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

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; E. John Wherry

doi:10.1101/2025.08.08.669213

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

Simone L. Park, Mark M. Painter, Sasikanth Manne +30 more

August 2025

bioRxiv

DOI

10.1101/2025.08.08.669213

Reproducible

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This paper passed independent validation.

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It ranks in the top 1% of preprints assessed in Immunology this quarter.

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Why this is interesting

Resolving a long-standing conflation between exhausted and memory tissue-resident T cells, this paper establishes TR-TEX as a distinct Tox-dependent lineage and shows that only TR-TEX respond to checkpoint blockade, reframing which cells immunotherapy actually reinvigorates.

QED claims analysis

Summary

Chronic antigen stimulation drives development of tissue-resident exhausted CD8+ T (TR-TEX) cells that are ontologically and functionally distinct from tissue-resident memory (TRM) cells generated after antigen clearance, with TR-TEX cells uniquely dependent on Tox for residency programming, unable to form from committed TEX cells after antigen withdrawal, and selectively responsive to PD-1 pathway blockade, while TRM cells retain developmental plasticity to differentiate into TEX cells during chronic stimulation but do not respond to checkpoint inhibition.

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Main Claim 1 –

Chronic antigen generates TR-TEX distinct from post-clearance TRM

Supporting evidence

Arm TRM expand better than matched chronic tissue-resident cells
TRM can differentiate into TEX during chronic antigen stimulation
Committed TEX cannot generate TRM after antigen withdrawal
TR-TEX derive from TEX progenitors during chronic infection
TR-TEX require chronic antigen for maintenance; TRM are antigen-independent

Main Claim 2 –

TR-TEX resemble TRM phenotypically but use distinct transcriptional networks

Supporting evidence

TRM and TR-TEX share Blimp1/Runx3 and sometimes Hobit dependence

Main Claim 3 –

TR-TEX uniquely require Tox for tissue-residency programming

Main Claim 4 –

TR-TEX transcriptional signatures selectively predict checkpoint blockade responses

Supporting evidence

CD73 and CD200R distinguish TRM from TR-TEX in tissues
TRM and TR-TEX programs remain stable under bystander chronic inflammation
TRM versus TR-TEX signatures differentially associate with cancer survival

Abstract

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

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