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

Nat Immunol. 2021 Sep;22(9):1140-1151. doi: 10.1038/s41590-021-01004-1. Epub 2021 Aug 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology*
  • Cell Plasticity / immunology*
  • Cellular Microenvironment / immunology*
  • Female
  • Immunologic Memory / immunology*
  • Integrin alpha Chains / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction / immunology
  • Transforming Growth Factor beta1 / metabolism


  • Antigens, CD
  • Integrin alpha Chains
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • alpha E integrins