Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted

Miguel Reina-Campos, Alexander Monell, Amir Ferry, Vida Luna, Kitty P. Cheung, Giovanni Galletti, Nicole E. Scharping, Kennidy K. Takehara, Sara Quon, Peter P. Challita, Brigid Boland, Yun Hsuan Lin, William H. Wong, Cynthia S. Indralingam, Hayley Neadeau, Suzie Alarcón, Gene W. Yeo, John T. Chang, Maximilian Heeg () and Ananda W. Goldrath ()
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Miguel Reina-Campos: University of California, San Diego
Alexander Monell: University of California, San Diego
Amir Ferry: University of California, San Diego
Vida Luna: University of California, San Diego
Kitty P. Cheung: University of California, San Diego
Giovanni Galletti: University of California, San Diego
Nicole E. Scharping: University of California, San Diego
Kennidy K. Takehara: University of California, San Diego
Sara Quon: University of California, San Diego
Peter P. Challita: University of California, San Diego
Brigid Boland: University of California, San Diego
Yun Hsuan Lin: University of California, San Diego
William H. Wong: University of California, San Diego
Cynthia S. Indralingam: University of California, San Diego
Hayley Neadeau: La Jolla Institute for Immunology
Suzie Alarcón: La Jolla Institute for Immunology
Gene W. Yeo: University of California, San Diego
John T. Chang: University of California, San Diego
Maximilian Heeg: University of California, San Diego
Ananda W. Goldrath: University of California, San Diego

Nature, 2025, vol. 639, issue 8054, 483-492

Abstract: Abstract Tissue-resident memory CD8 T (TRM) cells provide protection from infection at barrier sites. In the small intestine, TRM cells are found in at least two distinct subpopulations: one with higher expression of effector molecules and another with greater memory potential1. However, the origins of this diversity remain unknown. Here we proposed that distinct tissue niches drive the phenotypic heterogeneity of TRM cells. To test this, we leveraged spatial transcriptomics of human samples, a mouse model of acute systemic viral infection and a newly established strategy for pooled optically encoded gene perturbations to profile the locations, interactions and transcriptomes of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. Our study reveals that the regionalized signalling of the intestinal architecture supports two distinct TRM cell states: differentiated TRM cells and progenitor-like TRM cells, located in the upper villus and lower villus, respectively. This diversity is mediated by distinct ligand–receptor activities, cytokine gradients and specialized cellular contacts. Blocking TGFβ or CXCL9 and CXCL10 sensing by antigen-specific CD8 T cells revealed a model consistent with anatomically delineated, early fate specification. Ultimately, our framework for the study of tissue immune networks reveals that T cell location and functional state are fundamentally intertwined.

Date: 2025
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DOI: 10.1038/s41586-024-08466-x

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