GZMK-expressing tissue-resident memory CD8+ T cells mediate human intestinal acute graft-versus-host disease

Tissue-resident memory T cells (TRM) have recently emerged as crucial cellular players for murine acute graft-versus-host disease (aGVHD) development. However, the role of distinct subsets of CD8+TRM cells in human intestinal aGVHD is not well known yet. Herein,we combined multiplex immunohistochemical staining with single-cell RNA sequencing to elucidate the differentiation trajectory, lineage commitment, clonal expansion and functional properties of distinct CD8+TRM cell subsets in human intestinal aGVHD. We revealed seven functionally distinct CD8+TRM subsets and innovatively uncovered a significant GZMK+CD8+TRM subset. GZMK+CD8+TRM subset mediated human intestinal aGVHD by exhibiting enhanced clonal expansion, IFN signaling pathway-associated proinflammatory, and lineage bifurcation differentiation properties. High GZMK+CD8+TRM subset infiltration is correlated with human intestinal aGVHD severity and poor prognosis. Therefore, we demonstrated that human intestinal aGVHD is in good part mediated by pivotal GZMK+CD8+TRM subset. Targeting key CD8+TRM cell subsets could be a new treatment approach in the human intestinal aGVHD.