Spatiotemporal single-cell profiling reveals that invasive and tissue-resident memory donor CD8 ⁺ T cells drive gastrointestinal acute graft-versus-host disease

Abstract

Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting the transcriptional programs of newly recruited donor T cells from those of tissue-resident T cells in aGVHD target organs remains a challenge. Here, we combined the serial intravascular staining technique with single-cell RNA sequencing to dissect the tightly connected processes by which donor T cells initially infiltrate tissues and then establish a pathogenic tissue residency program in a rhesus macaque allo-HCT model that develops aGVHD. Our results enabled creation of a spatiotemporal map of the transcriptional programs controlling donor CD8+ T cell infiltration into the primary aGVHD target organ, the gastrointestinal (GI) tract. We identified the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphodepletion-driven, T cell infiltration. GI-infiltrating donor CD8+ T cells demonstrated a highly activated, cytotoxic phenotype while simultaneously developing a canonical tissue-resident memory T cell (TRM) transcriptional signature driven by interleukin-15 (IL-15)/IL-21 signaling. We found expression of a cluster of genes directly associated with tissue invasiveness, including those encoding adhesion molecules (ITGB2), specific chemokines (CCL3 and CCL4L1) and chemokine receptors (CD74), as well as multiple cytoskeletal proteins. This tissue invasion transcriptional signature was validated by its ability to discriminate the CD8+ T cell transcriptome of patients with GI aGVHD from those of GVHD-free patients. These results provide insights into the mechanisms controlling tissue occupancy of target organs by pathogenic donor CD8+ TRM cells during aGVHD in primate transplant recipients.

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“… 48 Both IL-15 and IL-27 contribute to maintain homeostasis of memory T cells. 49 , 50 As far, their association with survival in checkpoint blockade with or without conventional anti-tumor therapies was little known. Eotaxin-3 was the most highly induced gene in eosinophilic esophagitis patients compared with its expression level in healthy individuals.…”

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“…Additionally, within CD8 + CD69 + T cells, a decrease in CD103 + Trm cells and a relative increase of CD103 – Itgb2 high KLRG1 + GzmK + Trm cells was observed in inflamed ileum of CD patients. Recently, Tkachev et al 31 observed that pathogenic cells in graft-vs-host disease in a simian transplantation model comprise rapidly developed CD8 + CD69 + Trm cells, which were CD103 – but expressed ITGB2 , CCL4L1 , CD74 , and CCL3 among others. Another study recently linked appearance and accumulation of a GZMK + CD8 + T cell population to an inflammatory phenotype in immune aging.…”

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

“…ITGB2, CD74 and others). They surmised that alloreactivity may develop in the circulation/lymph system before tissue residency is established, though the timing and the site of initial T cell activation are still to be fully supported ( 69 ).…”