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


Affiliations
1 Division of Infectious Diseases and Geographic Medicine, Department of Medicine, 300 Pasteur Drive, Stanford University School of Medicine, Stanford, CA 94305-5107, United States
2 Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101, United States
 

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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  • Regulatory T Cells Resist Cyclosporine-Induced Cell Death Via CD44-Mediated Signaling Pathways

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Authors

Shannon M. Ruppert
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, 300 Pasteur Drive, Stanford University School of Medicine, Stanford, CA 94305-5107, United States
Ben A. Falk
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, 300 Pasteur Drive, Stanford University School of Medicine, Stanford, CA 94305-5107, United States
S. Alice Long
Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101, United States
Paul L. Bollyky
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, 300 Pasteur Drive, Stanford University School of Medicine, Stanford, CA 94305-5107, United States

Abstract


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.