Dataset Information

Interleukin-17-Producing ?? T Cells Originate from SOX13+ Progenitors that Are Independent of ??TCR Signaling.

ABSTRACT: Lineage-committed ?? and ?? T cells are thought to originate from common intrathymic multipotent progenitors following instructive T cell receptor (TCR) signals. A subset of lymph node and mucosal V?2+ ?? T cells is programmed intrathymically to produce IL-17 (T??17 cells), however the role of the ??TCR in development of these cells remains controversial. Here we generated reporter mice for the T??17 lineage-defining transcription factor SOX13 and identified fetal-origin, intrathymic Sox13+ progenitors. In organ culture developmental assays, T??17 cells derived primarily from Sox13+ progenitors, and not from other known lymphoid progenitors. Single cell transcriptome assays of the progenitors found in TCR-deficient mice demonstrated that T??17 lineage programming was independent of ??TCR. Instead, generation of the lineage committed progenitors and T??17 cells was controlled by TCF1 and SOX13. Thus, T lymphocyte lineage fate can be prewired cell-intrinsically and is not necessarily specified by clonal antigen receptor signals.

SUBMITTER: Spidale NA

PROVIDER: S-EPMC6249057 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Interleukin-17-Producing γδ T Cells Originate from SOX13<sup>+</sup> Progenitors that Are Independent of γδTCR Signaling.

Spidale Nicholas A NA Sylvia Katelyn K Narayan Kavitha K Miu Bing B Frascoli Michela M Melichar Heather J HJ Zhihao Wu W Kisielow Jan J Palin Amy A Serwold Thomas T Love Paul P Kobayashi Michihiro M Yoshimoto Momoko M Jain Nitya N Kang Joonsoo J

Immunity 20181106 5

Lineage-committed αβ and γδ T cells are thought to originate from common intrathymic multipotent progenitors following instructive T cell receptor (TCR) signals. A subset of lymph node and mucosal Vγ2<sup>+</sup> γδ T cells is programmed intrathymically to produce IL-17 (Tγδ17 cells), however the role of the γδTCR in development of these cells remains controversial. Here we generated reporter mice for the Tγδ17 lineage-defining transcription factor SOX13 and identified fetal-origin, intrathymic ...[more]

PMID: 30413363

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Project description:BackgroundIncreased frequency of CCR9+ CD4+ T cells in peripheral blood is linked to several gastrointestinal inflammatory diseases; however, its relationship with necrotizing enterocolitis (NEC) is not understood. We investigated whether the frequencies of CCR9+ CD4+ T cells and related subsets were increased in peripheral blood of both patients and mice with NEC.MethodsCCR9+ CD4+ T cells and related subsets were evaluated by flow cytometry in peripheral blood collected from both patients and mice with NEC and controls. The suppressive function of CCR9+ regulatory T (Treg) cells in NEC was assessed via in vitro suppression assay. An in vitro T cell polarization assay was performed to investigate the role of proinflammatory cytokines in Treg cell polarization. In vivo Treg cell polarization analysis was performed using NEC mice treated with anti-interleukin-6 (IL-6) receptor antibody.FindingsA higher proportion of CCR9+ CD4+ T cells occurred in peripheral blood of both patients and mice with NEC than in controls. Elevated CCR9+ CD4+ T cells were primarily CCR9+ IL-17-producing Treg cells, possessing features of conventional Treg cells, but their suppressive activity was seriously impaired and negatively correlated with the severity of intestinal tissue injury. IL-6 promoted polarization of CCR9+ Treg cells to CCR9+ IL-17-producing Treg cells, and blocking IL-6 signalling inhibited this conversion in vitro and ameliorated experimental NEC in vivo.InterpretationCollectively, these data suggested that CCR9+ IL-17-producing Treg cells may be a biomarker of severity and highlight the possibility that antibodies targeting IL-6R could ameliorate NEC by modulating lymphocyte balance. FUND: This work was supported by the Science and Technology Planning Project of Guangdong Province, China (2017A020215100), the Science and Technology Foundation of Guangzhou, China (201704020086 and 201604020154), the Medical Scientific Research Foundation of Guangdong Province, China (A2017304 and A2014704), and the Social Science and Technology Development Foundation of Dongguan, China (2016108101037).

Project description:Atherosclerosis is a chronic inflammatory disease. Interleukin-17-producing CD4+ T cells (Th17 cells) play important roles in the progression of atherosclerosis. However, most of the studies were focused on the advanced stage of atherosclerosis. In the current study, we investigated the roles of Th17 cells, relevant mechanisms in hyperlipidemic patients, and different stages of atherosclerotic mice. Human blood samples were collected, and percentages of Th17 cells, macrophages, and neutrophils were analyzed by flow cytometry. ApoE-/- mice were fed with high-fat diet (HFD) and sacrificed at different time points to evaluate the infiltration of inflammatory cells at different stages of atherosclerosis. Furthermore, essential mechanisms of IL-17A in atherosclerotic inflammatory milieu formation were studied in vivo by intraperitoneal injection with monoclonal anti-murine IL-17 antibody. Our study reveals the higher percentages of Th17 cells, monocytes, and neutrophils in hyperlipidemic patients compared to healthy donors. Meanwhile, we also identify an infiltration of Th17 cells in the early stage of atherosclerosis (4 weeks after HFD), which maintains at high level until late stage of atherosclerosis (20 weeks after HFD). What is more, inflammatory cells including macrophages and neutrophils were also accumulated in atherosclerotic lesions. Neutralization of IL-17 in ApoE-/- mice resulted in less infiltration of macrophages and neutrophils and smaller atherosclerotic lesions. Importantly, in accordance with what is found in the mouse model, positive correlations between Th17 cells and macrophages or neutrophils were observed in hyperlipidemic patients. In conclusion, our clinical and mouse model data together reveal a pro-atherogenic role of Th17 cells through the promotion of inflammation in hyperlipidemic conditions and different stages of atherosclerosis, which further supports the notion that IL-17 may be a therapy target for the treatment of atherosclerosis.

Dataset Information

Interleukin-17-Producing ?? T Cells Originate from SOX13+ Progenitors that Are Independent of ??TCR Signaling.

Publications

Interleukin-17-Producing γδ T Cells Originate from SOX13<sup>+</sup> Progenitors that Are Independent of γδTCR Signaling.

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