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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

Converted cells express CD25 and Foxp3 and are functional in vitro.A: Representative CD25-/Foxp3-expression after in vitro conversion into iTreg in the presence or absence of SB203580. B: In vitro suppressor assay using CD4+CD25− CFSE-labelled responder T cells isolated from spleen and suppressor T cells generated by in vitro conversion as described. Responder and suppressor cells were added at a ratio of 1∶1. Suppressor cells were washed three times before addition to the assay.
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pone-0003302-g004: Converted cells express CD25 and Foxp3 and are functional in vitro.A: Representative CD25-/Foxp3-expression after in vitro conversion into iTreg in the presence or absence of SB203580. B: In vitro suppressor assay using CD4+CD25− CFSE-labelled responder T cells isolated from spleen and suppressor T cells generated by in vitro conversion as described. Responder and suppressor cells were added at a ratio of 1∶1. Suppressor cells were washed three times before addition to the assay.

Mentions: In the absence of inhibitor, CD4+CD25− T cells cultured with TGF-beta1 acquired suppressive function and showed an increased Foxp3-expression (Figure 3B). In contrast, the presence of either p38 inhibitor dose-dependently blocked the TGF-beta-induced conversion into iTreg, as seen by a reduced suppressive activity and Foxp3-expression (Figure 3B). A representative analysis of CD25− and Foxp3-expression after the TGF-beta induced in vitro conversion in the presence or absence of the inhibitor SB203580 is shown in Figure 4. The inhibitor did not compromise viability of the cells, as determined by staining with propidium iodide (91.5% negative with inhibitor vs. 90.5% negative without inhibitor), and similar cell numbers could be obtained after culture (on average 6.8×105 with TGF-beta1 and inhibitor vs. 7.1×105 with TGF-beta1 and without the inhibitor).


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)

Converted cells express CD25 and Foxp3 and are functional in vitro.A: Representative CD25-/Foxp3-expression after in vitro conversion into iTreg in the presence or absence of SB203580. B: In vitro suppressor assay using CD4+CD25− CFSE-labelled responder T cells isolated from spleen and suppressor T cells generated by in vitro conversion as described. Responder and suppressor cells were added at a ratio of 1∶1. Suppressor cells were washed three times before addition to the assay.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003302-g004: Converted cells express CD25 and Foxp3 and are functional in vitro.A: Representative CD25-/Foxp3-expression after in vitro conversion into iTreg in the presence or absence of SB203580. B: In vitro suppressor assay using CD4+CD25− CFSE-labelled responder T cells isolated from spleen and suppressor T cells generated by in vitro conversion as described. Responder and suppressor cells were added at a ratio of 1∶1. Suppressor cells were washed three times before addition to the assay.
Mentions: In the absence of inhibitor, CD4+CD25− T cells cultured with TGF-beta1 acquired suppressive function and showed an increased Foxp3-expression (Figure 3B). In contrast, the presence of either p38 inhibitor dose-dependently blocked the TGF-beta-induced conversion into iTreg, as seen by a reduced suppressive activity and Foxp3-expression (Figure 3B). A representative analysis of CD25− and Foxp3-expression after the TGF-beta induced in vitro conversion in the presence or absence of the inhibitor SB203580 is shown in Figure 4. The inhibitor did not compromise viability of the cells, as determined by staining with propidium iodide (91.5% negative with inhibitor vs. 90.5% negative without inhibitor), and similar cell numbers could be obtained after culture (on average 6.8×105 with TGF-beta1 and inhibitor vs. 7.1×105 with TGF-beta1 and without the inhibitor).

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