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Project description:While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.
| S-EPMC8900676 | biostudies-literature
Project description:Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity
| PRJNA778252 | ENA
Project description:While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies in both humans and mice have implicated their roles in the development of extra-intestinal autoimmune diseases such as multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combining fate mapping with single-cell RNA sequencing to profile the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready-reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFNγ+ CXCR6+ T cells. Our study defines a direct relationship in vivo between IL-17+ non-pathogenic and GM-CSF+ and IFNγ+ pathogenic Th17 populations and provides, for the first time, a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.
2021-11-05 | GSE188320 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-06-13 | GSE234594 | GEO
Project description:Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (TRM) cells. However, the cellular origin of CD4 TRM cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 TRM cells derive from IL-17A-producing effector (TH17) cells following immunization with heat-killed Klebsiella pneumonia (Kp). These exTH17 TRM cells are maintained in the lung by IL-7, produced by lymphatic endothelial cells. During a memory response, neither antibodies, ?? T cells, nor circulatory T cells are sufficient for the rapid host defense required to eliminate Kp. Conversely, using parabiosis and depletion studies, we demonstrated that exTH17 TRM cells play an important role in bacterial clearance. Thus, we delineate the origin and function of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design.
| S-EPMC7057720 | biostudies-literature
Project description:Th17 cells are a heterogeneous population that is critical for tissue homeostasis and inflammation during clearance of infections and autoimmunity. Despite substantial efforts distinguishing homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells is poorly understood. In this study, we show that the inflammatory Th17 engaged in autoimmune colitis and those involved in infection-induced colitis are two distinguishable populations illustrated by their distinct responses to a pharmacological molecule, clofazimine (CLF). Distinct from existing Th17 inhibitors, CLF selectively inhibits pro-autoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells through restricting Aldh1l2expression. Using bulk RNA sequencing, we explored transcriptional response to CLF on in vitro differentiated inflammatory and homeostatic Th17 cells. Notably, we identified a unique suppression in the transcription of signature inflammatory genes in Th17 cells with a marginal effect on those elicited by infection.
2023-06-13 | GSE234593 | GEO
Project description:Repair of bone fracture requires recruitment and proliferation of stem cells with the capacity to differentiate to functional osteoblasts. Given the close association of bone and bone marrow (BM), it has been suggested that BM may serve as a source of these progenitors. To test the ability of hematopoietic stem cells (HSCs) to give rise to osteo-chondrogenic cells, we used a single HSC transplantation paradigm in uninjured bone and in conjunction with a tibial fracture model. Mice were lethally irradiated and transplanted with a clonal population of cells derived from a single enhanced green fluorescent protein positive (eGFP+) HSC. Analysis of paraffin sections from these animals showed the presence of eGFP+ osteocytes and hypertrophic chondrocytes. To determine the contribution of HSC-derived cells to fracture repair, non-stabilized tibial fracture was created. Paraffin sections were examined at 7 days, 2 weeks and 2 months after fracture and eGFP+ hypertrophic chondrocytes, osteoblasts and osteocytes were identified at the callus site. These cells stained positive for Runx-2 or osteocalcin and also stained for eGFP demonstrating their origin from the HSC. Together, these findings strongly support the concept that HSCs generate bone cells and suggest therapeutic potentials of HSCs in fracture repair.
| S-EPMC3521579 | biostudies-literature
Project description:Th17 cells are a heterogeneous population that is critical for tissue homeostasis and inflammation during clearance of infections and autoimmunity. Despite substantial efforts distinguishing homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells is poorly understood. In this study, we show that the inflammatory Th17 engaged in autoimmune colitis and those involved in infection-induced colitis are two distinguishable populations illustrated by their distinct responses to a pharmacological molecule, clofazimine (CLF). Distinct from existing Th17 inhibitors, CLF selectively inhibits pro-autoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells through restricting Aldh1l2expression. Using single-cell RNA sequencing, we explored inflammatory Th17 transcriptional response to CLF from the colonic tissue of mice during autoimmune colitis and Citrobacter rodentiuminfection using Rorc gfp/+ reportor mice. Notably, we identified a unique suppression in the transcription of signature inflammatory genes in Th17 cells from autoimmune colitis with a marginal effect on those elicited by infection. Additionally, we illustrate with these data that the transcriptionally programming of pro-autoimmune Th17 cells are, indeed, unique compared to infection-elicited Th17 cells. Finally, we analyzed the impact of CLF on human inflammatory Th17 cells from the inflammed colon of a patient with IBD.
2023-06-13 | GSE234592 | GEO
Project description:Single-cell clonotype tracing identifies a stem-like intestinal Th17 population that gives rise to pathogenic effector T cells during autoimmunity
| PRJNA778255 | ENA
Project description:Autoimmunity and infection give rise to distict inflammatory Th17 subsets
| PRJNA982096 | ENA