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

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Gavin Whitehouse ; Elizabeth Gray ; Sotiris Mastoridis ; Elliot Merritt ; Elisavet Kodela ; Jennie H.M. Yang ; Richard Danger ; Marta Mairal ; Sofia Christakoudi ; Juan J. Lozano ; Iain C. Macdougall ; Timothy I.M. Tree ; Alberto Sanchez-Fueyo ; Marc Martinez-Llordella

Original languageEnglish
Pages (from-to)7083-7088
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number27
Early online date5 Jun 2017
DOIs
StatePublished - 3 Jul 2017

King's Authors

Abstract

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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