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Regulatory T Cells Resist Cyclosporine-Induced Cell Death Via CD44-Mediated Signaling Pathways
Cyclosporine A (CSA) is an immunosuppressive agent that specifically targets T cells and also increases the percentage of protolerogenic CD4+Foxp3+ regulatory T cells (Treg) through unknown mechanisms.We previously reported that CD44, a receptor for the extracellularmatrix 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 ofCSA 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.
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