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

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 (T_EXEF) 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 T_EXEF 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 T_EXEF cells as key contributors to oral cGVHD pathology and potential therapeutic targets for mitigating sustained tissue injury in cGVHD.