Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity

Susan N Christo1, Maximilien Evrard1, Simone L Park1, Luke C Gandolfo1,2,3, Thomas N Burn1, Raissa Fonseca1, Dane M Newman1, Yannick O Alexandre1, Nicholas Collins1, Natasha M Zamudio1, Fernando Souza-Fonseca-Guimaraes4, Daniel G Pellicci1,5, David Chisanga3, Wei Shi3, Laurent Bartholin6, Gabrielle T Belz3,4, Nicholas D Huntington7, Andrew Lucas8, Michaela Lucas8, Scott N Mueller1, William R Heath1, Florent Ginhoux9, Terence P Speed2,3, Francis R Carbone1, Axel Kallies1,3, Laura K Mackay10

  1. Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
  2. School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia.
  3. Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia.
  4. Translational Research Institute, Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia.
  5. Cellular Immunology Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
  6. Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Lyon, France.
  7. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.
  8. Medical School, University of Western Australia, Perth, Western Australia, Australia.
  9. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.
  10. Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. lkmackay@unimelb.edu.au.

Abstract

Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFβ is a major driver of this diversity. Notably, dampened TGFβ signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFβ-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.

Presented By Susan N Christo | ORCID iD

Immunology & MicrobiologyNicholas Liao2021-09 (Sep)