Regulatory T Cells Resist Cyclosporine-Induced Cell Death via CD44-Mediated Signaling Pathways.
Regulatory T Cells Resist Cyclosporine-Induced Cell Death via CD44-Mediated Signaling Pathways.
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DOI：
10.1155/2015/614297
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发表时间：
2015
影响因子：
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通讯作者：
Bollyky PL
中科院分区：
文献类型：
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作者：
Ruppert SM;Falk BA;Long SA;Bollyky PL
环孢菌素A(CsA)是一种免疫抑制剂，它特异性地针对T细胞，并通过未知的机制增加亲耐受的CD4+Foxp3+调节性T细胞(Treg)的百分比。我们以前报道过CD44，一种细胞外基质糖胺聚糖透明质酸(HA)的受体，在IL-2低的环境中促进Treg的稳定性。在这里，我们询问CD44信号是否也促进Treg对CsA的抵抗。我们发现，在CsA治疗的背景下，CD44交联促进了Foxp3的表达和Treg的活性。这种作用不依赖于IL-2，但可被STAT5-磷酸化抑制剂sc-355979抑制。此外，我们发现抑制HA的合成会损害Treg的动态平衡，但这种影响可以被外源IL-2或CD44交联所克服。综上所述，这些数据支持一种模型，即在面对CsA时，HA通过CD44交联促进IL-2非依赖性Foxp3的表达和Treg生存。
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.