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Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency

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机构： [1]Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia [2]Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia [3]School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia [4]Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia [5]Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China [6]Olivia Newton-John Cancer Research Institute, LaTrobe University School of Cancer Medicine, Heidelberg, VIC, Australia [7]Department of Pathology, Stanford University, Stanford, CA, USA [8]Program in Immunology, Stanford University, Stanford, CA, USA [9]Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany [10]Institute for Molecular Physiology and Biotechnology of Plants, University of Bonn, Bonn, Germany [11]Australian BioResources Pty Ltd, Moss Vale, NSW, Australia [12]Animal Services, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia [13]Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA [14]Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA [15]Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA [16]Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA [17]Precision Immunology Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia [18]St Vincent’s Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia

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Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that whereas skin TRM cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive TRM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal TRM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated TRM cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.Copyright © 2024 Elsevier Inc. All rights reserved.

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第一作者机构： [1]Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia

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