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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 27; pp. 7083 - 7088
• Main Authors: Whitehouse, Gavin, Gray, Elizabeth, Mastoridis, Sotiris, Merritt, Elliot, Kodela, Elisavet, Yang, Jennie H. M., Danger, Richard, Mairal, Marta, Christakoudi, Sofia, Lozano, Juan J., Macdougall, Iain C., Tree, Timothy I. M., Sanchez-Fueyo, Alberto, Martinez-Llordella, Marc
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.07.2017
• Series: From the Cover
• Subjects: Adult; Aged; Animals; Apoptosis; Bcl-2 protein; Biological Sciences; Calcineurin; Calcineurin inhibitors; Calcineurin Inhibitors - pharmacology; Case-Control Studies; CD25 antigen; CD4 antigen; Chronic Disease; Effector cells; End Stage Liver Disease - surgery; Female; Flow Cytometry; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene expression; Gene Expression Regulation; Graft Survival; Humans; Immunological tolerance; Immunology; Immunomodulation; Immunoregulation; Immunosuppression Therapy; Immunosuppressive Agents - pharmacology; Inhibitors; Interleukin 2; Interleukin-2 - pharmacology; Interleukin-7 - metabolism; Kidney Transplantation; Leukocyte Common Antigens - metabolism; Liver Transplantation; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; NF-AT protein; Phenotype; Signal Transduction; Skin; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - drug effects; Tacrolimus - pharmacology; Transplantation Tolerance; Transplants & implants; regulatory T cells; IL-2 therapy; NFAT translocation; transplantation; calcineurin inhibitors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1620835114

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.