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

Andreas Obers¹, Tobias Poch¹, Grace Rodrigues², Susan N Christo¹, Luke C Gandolfo³, Raissa Fonseca¹, Ali Zaid¹, Joey En Yu Kuai¹, Hongjin Lai⁴, Pirooz Zareie¹, Marina H Yakou⁵, Lachlan Dryburgh¹, Thomas N Burn¹, James Dosser¹, Frank A Buquicchio⁶, Caleb A Lareau⁶, Calum Walsh¹, Louise Judd¹, Maria Rafailia Theodorou⁷, Katharina Gutbrod⁸, Peter Dörmann⁸, Jenny Kingham⁹, Tim Stinear¹, Axel Kallies¹, Jan Schroeder¹, Scott N Mueller¹, Simone L Park¹⁰, Terence P Speed¹¹, Ansuman T Satpathy¹², Tri Giang Phan¹³, Christoph Wilhelm⁷, Colby Zaph², Maximilien Evrard¹⁴, Laura K Mackay¹⁵

Affiliations

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 Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia; Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia.
⁴ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China.
⁵ Olivia Newton-John Cancer Research Institute, LaTrobe University School of Cancer Medicine, Heidelberg, VIC, Australia.
⁶ Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA.
⁷ Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
⁸ Institute for Molecular Physiology and Biotechnology of Plants, University of Bonn, Bonn, Germany.
⁹ Australian BioResources Pty Ltd, Moss Vale, NSW, Australia; Animal Services, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia.
¹⁰ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia; Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia.
¹² Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
¹³ Precision Immunology Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; St Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁴ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. Electronic address: maximilien.evrard@unimelb.edu.au.
¹⁵ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. Electronic address: lkmackay@unimelb.edu.au.

PMID: 39406245
DOI: 10.1016/j.immuni.2024.09.015

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

Andreas Obers et al. Immunity. 2024.

. 2024 Nov 12;57(11):2615-2633.e10.

doi: 10.1016/j.immuni.2024.09.015. Epub 2024 Oct 14.

Authors

Affiliations

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 Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia; Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia.
⁴ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China.
⁵ Olivia Newton-John Cancer Research Institute, LaTrobe University School of Cancer Medicine, Heidelberg, VIC, Australia.
⁶ Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA.
⁷ Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
⁸ Institute for Molecular Physiology and Biotechnology of Plants, University of Bonn, Bonn, Germany.
⁹ Australian BioResources Pty Ltd, Moss Vale, NSW, Australia; Animal Services, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia.
¹⁰ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia; Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia.
¹² Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
¹³ Precision Immunology Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; St Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁴ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. Electronic address: maximilien.evrard@unimelb.edu.au.
¹⁵ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. Electronic address: lkmackay@unimelb.edu.au.

PMID: 39406245
DOI: 10.1016/j.immuni.2024.09.015

Abstract

Tissue-resident memory T (T_RM) 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 T_RM cell fate remains poorly understood. Here, we show that whereas skin T_RM 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 T_RM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal T_RM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated T_RM 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.

Keywords: CD8(+) T cells; IEL; T cell memory; TRM cells; dirty mice; mucosal immunity; retinoic acid; tissue-resident memory T cells; transforming growth factor beta.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Comment in

Home at last: Mixed signals guide memory T cells to residency.
Liimatta K, Zúñiga EI. Liimatta K, et al. Immunity. 2024 Nov 12;57(11):2486-2488. doi: 10.1016/j.immuni.2024.10.008. Immunity. 2024. PMID: 39536712

References

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

HHMI/Howard Hughes Medical Institute/United States

LinkOut - more resources

Full Text Sources
- Elsevier Science

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources