T cell exhaustion in focus: single-cell mapping of CD8+ T cell dynamics in mucosal chronic graft-versus-host disease 3680

Abstract Description Chronic graft-versus-host disease (cGVHD) is an alloimmune disease that can follow non-self hematopoietic stem cell transplantation, driven by dysregulated T cell and other immune responses. Detailed analysis of naïve and memory T cells with antigen presenting cells has not yet been paired with the role of exhausted T cells in mucosal cGVHD. Using oral mucosa (OM) biopsies collected from patients six months post-transplant, we characterized, at single-cell resolution, T cell exhaustion using transcriptomic and protein level analyses in cGVHD. Single-cell RNA sequencing identified CD8+T cell clusters with apparent dysfunction, including a CXCL13+CD8+ T cell cluster with a dual phenotype characterized by cytotoxic markers (GZMB, PRF1) and exhaustion signatures (TIM3, LAG3). Increased frequency of this cluster correlated significantly with clinical severity score, connecting these cells to disease severity. In unaffected patients, LYVE1+ macrophages and CD1C+ dendritic cells signaling supported immune homeostasis, but these populations were diminished in cGVHD, coinciding with disease progression. CODEX analysis mapped expansion of FOXP3+CD4+T cells and their proximity to CD8+T cells in cGVHD, yet this regulatory influence was insufficient to halt tissue damage. In summary, dysregulated CD8+T cells that combine exhaustion and cytotoxic functions could drive persistent damage and thwart anti-inflammatory signals, underscoring the central role of exhaustion in cGVHD pathogenesis. Funding Sources NIH Intramural Program Topic Categories Immune Mechanisms of Human Disease (HUM)