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Low-dose IL-2 selectively activates subsets of CD4⁺ Tregs and NK cells.

ABSTRACT: CD4⁺ regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios⁺ CD4Tregs and CD56^brightCD16^- NK cells in vitro. Preferential activation and expansion of Helios⁺ CD4Tregs and CD56^brightCD16^- NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios^- CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4⁺ T cells and CD8⁺ T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios⁺ CD4Tregs and CD56^bright NK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo.

SUBMITTER: Hirakawa M

PROVIDER: S-EPMC5085610 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Low-dose IL-2 selectively activates subsets of CD4<sup>+</sup> Tregs and NK cells.

Hirakawa Masahiro M Matos Tiago R TR Liu Hongye H Koreth John J Kim Haesook T HT Paul Nicole E NE Murase Kazuyuki K Whangbo Jennifer J Alho Ana C AC Nikiforow Sarah S Cutler Corey C Ho Vincent T VT Armand Philippe P Alyea Edwin P EP Antin Joseph H JH Blazar Bruce R BR Lacerda Joao F JF Soiffer Robert J RJ Ritz Jerome J

JCI insight 20161103 18

CD4<sup>+</sup> regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of l ...[more]

PMID: 27812545

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Project description:Cytokines are major players regulating immune responses toward inflammatory and tolerogenic results. In organ and bone marrow transplantation, new reagents are needed to inhibit tissue destructive mechanisms and eventually induce immune tolerance without overall immunosuppression. IL-34 is a cytokine with no significant homology with any other cytokine but that acts preferentially through CSF-1R, as CSF-1 does, and through PTPζ and CD138. Although IL-34 and CSF-1 share actions, a detailed analysis of their effects on immune cells needs further research. We previously showed that both CD4+ and CD8+ FOXP3+ Tregs suppress effector T cells through the production of IL-34, but not CSF-1, and that this action was mediated through antigen-presenting cells. We showed here by single-cell RNAseq and cytofluorimetry that different subsets of human monocytes expressed different levels of CSF-1R, CD138, and PTPζ and that both CD4+ and CD8+ FOXP3+ Tregs expressed higher levels of CSF-1R than conventional T cells. The effects of IL-34 differed in the survival of these different subpopulations of monocytes and RNAseq analysis showed several genes differentially expressed between IL-34, CSF-1, M0, M1, and also M2 macrophages. Acute graft-vs.-host disease (aGVHD) in immunodeficient NSG mice injected with human PBMCs was decreased when treated with IL-34 in combination with an anti-CD45RC mAb that depleted conventional T cells. When IL-34-differentiated monocytes were used to expand Tregs in vitro, both CD4+ and CD8+ FOXP3+ Tregs were highly enriched and this effect was superior to the one obtained with CSF-1. Human CD8+ Tregs expanded in vitro with IL-34-differentiated allogeneic monocytes suppressed human immune responses in an NSG mouse aGVHD model humanized with hPBMCs. Overall, we showed that IL-34 induced the differentiation of human monocytes with a particular transcriptional profile and these cells favored the development of potent suppressor FOXP3+ Tregs.

Dataset Information

Low-dose IL-2 selectively activates subsets of CD4⁺ Tregs and NK cells.

Publications

Low-dose IL-2 selectively activates subsets of CD4<sup>+</sup> Tregs and NK cells.

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Dataset Information

Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells.

Publications

Low-dose IL-2 selectively activates subsets of CD4<sup>+</sup> Tregs and NK cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Low-dose IL-2 selectively activates subsets of CD4⁺ Tregs and NK cells.