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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

p38 MAP kinase inhibitor SB203580 specifically inhibits the phosphorylation of p38 MAP kinase downstream target MAPKAP2.A: CD4+CD25− T cells were cultured with TGF-beta1 (2 ng/ml) and SB203580 (10 µM), SP600125 (10 µM), or PD89059 (50 µM) for 45 min. Control cells were cultured without TGF-beta1. B: CD4+CD25− T cells were cultured for 4 hours with TGF-beta1 (2 ng/ml) and SB203580 (10 µM). P-MAPKAP2, p-ERK, p-c-jun, p-Smad 3 and actin were determined using Western blot. Results are representative of two independent experiments.
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pone-0003302-g005: p38 MAP kinase inhibitor SB203580 specifically inhibits the phosphorylation of p38 MAP kinase downstream target MAPKAP2.A: CD4+CD25− T cells were cultured with TGF-beta1 (2 ng/ml) and SB203580 (10 µM), SP600125 (10 µM), or PD89059 (50 µM) for 45 min. Control cells were cultured without TGF-beta1. B: CD4+CD25− T cells were cultured for 4 hours with TGF-beta1 (2 ng/ml) and SB203580 (10 µM). P-MAPKAP2, p-ERK, p-c-jun, p-Smad 3 and actin were determined using Western blot. Results are representative of two independent experiments.

Mentions: To further confirm the specificity of inhibition by the inhibitor SB203580 and the control inhibitors of JNK (SP600125) and ERK (PD98059), we analysed the activities of the p38, JNK and ERK pathways during in vitro conversion into iTreg (Figure 5A). We found that the p38 inhibitor SB203580 selectively blocked the phosphorylation of MAPKAP2, which is a downstream target of p38 MAP kinase (Figure 5A). Accordingly, PD98059 blocked the phosphorylation of ERK, but not MAPKAP2. The JNK pathway seemed to be only minimally activated in vitro (data not shown) and we could therefore not detect any phosphorylation of the JNK downstream target c-jun, making it difficult to prove a selective effect of SP600125 on the JNK pathway (Figure 5A). Of note, the p38 inhibitor SB203580 did not block Smad signaling, but rather seemed to induce Smad 3 activation itself (Figure 5B).


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)

p38 MAP kinase inhibitor SB203580 specifically inhibits the phosphorylation of p38 MAP kinase downstream target MAPKAP2.A: CD4+CD25− T cells were cultured with TGF-beta1 (2 ng/ml) and SB203580 (10 µM), SP600125 (10 µM), or PD89059 (50 µM) for 45 min. Control cells were cultured without TGF-beta1. B: CD4+CD25− T cells were cultured for 4 hours with TGF-beta1 (2 ng/ml) and SB203580 (10 µM). P-MAPKAP2, p-ERK, p-c-jun, p-Smad 3 and actin were determined using Western blot. Results are representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003302-g005: p38 MAP kinase inhibitor SB203580 specifically inhibits the phosphorylation of p38 MAP kinase downstream target MAPKAP2.A: CD4+CD25− T cells were cultured with TGF-beta1 (2 ng/ml) and SB203580 (10 µM), SP600125 (10 µM), or PD89059 (50 µM) for 45 min. Control cells were cultured without TGF-beta1. B: CD4+CD25− T cells were cultured for 4 hours with TGF-beta1 (2 ng/ml) and SB203580 (10 µM). P-MAPKAP2, p-ERK, p-c-jun, p-Smad 3 and actin were determined using Western blot. Results are representative of two independent experiments.
Mentions: To further confirm the specificity of inhibition by the inhibitor SB203580 and the control inhibitors of JNK (SP600125) and ERK (PD98059), we analysed the activities of the p38, JNK and ERK pathways during in vitro conversion into iTreg (Figure 5A). We found that the p38 inhibitor SB203580 selectively blocked the phosphorylation of MAPKAP2, which is a downstream target of p38 MAP kinase (Figure 5A). Accordingly, PD98059 blocked the phosphorylation of ERK, but not MAPKAP2. The JNK pathway seemed to be only minimally activated in vitro (data not shown) and we could therefore not detect any phosphorylation of the JNK downstream target c-jun, making it difficult to prove a selective effect of SP600125 on the JNK pathway (Figure 5A). Of note, the p38 inhibitor SB203580 did not block Smad signaling, but rather seemed to induce Smad 3 activation itself (Figure 5B).

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