Abstract
Pathogenic CD4+ memory T cells (Tm) sustain chronic inflammation, but mechanisms remain undefined. Here, we identify four donor-type CD4+ Tm subsets in the target tissues of autoimmune-like chronic graft-versus-host disease in mice: Ly108+CD69− stem-like memory T cells (Tsm), Ly108+CD69+ resident memory progenitor T cells (Trmp), Ly108−CD69+ terminally differentiated tissue-resident T cells (Trm), and Ly108−CD69− intermediate T cells (Tint). Trm are terminally differentiated but not exhausted and show highly biased clonotypes with high proinflammatory cytokine expression. Tsm cells require TCR-MHCII interactions for their maintenance and expansion and show greater capacity than Trmp cells in self-renewal/expansion, generation of Trm, and pathogenicity in adoptive recipients. The transcription factors TCF1/BCL6 and BHLHE40 differentially regulate the stemness and differentiation of Tsm into Trm, respectively, and their selective targeting reduces the number of Trm in tissues and ameliorates inflammation. Thus, our findings indicate that targeting the Tsm subset, involved in the maintenance of the pathogenic Tm pool, offers an attractive approach to treat T cell-mediated chronic inflammation.
Data availability
The bulk RNA-sequencing, ATAC-sequencing and single cell RNA-TCR-seq data have been deposited and publicly available under accession codes GSE263810, GSE263811, GSE263812, GSE263813. All data are included in the Supplementary Information or available from the authors, as are unique reagents used in this Article. The raw numbers for charts and graphs are available in the Source Data file whenever possible. Source data are provided with this paper.
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Acknowledgements
This work was supported by NIH 1R01HL170099 and R01HL162847 and Excellence Award of The Beckman Research Institute (to D. Zeng), and institutional NCI P30CA033572. Graduate Academic Exchange Scholarship of Fujian Medical University and Riggs-Union International Exchange Scholarship of Fujian Medical University Union Hospital partially supported B. Wang’s living stipend. We thank Lucy Brown and her staff at the COH Flow Cytometry Facility; Raju Pillai, Aimin Li and staff at COH Pathology-Solid Tumor Core; Brian Armstrong and his staff at COH Light Microscopy Core; and Dr. Richard Ermel and his staff at COH Animal Research Center for providing excellent service. We also thank Dr. Cecelia Yeung and David Woolston at the Fred Hutchinson Cancer Center for assistance in providing sections of liver biopsies from patients with chronic GVHD.
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XK designed and performed experiments, acquired and analyzed data, prepared manuscript and wrote the draft manuscript. BW designed and performed experiments, acquired and analyzed data. XW and HQ performed scRNA/scTCR-sequencing, bulk-cell RNA-seq/ATAC-seq, and XW, HC, XK performed data analysis. WF, QL, RZ, MZ, UN and AW assisted in experiments. JL, TO provided Hobit−/− mice. RN, RP provided advice on human-related studies, organized human samples, and reviewed the manuscript. PJM provided advice on experimental design and critical review and editing of the manuscript. YC is BW’s PhD advisor. DZ designed and supervised the research and wrote the manuscript.
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Kong, X., Wang, B., Wu, X. et al. Stem-like memory-T maintenance and differentiation into tissue-resident T cells sustain chronic graft-versus-host disease in mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69975-z
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DOI: https://doi.org/10.1038/s41467-026-69975-z
