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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

CSA increases Treg percentages in a CD44 dependent manner. Fold increase (FI) in the percentage of GFP/Foxp3+ cells of (a) CD44-containing or (b) CD44-deficient, murine CD4+ T cells after 3 days of culture in the settings of anti-CD3 and anti-CD28 with or without CSA in various concentrations. (c) Fold increase (FI) in percentage of GFP/Foxp3+ cells after 3 days of culture in the setting of anti-CD3 and anti-CD28 alone or in conjunction with anti-CD44 Ab. n = 5 replicate wells.
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fig1: CSA increases Treg percentages in a CD44 dependent manner. Fold increase (FI) in the percentage of GFP/Foxp3+ cells of (a) CD44-containing or (b) CD44-deficient, murine CD4+ T cells after 3 days of culture in the settings of anti-CD3 and anti-CD28 with or without CSA in various concentrations. (c) Fold increase (FI) in percentage of GFP/Foxp3+ cells after 3 days of culture in the setting of anti-CD3 and anti-CD28 alone or in conjunction with anti-CD44 Ab. n = 5 replicate wells.

Mentions: We observed that CSA treatment significantly increased the percentage of Foxp3+ Treg among total CD4+ T cells. This effect was significant at a range of CSA concentrations but was most pronounced at moderate CSA levels (50 μg/mL) (Figure 1(a)). This effect is due to increased cell death among the GFP/Foxp3−, conventional T cell fraction and not the GFP/Foxp3+ Treg fraction (data not shown).


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)

CSA increases Treg percentages in a CD44 dependent manner. Fold increase (FI) in the percentage of GFP/Foxp3+ cells of (a) CD44-containing or (b) CD44-deficient, murine CD4+ T cells after 3 days of culture in the settings of anti-CD3 and anti-CD28 with or without CSA in various concentrations. (c) Fold increase (FI) in percentage of GFP/Foxp3+ cells after 3 days of culture in the setting of anti-CD3 and anti-CD28 alone or in conjunction with anti-CD44 Ab. n = 5 replicate wells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: CSA increases Treg percentages in a CD44 dependent manner. Fold increase (FI) in the percentage of GFP/Foxp3+ cells of (a) CD44-containing or (b) CD44-deficient, murine CD4+ T cells after 3 days of culture in the settings of anti-CD3 and anti-CD28 with or without CSA in various concentrations. (c) Fold increase (FI) in percentage of GFP/Foxp3+ cells after 3 days of culture in the setting of anti-CD3 and anti-CD28 alone or in conjunction with anti-CD44 Ab. n = 5 replicate wells.
Mentions: We observed that CSA treatment significantly increased the percentage of Foxp3+ Treg among total CD4+ T cells. This effect was significant at a range of CSA concentrations but was most pronounced at moderate CSA levels (50 μg/mL) (Figure 1(a)). This effect is due to increased cell death among the GFP/Foxp3−, conventional T cell fraction and not the GFP/Foxp3+ Treg fraction (data not shown).

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