PREreviews of “Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8+ T cells underlies distinct functional potential”

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Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8⁺ T cells underlies distinct functional potential

by Simone L. Park, Mark M. Painter, Sasikanth Manne, Victor Alcalde, Maura McLaughlin, Matthew A. Sullivan, Divij Mathew, Leonel Torres, Yinghui J. Huang, David B. Reeg, Naomi R. Douek, Trenton Campos, Max Klapholz, Maria A. Cardenas, Victoria Fang, Shin Foong Ngiow, KC Wumesh, Rishi R. Goel, Amy E. Baxter, Jennifer E. Wu, Melody Tan, Corbett T. Berry, Christoph T. Ellebrecht, Alexander C. Huang, Emily Papazian, Ying Liu, Karthik Rajasekaran, Robert M. Brody, Erica R. Thaler, Devraj Basu, Ahmed Diab, Josephine R. Giles, and E. John Wherry

Posted: August 11, 2025
Server: bioRxiv
DOI: 10.1101/2025.08.08.669213

Abstract

Persistent antigen stimulation promotes differentiation of exhausted CD8⁺ T (T_EX) cells. T_EX cells are distinct from circulating memory T (T_CIRCM) cells but share many features with tissue-resident memory (T_RM) cells established following infection resolution. CD8⁺ T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional T_RM or T_EX cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident T_EX (TR-T_EX) cells that are ontologically and functionally distinct from T_RM cells generated after antigen clearance. TR-T_EX phenotypically resembled T_RM cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although T_EX progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional T_RM cells after antigen withdrawal. Conversely, T_RM cells were able to differentiate into T_EX cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-T_EX cells with patient responses to immune checkpoint blockade, and only TR-T_EX but not T_RM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T_EX and T_RM cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.

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PREreview by Cori Fain et al.

Authored by Cori Fain and John Harty

Manuscript title: Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8+ T cells underlies distinct functional potential
Summary: This manuscript presents an ambitious and comprehensive dissection of CD8+ tissue-resident memory (TRM) and tissue-resident exhausted (TR-TEX)…

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PREreviews of Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8+ T cells underlies distinct functional potential

1 PREreview

PREreviews of Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8⁺ T cells underlies distinct functional potential