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

Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7083-7088. doi: 10.1073/pnas.1620835114. Epub 2017 Jun 5.


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.

Keywords: IL-2 therapy; NFAT translocation; calcineurin inhibitors; regulatory T cells; transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis
  • Calcineurin Inhibitors / pharmacology*
  • Case-Control Studies
  • Chronic Disease
  • End Stage Liver Disease / surgery
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Graft Survival
  • Humans
  • Immunosuppression Therapy
  • Immunosuppressive Agents / pharmacology
  • Interleukin-2 / pharmacology*
  • Interleukin-7 / metabolism
  • Kidney Transplantation
  • Leukocyte Common Antigens / metabolism
  • Liver Transplantation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Middle Aged
  • Phenotype
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • Tacrolimus / pharmacology
  • Transplantation Tolerance


  • Calcineurin Inhibitors
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL7 protein, human
  • Immunosuppressive Agents
  • Interleukin-2
  • Interleukin-7
  • Leukocyte Common Antigens
  • Tacrolimus