Oral Presentation 9th Australasian Vaccines & Immunotherapeutics Development Meeting 2022

Single-cell landscape of tissue-resident memory T cell development (#39)

Raissa Fonseca 1 , Frank Buquicchio 2 , Ansuman Satpathy 2 , Laura Mackay 1
  1. Peter Doherty Institute, Melbourne, VIC, Australia
  2. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Tissue-resident memory T (TRM) cells exist throughout the body where they are poised to mediate local immune responses against infections and cancer (1, 2). Although studies have defined a common mechanism of residency independent of location, there is likely to be a level of specialization that adapts TRM cells to a given tissue. To identify pathways involved in TRM generation that could be modulated to improve novel vaccines, we explored changes occurring in chromatin accessibility during TRM cell formation in different tissues. Analyses of scATAC-seq profiles from LCMV- and HSV-specific CD8+ T cells identify changes in gene accessibility of liver and skin TRM cells and reveal both exclusive and common chromatin regulators involved in the residency program. UMAP analysis of peak accessibility display clustering of cells in a time-sensitive and tissue-specific fashion, indicating heterogeneity of effector cells and TRM populations across organs and at different times post infection. Reconstruction of cellular developmental trajectories display a common pathway for circulating memory T cells found in the liver and the spleen with late divergence involved in the formation of effector and central memory T cells. Contrarily, liver TRM cells display a unique trajectory indicating the most epigenetic disparity when compared to the other memory subsets. Further, by integrating deviations in motifs and gene activity scores, we identified transcription factors critical for skin and liver TRM development in a tissue-specific manner. Finally, pathway analysis of liver and skin TRM cell exclusive motifs revealed cytokine-associated terms (2020 MSigDB), indicating an involvement of IFN signaling for liver and TGFb for skin TRM development. Critically, we are now identifying adjuvants that modulate the identified pathways to improve TRM formation in an organ-specific manner to promote peripheral immunity and enable improvement of current vaccine protocols.

  1. 1. Okla, K., Farber, D. L. & Zou, W. Tissue-resident memory T cells in tumor immunity and immunotherapy. J. Exp. Med. 218, 1–14 (2021).
  2. 2. Masopust, D. & Soerens, A. G. Tissue-Resident T Cells and Other Resident Leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).