Deep profiling deconstructs features associated with memory CD8+ T cell tissue residence

Milcah C Scott; Zoë Steier; Mark J Pierson; J Michael Stolley; Stephen D O'Flanagan; Andrew G Soerens; Sathi P Wijeyesinghe; Lalit K Beura; Gayathri Dileepan; Brandon J Burbach; Marco Künzli; Clare F Quarnstrom; Olivia C Ghirardelli Smith; Eyob Weyu; Sara E Hamilton; Vaiva Vezys; Alex K Shalek; David Masopust

doi:10.1016/j.immuni.2024.11.007

Deep profiling deconstructs features associated with memory CD8⁺ T cell tissue residence

Immunity. 2024 Dec 3:S1074-7613(24)00522-3. doi: 10.1016/j.immuni.2024.11.007. Online ahead of print.

Authors

Milcah C Scott¹, Zoë Steier², Mark J Pierson³, J Michael Stolley¹, Stephen D O'Flanagan¹, Andrew G Soerens¹, Sathi P Wijeyesinghe¹, Lalit K Beura¹, Gayathri Dileepan¹, Brandon J Burbach¹, Marco Künzli¹, Clare F Quarnstrom¹, Olivia C Ghirardelli Smith¹, Eyob Weyu¹, Sara E Hamilton³, Vaiva Vezys¹, Alex K Shalek⁴, David Masopust⁵

Affiliations

¹ Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
² Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
³ Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
⁴ Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: [email protected].

PMID: 39708817
DOI: 10.1016/j.immuni.2024.11.007

Abstract

Tissue-resident memory CD8⁺ T (Trm) cells control infections and cancer and are defined by their lack of recirculation. Because migration is difficult to assess, residence is usually inferred by putative residence-defining phenotypic and gene signature proxies. We assessed the validity and universality of residence proxies by integrating mouse parabiosis, multi-organ sampling, intravascular staining, acute and chronic infection models, dirty mice, and single-cell multi-omics. We report that memory T cells integrate a constellation of inputs-location, stimulation history, antigen persistence, and environment-resulting in myriad differentiation states. Thus, current Trm-defining methodologies have implicit limitations, and a universal residence-specific signature may not exist. However, we define genes and phenotypes that more robustly correlate with tissue residence across the broad range of conditions that we tested. This study reveals broad adaptability of T cells to diverse stimulatory and environmental inputs and provides practical recommendations for evaluating Trm cells.

Keywords: CD69; CITE-seq; antigen persistence; cell markers; dirty mice; infection; memory CD8(+) T cells; migration; tissue-resident memory T cells.