*Purpose: Graft-versus-host disease (GVHD) is a relatively common and highly morbid complication after intestinal transplantation. Its pathophysiology remains poorly understood. Resident memory T cells (TRM) are a newly described T cell subset with memory phenotype localizing to peripheral tissue rather than blood/lymphatics. We hypothesized that the pathophysiology of GVHD might be related to increased donor TRM in the graft subsequently migrating into host blood and tissue.

*Methods: Intestinal transplantation from deceased donors was performed using our standard method. Graft and blood lymphocytes from 10 patients with GVHD and 34 without were longitudinally analyzed using flow cytometry.

*Results: In the grafts of GVHD vs. stable patients there were approximately 20% more CD4 and CD8 TRM cells prior to implantation and significantly higher percentages of CD4 and CD8 TRM cells at the time of GVHD (p = 0.02 and 0.04). There was also a mean 60.3% higher level of CD8 TRM cells in native bowel of GVHD patients compared to controls and 20-30% higher levels of IFN-γ and TNF-α expressing CD4 cells and TNF-α expressing CD8 cells in both graft and native bowel of GVHD patients. Importantly, the percentage of CD4 and CD8 TRM in the blood of GVHD vs. stable patients, initially similar, significantly increased during GVHD (p = 0.005). Peripheral blood T cells in GVHD patients also had higher level of mature, antigen-experienced, and/or exhaustion markers than in stable patients. There were significant differences in CD4/CD57 (p = 0.01), CD4/HLA-DR (p = 0.044), CD8/HLA-DR (p = 0.007), CD8/CD28 (p = 0.039), CD4/PD-1 (p = 0.041), and CD8/PD-1 (p = 0.038). There were also significant increases in CD8 effector memory cells (p = 0.0056) and decreases in naïve cells (p = 0.0034) not seen in stable patients. Notably, CD8/PD-1 was also significantly elevated prior to transplantation in patients who later had GVHD (p = 0.025).

*Conclusions: In the largest longitudinal analysis to date, we demonstrate that increased TRM percentage and inflammatory cytokine expression in graft bowel correspond with increased TRM in blood and native bowel and increased cytokine expression in native bowel at time of GVHD. Thus GVHD pathogenesis may depend on donor TRM in graft bowel migrating to the blood and native tissue of recipients. Recipients with higher PD-1 expression, indicating T cell exhaustion, might be more vulnerable, providing a possible biomarker for GVHD risk.

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