Elevated exhausted effector tissue resident CD8+ T-cells in Chronic Graft versus Host Disease patient Oral mucosa unveiled by spatial transcriptomics and scRNA seq analysis

Abstract Chronic graft-versus-host disease (cGVHD), an autoimmune-like following allogeneic hematopoietic stem cell transplantation where T cells can attack host tissue. Oral mucosa (OM) is a most common cGVHD effector site in the oral cavity. We studied populations and tissue-specific signals that regulate their differentiation functionality. Patient OM biopsies from ongoing clinical trials (NCT03602599, NCT00331968) were taken at 6 months post-transplant. found enrichment of immune mainly CD8 T-cell cluster identified two unique patients: one characterized by expression proliferative markers other more prominent, exhaustion makers (TIM3, LAG3, TIGIT). The latter had low CD69 but expressed tissue residency; CD103, BLIMP1, PD1, FABP5. Interestingly, this population showed high BATF, IRF4, RUNX3, transcription factors induce sustained programming. These exhausted displayed higher molecules IFNG, GZMB, PRF1 inducing function. Ligand-receptor analysis revealed strong interactions between CXCL9-CXCR3 T-cells myeloid cells. Spatial transcriptomic confirmed infiltration submucosal region colocalizing with elevated exhaustion, surrounded cells, thus confirming striking interaction CXCL9 CXCR3. may play important role pathogenesis causing driving damage could serve as might be used novel target for therapy. This work was supported intramural programs NIDCR NCI.