IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

Significance Preservation and/or enhancement of Treg function is becoming a key component of modern immunotherapeutic strategies, but the direct influence of many immunosuppressive drugs on Tregs remains unknown. Calcineurin inhibitors (CNIs), which are widely used to treat inflammatory disorders, reduce the size of the Treg pool substantially, and this reduction might hinder their overall beneficial effects. Here we show that the decrease in Treg numbers is caused by increased cell death as a result of the limited availability of the IL-2 growth factor. Hence, the addition of IL-2 restores the survival and suppressive properties of Tregs exposed to CNIs and improves allograft survival. Our data provide a strong rationale for combining CNIs with IL-2 therapy to maximize effective immunosuppression and to promote tolerance acquisition. CD4+CD25+FOXP3+ Tregs constitute a heterogeneous lymphocyte subpopulation essential for curtailing effector T cells and establishing peripheral tolerance. Calcineurin inhibitors (CNIs) are among the most effective agents in controlling effector T-cell responses in humans. However, CNIs also reduce the size of the Treg pool. The functional consequences of this negative effect and the mechanisms responsible remain to be elucidated. We report here that CNIs compromise the overall Treg immunoregulatory capacity to a greater extent than would be predicted by the reduction in the size of the Treg compartment, given that they selectively promote the apoptosis of the resting and activated Treg subsets that are known to display the most powerful suppressive function. These effects are caused by reduced access to IL-2, because Tregs remain capable of translocating NFAT even in the presence of high CNI levels. Exogenous IL-2 restores the phenotypic changes and overall gene-expression effects exerted by CNIs and can even promote Treg expansion by enhancing antiapoptotic Bcl-2 expression. In a skin transplant model, the addition of IL-2 synergizes with CNIs treatment, promoting intragraft accumulation of Tregs and prolonged allograft survival. Hence, the combination of IL-2 and CNIs constitutes an optimal immunomodulatory regimen that enhances the pool of suppressive Treg subsets while effectively controlling cytopathic T cells.

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