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

ABSTRACT: CNIs drastically modify the Treg specific transcriptional program in vivo in an IL-2 dependent manner CD4+CD25+FOXP3+ regulatory T cells (Tregs) constitute a heterogeneous lymphocyte subpopulation essential for establishing peripheral immune tolerance. Interleukin-2 (IL-2) plays a critical role in maintaining immune homeostasis promoting optimal development, survival and function of Tregs. Because of their suppressive properties, manipulation of Tregs represents a clear target to modulate immune responses in transplantation and autoimmunity. However, the specific effects of adjunctive immunosuppressive drugs to the maintenance and function of the different Treg subsets remain unclear. Calcineurin inhibitors (CNIs), which are the mainstay immunosuppressants in transplantation, are the most effective agents in controlling alloreactive effector T cells, but also hamper Treg activity. In this study we sought to investigate the differential effects of CNIs on the homeostasis of Treg subsets, and the extent to which these effects are dependent on the overall availability of IL-2. Overall design: 30 total samples were analyzed and classified in 8 different groups (at least 3 replicates per group): Treg and Teff from mouse treated with PBS (CN), tacrolimus (TAC), IL2 and combination of tacrolimus and IL-2 (TAC+IL-2). Treg specific signature was identified by comparing Tref-CN vs Teff-CN. The genes were ranked based on FDR and the TOP50 were selected as Treg-related genes. To assess the transcriptional effect of tacrolimus and IL-2 to Tregs, the gene expression of the different Treg isolated from the treated mice were compared to Teff-CN or Treg-CN.

INSTRUMENT(S): [MoGene-2_1-st] Affymetrix Mouse Gene 2.1 ST Array [CDF: mogene21st_Mm_ENTREZG_18.0.0]


PROVIDER: GSE80814 | GEO | 2017-05-24



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

Whitehouse Gavin G   Gray Elizabeth E   Mastoridis Sotiris S   Merritt Elliot E   Kodela Elisavet E   Yang Jennie H M JHM   Danger Richard R   Mairal Marta M   Christakoudi Sofia S   Lozano Juan J JJ   Macdougall Iain C IC   Tree Timothy I M TIM   Sanchez-Fueyo Alberto A   Martinez-Llordella Marc M  

Proceedings of the National Academy of Sciences of the United States of America 20170605 27

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 immunoregulat  ...[more]

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