GZMK-expressing tissue-resident memory CD8+ T cells participate in human intestinal acute graft-versus-host disease
Yiming Sun, Yutong Xue, Chenyuyao Song, Xinyu Liu, Ruoyang Shao, Zhiping Fan, Ren Lin, Fen Huang, Na Xu, Li Xuan, Min Dai, Jing Sun, Qifa Liu, Hua Jin
Yiming Sun, Yutong Xue, Chenyuyao Song, Xinyu Liu, Ruoyang Shao, Zhiping Fan, Ren Lin, Fen Huang, Na Xu, Li Xuan, Min Dai, Jing Sun, Qifa Liu, Hua Jin
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Research Article Hematology Immunology

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

Abstract

Intestinal acute graft-versus-host disease (aGVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although tissue-resident memory T (TRM) cells are thought to play a pathophysiological role in animal models of aGVHD, little is known about the role of distinct subsets of TRM cells in human intestinal aGVHD. 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 identified a predominant GZMK+CD8+ TRM subset, characterized by the GZMK and CD49A markers. Intestinal aGVHD was associated with infiltration of GZMK+CD8+ T cells with TRM features, which showed enhanced clonal expansion, IFN signaling pathway–associated proinflammatory pathway expression, and lineage bifurcation differentiation properties. High GZMK+CD8+ TRM subset infiltration was associated with greater human intestinal aGVHD severity and poor prognosis. Together, our studies highlight the importance of the GZMK+CD8+ TRM subset in human intestinal aGVHD, and interest for designing GZMK+CD8+ TRM cell–targeted therapies.

Authors

Yiming Sun, Yutong Xue, Chenyuyao Song, Xinyu Liu, Ruoyang Shao, Zhiping Fan, Ren Lin, Fen Huang, Na Xu, Li Xuan, Min Dai, Jing Sun, Qifa Liu, Hua Jin

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Figure 2

Donor-derived CD8+ TRM cells are enriched in the intestines of aGVHD patients.

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Donor-derived CD8+ TRM cells are enriched in the intestines of aGVHD pat...
(A) Uniform manifold approximation and projection (UMAP) plot of 46,346 CD8+ T cells from 4 intestinal aGVHD patients, which demonstrated subclustering of CD8+ T cells into 7 phenotypes. Each dot represents a single cell (left). (B) Left: UMAP plot of the distribution of CD8+ T cell clusters separated according to intestinal tissues and peripheral blood (PB). Right: Stacked bar plots of the distribution of CD8+ T cell clusters in each sample. (C) Volcano plots showing the differentially expressed genes (DEGs) between CD8+ resident memory T (TRM) cells and CD8+ circulating T cells. Benjamini-Hochberg–adjusted P values ≤ 0.05 and log2(fold change) (log2FC) values ≥ 0.25 were calculated via the Wilcoxon rank-sum test. Respective genes were annotated. (D) Gene set enrichment analysis (GSEA) curves for resident and circulating signatures in CD8+ TRM cells and CD8+ circulating T cells. (E) GSEA (KEGG, HALLMARK, and GO) analyses were performed on highly expressed genes in CD8+ TRM cells. (F) Left: Representative image of FISH for X (green) and Y (red) chromosomes in the peripheral blood mononuclear cells (PBMCs) of an allo-HSCT patient (female recipient received male allograft). Right: Proportion of donor cells in PBMCs (n = 14). (G) Representative image of combined immunostaining and FISH-XY in the intestine of an allo-HSCT patient (female recipient received male allograft). Left: The white boxes indicate donor CD8+CD69+ TRM cells. Right: Proportion of donor TRM cells in intestinal TRM cells (n = 14). Scale bars: 20 μm (F and G).