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P38 MAP kinase signaling is required for the conversion of CD4+CD25- T cells into iTreg.

Huber S, Schrader J, Fritz G, Presser K, Schmitt S, Waisman A, Lüth S, Blessing M, Herkel J, Schramm C - PLoS ONE (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

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.

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Related in: MedlinePlus

TGF-beta1 activates Smad 3 and p38 MAP kinase in CD4+CD25− T cells.Freshly isolated CD4+CD25− T cells (4×106) were cultured with or without TGF-beta1 for 4 or 16 hours. Cells were activated with plate bound anti-CD3 mAb (2 µg/ml) and soluble anti-CD28 mAb (2 µg/ml) as indicated. Smad 3 and p38 activation were measured using Western blot. The experiments were repeated three times giving similar results.
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pone-0003302-g002: TGF-beta1 activates Smad 3 and p38 MAP kinase in CD4+CD25− T cells.Freshly isolated CD4+CD25− T cells (4×106) were cultured with or without TGF-beta1 for 4 or 16 hours. Cells were activated with plate bound anti-CD3 mAb (2 µg/ml) and soluble anti-CD28 mAb (2 µg/ml) as indicated. Smad 3 and p38 activation were measured using Western blot. The experiments were repeated three times giving similar results.

Mentions: It has been shown that TGF-beta1 induces Foxp3 transcription in peripheral naïve CD4 T cells [3]. This conversion to iTreg seems to depend on Smad 3 activation [17]. We therefore first analyzed TGF-beta1 signaling pathways in freshly isolated CD4+CD25− T cells. In the absence of activating signals and TGF-beta1, spontaneous activation of p38 MAP kinase as well as Smad 3 was observed (Figure S 1), which may have been caused by the isolation procedure and/or cytokines carried over into the culture. The spontaneous Smad 3 activation lasted for at least 2 hours, that of p38 lasted for at least 4 hours (Figure S 1). Addition of TGF-beta1 in the absence of activating signals induced the activation of both Smad 3 and p38, detectable at 4 hours and 16 hours of culture (Figure 2). At 16 hours, but not at 4 hours of culture, T cell activation by CD3 and CD28 antibody enhanced the TGF-beta1-induced p38 and Smad 3 activation (Figure 2). T cell activation in the absence of TGF-beta1 did not induce Smad 3 activation, but p38 phosphorylation, weakly at 4 hours and strongly at 16 hours of culture (Figure 2). Thus, in addition to Smad signaling, TGF-beta1 seemed to induce early p38 activation, detectable at 4 hours of culture (Figure 2).


P38 MAP kinase signaling is required for the conversion of CD4+CD25- T cells into iTreg.

Huber S, Schrader J, Fritz G, Presser K, Schmitt S, Waisman A, Lüth S, Blessing M, Herkel J, Schramm C - PLoS ONE (2008)

TGF-beta1 activates Smad 3 and p38 MAP kinase in CD4+CD25− T cells.Freshly isolated CD4+CD25− T cells (4×106) were cultured with or without TGF-beta1 for 4 or 16 hours. Cells were activated with plate bound anti-CD3 mAb (2 µg/ml) and soluble anti-CD28 mAb (2 µg/ml) as indicated. Smad 3 and p38 activation were measured using Western blot. The experiments were repeated three times giving similar results.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553190&req=5

pone-0003302-g002: TGF-beta1 activates Smad 3 and p38 MAP kinase in CD4+CD25− T cells.Freshly isolated CD4+CD25− T cells (4×106) were cultured with or without TGF-beta1 for 4 or 16 hours. Cells were activated with plate bound anti-CD3 mAb (2 µg/ml) and soluble anti-CD28 mAb (2 µg/ml) as indicated. Smad 3 and p38 activation were measured using Western blot. The experiments were repeated three times giving similar results.
Mentions: It has been shown that TGF-beta1 induces Foxp3 transcription in peripheral naïve CD4 T cells [3]. This conversion to iTreg seems to depend on Smad 3 activation [17]. We therefore first analyzed TGF-beta1 signaling pathways in freshly isolated CD4+CD25− T cells. In the absence of activating signals and TGF-beta1, spontaneous activation of p38 MAP kinase as well as Smad 3 was observed (Figure S 1), which may have been caused by the isolation procedure and/or cytokines carried over into the culture. The spontaneous Smad 3 activation lasted for at least 2 hours, that of p38 lasted for at least 4 hours (Figure S 1). Addition of TGF-beta1 in the absence of activating signals induced the activation of both Smad 3 and p38, detectable at 4 hours and 16 hours of culture (Figure 2). At 16 hours, but not at 4 hours of culture, T cell activation by CD3 and CD28 antibody enhanced the TGF-beta1-induced p38 and Smad 3 activation (Figure 2). T cell activation in the absence of TGF-beta1 did not induce Smad 3 activation, but p38 phosphorylation, weakly at 4 hours and strongly at 16 hours of culture (Figure 2). Thus, in addition to Smad signaling, TGF-beta1 seemed to induce early p38 activation, detectable at 4 hours of culture (Figure 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

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.

Show MeSH
Related in: MedlinePlus