Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Discrete tissue microenvironments instruct diversity in resident memory T cell functionality (#79)

Susan N Christo 1 , Maximilien Evrard 1 , Simone L Park 1 , Luke C Gandolfo 1 2 3 , Thomas N Burn 1 , Raissa Fonseca 1 , Dane M Newman 1 , Yannick O Alexandre 1 , Nicholas Collins 1 , Natasha M Zamudio 1 , Scott N Mueller 1 , William R Heath 1 , Florent Ginhoux 4 , Terrence P Speed 2 3 , Francis R Carbone 1 , Axel Kallies 1 , Laura K Mackay 1
  1. Department of Microbiology and Immunology , The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  2. School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia
  3. Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
  4. Singapore Immunology Group (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore

Tissue-resident memory T cells (TRM) are non-recirculating cells that exist throughout the body and mediate local protection, therefore harnessing TRM functionality is an advantageous strategy for bolstering durable immunity. However, the influence of local microenvironmental imprinting on TRM functionality and fate in remains incomplete. Here, we chart phenotypic and transcriptional TRM heterogeneity between sites and find that the different environments in which these cells differentiate dictate TRM function, durability and malleability. Using organ transplantation and TRM transfer experiments, we uncover TGF-β as the major driver of functional heterogeneity between TRM in epithelial and non-epithelial tissues. We found that the absence of TGF-β signaling engendered CD103- TRM with increased proliferative potential, enhanced function, and trans-differentiation capacity compared to their TGF-β-responsive CD103+ TRM counterparts. Thus, despite common requirements for TRM development, tissue adaptation of these cells confers discrete functional properties that affect TRM-mediated secondary immune responses. Therefore, exploiting these mechanisms will inform new immunotherapy strategies to bolster site-specific TRM-mediated immunity.   

  1. Christo, S.N., Evrard, M., Park, S.L. et al. Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity. Nat Immunol 22, 1140–1151 (2021). https://doi.org/10.1038/s41590-021-01004-1