Spatiotemporal single-cell profiling reveals T cell clonal dynamics and phenotypic plasticity in human graft-versus-host disease.

Authors

Lingting Shi, Ajna Uzuni, Ximi K Wang, Michael Pressler, David W Harle, Shami Chakrabarti, Rodney Macedo, Kirubel Belay, Christian A Gordillo, Thomas McMahon-Skates, Erik Raps, Jia Yi Ady Zhang, Achille Nazaret, Joy L Fan, Yinuo Jin, Xumin Shen, Joshua S Fuller, Tamjeed Azad, Jessie Huang, Pranik Chainani, Jose Pomarino Nima, Julian A Abrams, Armando Del Portillo, Markus Y Mapara, Mohamed Alhamar, Megan Sykes, José L McFaline-Figueroa, Elham Azizi, Ran Reshef

Published in

Nature immunology. Sep 17, 2026. Epub Sep 17, 2026.

Abstract

Allogeneic hematopoietic cell transplantation cures hematologic diseases but is limited by acute graft‑versus‑host disease. How human T cell clones drive epithelial injury remains poorly mapped. We studied 31 transplant recipients, integrating longitudinal T cell antigen receptor (TCR) profiling with single-cell RNA sequencing/TCR sequencing and spatial transcriptomics to track T cell clonal dynamics. We developed DecompTCR to resolve temporal dynamics and adapted computational tools to map clone phenotypes and niches in tissue. Our analyses revealed that cyclophosphamide selectively depletes alloreactive clones, although insufficient early expansion leads to incomplete depletion and severe disease. Severe graft‑versus‑host disease is marked by persistent expansion of alloreactive clones, rewiring of homeostatic cell types and diversification of donor-derived CD8⁺ clonotypes that acquire Hobit (ZNF683)⁺ tissue‑resident memory T (T_RM) cell programs during migration to epithelium. Spatial deconvolution identified CD8⁺ effector/Hobit⁺ T_RM hubs near intestinal stem‑cell-rich crypt bases and crypt‑loss regions. This clonotype‑resolved framework links tissue‑instructed T_RM cell remodeling to localized epithelial injury, nominating early-repertoire dynamics and spatial hub burden as biomarkers.

PMID:
42754741
Bibliographic data and abstract were imported from PubMed on 18 Sep 2026.

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