Exhausted-like effector CD8 T cells mediate immune-stromal interactions at mucosal Chronic Graft-versus-Host Disease onset

Ana Caroline Costa-da-Silva; Rubina Sharma; Marit H Aure; Daniel Martin; Noemi Kedei; Damilola F Killanin; Ayesha Javaid; Francis A Boksa; Drashty P Mody; Joe T Nguyen; Sukirth M Ganesan; Joshua T Dodge; Clara H Kim; Marie Kao-Hsieh; David E Kleiner; Christopher G Kanakry; Steven Z Pavletic; Jacqueline W Mays

doi:10.1101/2025.09.11.675642

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Exhausted-like effector CD8 T cells mediate immune-stromal interactions at mucosal Chronic Graft-versus-Host Disease onset

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Exhausted-like effector CD8 T cells mediate immune-stromal interactions at mucosal Chronic Graft-versus-Host Disease onset

Ana Caroline Costa-da-Silva, Rubina Sharma, Marit H Aure, Daniel Martin, Noemi Kedei, Damilola F Killanin, Ayesha Javaid, Francis A Boksa, Drashty P Mody, Joe T Nguyen, …

bioRxiv

Cold Spring Harbor Laboratory

09/16/2025

DOI: 10.1101/2025.09.11.675642

PMCID: PMC12458946

PMID: 41000699

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https://doi.org/10.1101/2025.09.11.675642View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Chronic graft-versus-host disease (cGVHD) frequently follows allogeneic hematopoietic stem cell transplantation and impacts the mucosa. This atlas study highlights the role of exhausted-like effector CD8+ T cells (TEXEF) in oral mucosal cGVHD pathogenesis. Biopsies from the oral mucosa were collected at oral cGVHD onset or at six months post-transplant and analyzed using single-cell RNA sequencing and other modalities. At cGVHD onset, in addition to changes in the myeloid compartment, two distinct populations of CD8+T cells with a TEXEF phenotype were prevalent: an inflammatory CD8T cell cluster (CD8T_4) expressing CCL4, CD69, and TNFSF9, and an exhausted CD8T cell cluster (CD8T_5) characterized by the expression of CXCL13, HIF1A, and HLA-DRA, both correlated with clinical disease severity. Pseudo-time analysis suggests a transition from the inflammatory pre-exhausted CD8T_4 cluster to the cytolytic, terminally exhausted CD8T_5 cluster. The CXCL9-CXCR3 interactions among CD8+ T cells, fibroblasts and myeloid cells are implicated in tissue damage. Onset of cGVHD despite frequent oral mucosal FOXP3⁺ regulatory CD4⁺T cells suggests potential impaired Treg function or CD8+T cell dysfunction. These findings highlight TEXEF cells as key contributors to oral cGVHD pathology and potential therapeutic targets for mitigating sustained tissue injury in cGVHD.

Details

Title: Subtitle: Exhausted-like effector CD8 T cells mediate immune-stromal interactions at mucosal Chronic Graft-versus-Host Disease onset
Creators: Ana Caroline Costa-da-Silva - National Institute of Dental and Craniofacial Research
Rubina Sharma - National Institute of Dental and Craniofacial Research
Marit H Aure - National Institute of Dental and Craniofacial Research
Daniel Martin
Noemi Kedei - Office of the Director
Damilola F Killanin - National Institute of Dental and Craniofacial Research
Ayesha Javaid - National Institute of Dental and Craniofacial Research
Francis A Boksa - National Institute of Dental and Craniofacial Research
Drashty P Mody - National Institute of Dental and Craniofacial Research
Joe T Nguyen - National Institute of Dental and Craniofacial Research
Sukirth M Ganesan - National Institute of Dental and Craniofacial Research
Joshua T Dodge - National Institute of Dental and Craniofacial Research
Clara H Kim - National Institute of Dental and Craniofacial Research
Marie Kao-Hsieh - National Institute of Dental and Craniofacial Research
David E Kleiner - National Cancer Institute
Christopher G Kanakry - National Cancer Institute
Steven Z Pavletic - National Institutes of Health
Jacqueline W Mays - National Institute of Dental and Craniofacial Research
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2025.09.11.675642
PMID: 41000699
PMCID: PMC12458946
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory; United States
Language: English
Date posted: 09/16/2025
Academic Unit: Periodontics
Record Identifier: 9984966341202771

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