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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 signaling is not required for the in vitro suppressive function of CD4+CD25+ T cells.Freshly isolated CD4+CD25− T cells from spleen were labelled with CFSE and cultured for four days under CD3 stimulation (3 µg/ml) in the presence of allogeneic CD3− spleen cells with or without CD4+CD25+ T cells freshly isolated from wild type mice, added at the indicated cell numbers (responder+suppressor cells×105). DMSO or SB203580 (10 µM) were added to the culture twice daily as indicated. CFSE dilution was measured by flow cytometry after 4 days of coculture. Data are representative of four independent experiments.
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pone-0003302-g006: P38 MAP kinase signaling is not required for the in vitro suppressive function of CD4+CD25+ T cells.Freshly isolated CD4+CD25− T cells from spleen were labelled with CFSE and cultured for four days under CD3 stimulation (3 µg/ml) in the presence of allogeneic CD3− spleen cells with or without CD4+CD25+ T cells freshly isolated from wild type mice, added at the indicated cell numbers (responder+suppressor cells×105). DMSO or SB203580 (10 µM) were added to the culture twice daily as indicated. CFSE dilution was measured by flow cytometry after 4 days of coculture. Data are representative of four independent experiments.

Mentions: The above findings indicate that p38 MAP kinase could be a therapeutic target for preventing the peripheral generation of iTreg in the context of malignancies or chronic viral infection. However, a complete inhibition of Treg suppressive function could have adverse effects and induce autoimmune disease. We therefore tested whether p38 inhibition may inhibit the suppressive function of nTreg. To that end, the p38 inhibitor SB203580 was added to an in vitro suppressor assay twice daily (Figure 6). We did not find a significant difference in the suppressive capacity of nTreg with or without p38 inhibitor (1+1, % of undivided cells: 54% (DMSO) vs. 50% (SB203580)). Similar results were obtained using another p38 MAP kinase inhibitor (SB202190, not shown). These findings indicate that the in vitro suppressive function of established nTreg is not blocked by inhibition of the p38 MAP kinase pathway.


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 signaling is not required for the in vitro suppressive function of CD4+CD25+ T cells.Freshly isolated CD4+CD25− T cells from spleen were labelled with CFSE and cultured for four days under CD3 stimulation (3 µg/ml) in the presence of allogeneic CD3− spleen cells with or without CD4+CD25+ T cells freshly isolated from wild type mice, added at the indicated cell numbers (responder+suppressor cells×105). DMSO or SB203580 (10 µM) were added to the culture twice daily as indicated. CFSE dilution was measured by flow cytometry after 4 days of coculture. Data are representative of four independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003302-g006: P38 MAP kinase signaling is not required for the in vitro suppressive function of CD4+CD25+ T cells.Freshly isolated CD4+CD25− T cells from spleen were labelled with CFSE and cultured for four days under CD3 stimulation (3 µg/ml) in the presence of allogeneic CD3− spleen cells with or without CD4+CD25+ T cells freshly isolated from wild type mice, added at the indicated cell numbers (responder+suppressor cells×105). DMSO or SB203580 (10 µM) were added to the culture twice daily as indicated. CFSE dilution was measured by flow cytometry after 4 days of coculture. Data are representative of four independent experiments.
Mentions: The above findings indicate that p38 MAP kinase could be a therapeutic target for preventing the peripheral generation of iTreg in the context of malignancies or chronic viral infection. However, a complete inhibition of Treg suppressive function could have adverse effects and induce autoimmune disease. We therefore tested whether p38 inhibition may inhibit the suppressive function of nTreg. To that end, the p38 inhibitor SB203580 was added to an in vitro suppressor assay twice daily (Figure 6). We did not find a significant difference in the suppressive capacity of nTreg with or without p38 inhibitor (1+1, % of undivided cells: 54% (DMSO) vs. 50% (SB203580)). Similar results were obtained using another p38 MAP kinase inhibitor (SB202190, not shown). These findings indicate that the in vitro suppressive function of established nTreg is not blocked by inhibition of the p38 MAP kinase pathway.

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