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

Abstract EN

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.