3 research outputs found
A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice
Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu
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Immune microniches shape intestinal Treg function.
Acknowledgements: The authors thank the Kennedy Institute of Rheumatology (KIR) Flow Cytometry Facility and the manager, J. Webber, for help with flow cytometry and FACS; the KIR Biomedical Services Unit, especially L. Barker for help with animal care and husbandry; the KIR microscopy facility and manager C. Lagerholm; I. Parisi, B. Stott and R. Cook for tissue processing and staining; A. Lee and M. Attar (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of sequencing data; S. van Dongen and P. V. Mazin and the Teichmann laboratory for discussion and support with scripts. We acknowledge the generous support of the Kennedy Trust for Rheumatology Research, IDRM and Carl Zeiss GMBH for the microscopy facilities (Zeiss 980) used in this research. We acknowledge the generous support of the Kennedy Trust for Rheumatology Research and a Wellcome Trust Multi-User Equipment Grant 202911/Z/16/Z for the microscope purchase (Zeiss 880 multiphoton) and facilities used in this research. Experimental design and summary diagrams were created with BioRender.com. Y.G. was funded by a Wellcome Trust Clinical Research Fellowship (CRTF), grant reference 201224/Z/16/Z. RB-C Grant 315307, Forskerprosjekt 2020, Researcher Project/International Mobility Grant from the Research Council of Norway and travel grant from the Per Brandtzæg’s Fund for Research in Mucosal Immunology. E.E.T. was supported by Wellcome Trust (095688/Z/11/Z and 212240/Z/18/Z, awarded to F.P.), Nuffield Department of Medicine, and MRC core grant reference MC_UU_00008. F.P. was supported by Wellcome Trust (095688/Z/11/Z and 212240/Z/18/Z). This research was funded in whole, or in part, by the Wellcome Trust 212240/Z/18/Z. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (Treg) cell development and function have been identified3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive Treg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector Treg (eTreg) cell function. eTreg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103+SIRPα+ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206+ macrophages and eTreg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies