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IL-23 drives differentiation of peripheral ??17 T cells from adult bone marrow-derived precursors.

ABSTRACT: Pro-inflammatory interleukin (IL)-17-producing ?? (??17) T cells are thought to develop exclusively in the thymus during fetal/perinatal life, as adult bone marrow precursors fail to generate ??17 T cells under homeostatic conditions. Here, we employ a model of experimental autoimmune encephalomyelitis (EAE) in which hematopoiesis is reset by bone marrow transplantation and demonstrate unequivocally that V?4⁺ ??17 T cells can develop de novo in draining lymph nodes in response to innate stimuli. In vitro, ?? T cells from IL-17 fate-mapping reporter mice that had never activated the Il17 locus acquire IL-17 expression upon stimulation with IL-1? and IL-23. Furthermore, IL-23R (but not IL-1R1) deficiency severely compromises the induction of ??17 T cells in EAE, demonstrating the key role of IL-23 in the process. Finally, we show, in a composite model involving transfers of both adult bone marrow and neonatal thymocytes, that induced ??17 T cells make up a substantial fraction of the total IL-17-producing V?4⁺ T-cell pool upon inflammation, which attests the relevance of this novel pathway of peripheral ??17 T-cell differentiation.

SUBMITTER: Papotto PH

PROVIDER: S-EPMC5666615 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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IL-23 drives differentiation of peripheral γδ17 T cells from adult bone marrow-derived precursors.

Papotto Pedro H PH Gonçalves-Sousa Natacha N Schmolka Nina N Iseppon Andrea A Mensurado Sofia S Stockinger Brigitta B Ribot Julie C JC Silva-Santos Bruno B

EMBO reports 20170830 11

Pro-inflammatory interleukin (IL)-17-producing γδ (γδ17) T cells are thought to develop exclusively in the thymus during fetal/perinatal life, as adult bone marrow precursors fail to generate γδ17 T cells under homeostatic conditions. Here, we employ a model of experimental autoimmune encephalomyelitis (EAE) in which hematopoiesis is reset by bone marrow transplantation and demonstrate unequivocally that Vγ4<sup>+</sup> γδ17 T cells can develop <i>de novo</i> in draining lymph nodes in response ...[more]

PMID: 28855306

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Project description:Myeloid-lymphatic endothelial cell progenitors (M-LECP) are a subset of bone marrow (BM)-derived cells characterized by expression of M2-type macrophage markers. We previously showed significant contribution of M-LECP to tumor lymphatic formation and metastasis in human clinical breast tumors and corresponding mouse models. Since M2 type is induced in macrophages by immunosuppressive Th2 cytokines IL-4, IL-13, and IL-10, we hypothesized that these factors might promote pro-lymphatic specification of M-LECP during their differentiation from BM myeloid precursors. To test this hypothesis, we analyzed expression of Th2 cytokines and their receptors in mouse BM cells under conditions leading to M-LECP differentiation, namely, CSF-1 treatment followed by activation of TLR4. We found that under these conditions, all three Th2 receptors were strongly upregulated in >95% of the cells that also secrete endogenous IL-10, but not IL-4 or IL-13 ligands. However, addition of any of the Th2 factors to CSF-1 primed cells significantly increased generation of myeloid-lymphatic progenitors as indicated by co-induction of lymphatic-specific (eg, Lyve-1, integrin-a9, collectin-12, and stabilin-1) and M2-type markers (eg, CD163, CD204, CD206, and PD-L1). Antibody-mediated blockade of either IL-10 receptor (IL-10R) or IL-10 ligand significantly reduced both immunosuppressive and lymphatic phenotypes. Moreover, tumor-recruited Lyve-1+ lymphatic progenitors in vivo expressed all Th2 receptors as well as corresponding ligands, including IL-4 and IL-13, which were absent in BM cells. This study presents original evidence for the significant role of Th2 cytokines in co-development of immunosuppressive and lymphatic phenotypes in tumor-recruited M2-type myeloid cells. Progenitor-mediated increase in lymphatic vessels can enhance immunosuppression by physical removal of stimulatory immune cells. Thus, targeting Th2 pathways might simultaneously relieve immunosuppression and inhibit differentiation of pro-lymphatic progenitors that ultimately promote tumor spread.

Dataset Information

IL-23 drives differentiation of peripheral ??17 T cells from adult bone marrow-derived precursors.

Publications

IL-23 drives differentiation of peripheral γδ17 T cells from adult bone marrow-derived precursors.

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