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Regulatory T Cells Resist Cyclosporine-Induced Cell Death via CD44-Mediated Signaling Pathways.

Ruppert SM, Falk BA, Long SA, Bollyky PL - Int J Cell Biol (2015)

Bottom Line: We found that CD44 cross-linking promoted Foxp3 expression and Treg viability in the setting of CSA treatment.This effect was IL-2 independent but could be suppressed using sc-355979, an inhibitor of Stat5-phosphorylation.Moreover, we found that inhibition of HA synthesis impairs Treg homeostasis but that this effect could be overcome with exogenous IL-2 or CD44-cross-linking.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, 300 Pasteur Drive, Stanford University School of Medicine, Stanford, CA 94305-5107, USA.

ABSTRACT
Cyclosporine A (CSA) is an immunosuppressive agent that specifically targets T cells and also increases the percentage of pro-tolerogenic CD4+Foxp3+ regulatory T cells (Treg) through unknown mechanisms. We previously reported that CD44, a receptor for the extracellular matrix glycosaminoglycan hyaluronan (HA), promotes Treg stability in IL-2-low environments. Here, we asked whether CD44 signaling also promotes Treg resistance to CSA. We found that CD44 cross-linking promoted Foxp3 expression and Treg viability in the setting of CSA treatment. This effect was IL-2 independent but could be suppressed using sc-355979, an inhibitor of Stat5-phosphorylation. Moreover, we found that inhibition of HA synthesis impairs Treg homeostasis but that this effect could be overcome with exogenous IL-2 or CD44-cross-linking. Together, these data support a model whereby CD44 cross-linking by HA promotes IL-2-independent Foxp3 expression and Treg survival in the face of CSA.

No MeSH data available.


Related in: MedlinePlus

CD44-mediated Foxp3 expression is Stat5-dependent. (a) Representative histograms for GFP/Foxp3 expression of CD4+GFP/Foxp3+ Treg following culture in the presence of sc-35597, a selective pStat5 inhibitor. (b) Representative histograms for GFP/Foxp3 following 3 days of culture with aCD3/28/44 together with increasing concentrations of sc-35597. (c) Representative histograms depicting GFP/Foxp3 persistence following culture with CSA (50 ng/mL) alone or in conjunction with sc-35597. Data for (a–c) are representative of at least 3 experiments.
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fig5: CD44-mediated Foxp3 expression is Stat5-dependent. (a) Representative histograms for GFP/Foxp3 expression of CD4+GFP/Foxp3+ Treg following culture in the presence of sc-35597, a selective pStat5 inhibitor. (b) Representative histograms for GFP/Foxp3 following 3 days of culture with aCD3/28/44 together with increasing concentrations of sc-35597. (c) Representative histograms depicting GFP/Foxp3 persistence following culture with CSA (50 ng/mL) alone or in conjunction with sc-35597. Data for (a–c) are representative of at least 3 experiments.

Mentions: We observed that the ability of CD44 cross-linking to promote Foxp3 expression was lost upon treatment with sc-355979, a selective inhibitor of pStat5 (Figure 5(a)). This capacity of sc-355979 to overcome CD44-mediated Foxp3 expression was dose dependent (Figure 5(b)). Finally, whereas CSA treatment alone did not affect Foxp3 expression induced by CD44, combined treatment with CSA and pStat5 inhibition did impair CD44-mediated Foxp3 expression (Figure 5(c)).


Regulatory T Cells Resist Cyclosporine-Induced Cell Death via CD44-Mediated Signaling Pathways.

Ruppert SM, Falk BA, Long SA, Bollyky PL - Int J Cell Biol (2015)

CD44-mediated Foxp3 expression is Stat5-dependent. (a) Representative histograms for GFP/Foxp3 expression of CD4+GFP/Foxp3+ Treg following culture in the presence of sc-35597, a selective pStat5 inhibitor. (b) Representative histograms for GFP/Foxp3 following 3 days of culture with aCD3/28/44 together with increasing concentrations of sc-35597. (c) Representative histograms depicting GFP/Foxp3 persistence following culture with CSA (50 ng/mL) alone or in conjunction with sc-35597. Data for (a–c) are representative of at least 3 experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581548&req=5

fig5: CD44-mediated Foxp3 expression is Stat5-dependent. (a) Representative histograms for GFP/Foxp3 expression of CD4+GFP/Foxp3+ Treg following culture in the presence of sc-35597, a selective pStat5 inhibitor. (b) Representative histograms for GFP/Foxp3 following 3 days of culture with aCD3/28/44 together with increasing concentrations of sc-35597. (c) Representative histograms depicting GFP/Foxp3 persistence following culture with CSA (50 ng/mL) alone or in conjunction with sc-35597. Data for (a–c) are representative of at least 3 experiments.
Mentions: We observed that the ability of CD44 cross-linking to promote Foxp3 expression was lost upon treatment with sc-355979, a selective inhibitor of pStat5 (Figure 5(a)). This capacity of sc-355979 to overcome CD44-mediated Foxp3 expression was dose dependent (Figure 5(b)). Finally, whereas CSA treatment alone did not affect Foxp3 expression induced by CD44, combined treatment with CSA and pStat5 inhibition did impair CD44-mediated Foxp3 expression (Figure 5(c)).

Bottom Line: We found that CD44 cross-linking promoted Foxp3 expression and Treg viability in the setting of CSA treatment.This effect was IL-2 independent but could be suppressed using sc-355979, an inhibitor of Stat5-phosphorylation.Moreover, we found that inhibition of HA synthesis impairs Treg homeostasis but that this effect could be overcome with exogenous IL-2 or CD44-cross-linking.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, 300 Pasteur Drive, Stanford University School of Medicine, Stanford, CA 94305-5107, USA.

ABSTRACT
Cyclosporine A (CSA) is an immunosuppressive agent that specifically targets T cells and also increases the percentage of pro-tolerogenic CD4+Foxp3+ regulatory T cells (Treg) through unknown mechanisms. We previously reported that CD44, a receptor for the extracellular matrix glycosaminoglycan hyaluronan (HA), promotes Treg stability in IL-2-low environments. Here, we asked whether CD44 signaling also promotes Treg resistance to CSA. We found that CD44 cross-linking promoted Foxp3 expression and Treg viability in the setting of CSA treatment. This effect was IL-2 independent but could be suppressed using sc-355979, an inhibitor of Stat5-phosphorylation. Moreover, we found that inhibition of HA synthesis impairs Treg homeostasis but that this effect could be overcome with exogenous IL-2 or CD44-cross-linking. Together, these data support a model whereby CD44 cross-linking by HA promotes IL-2-independent Foxp3 expression and Treg survival in the face of CSA.

No MeSH data available.


Related in: MedlinePlus