β-induced FOXP3 expression and compensate for the loss of defective SMAD-dependent TGF-β signaling in iTreg differentiation (21).…”

Targeted inhibition of IL‐10‐secreting CD25− Treg via p38 MAPK suppression in cancer immunotherapy

“…We now suspect that the dominant p38 activation in response to other MAPK (ERK and JNK) in in vivo Ag-induced iTreg is related to both the suppressor function via IL-10 production and the anergic state via cell cycle arrest and p27 expression and not via IL-10 [14]. Recent studies have indicated that p38 activation is required for TGF-b-induced in vitro conversion to iTreg [23,24] and is involved in IL-10 production via innate TLR2 signaling of HSP60 in iTreg [25] or in the induction to iTreg through tDC treated with CpG [26]. We suspect that p38-dependent IL-10 production is mediated by TAB1.…”

Activin A Promotes the TGF-β-Induced Conversion of CD4+CD25− T Cells into Foxp3+ Induced Regulatory T Cells

“…Recently it has been reported that Smad3 (42) and p38 MAPK activation (43) play an important role for the conversion of CD4 ϩ CD25 Ϫ T cells into iTreg.…”