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

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Science Translational Medicine  13 Jan 2021:
Vol. 13, Issue 576, eabc0227
DOI: 10.1126/scitranslmed.abc0227

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SIVSing through GVHD

Currently, there are few ways to track leukocyte movements in vivo. Potter and colleagues developed a method to track leukocyte migration in vivo called serial intravascular staining or SIVS. The authors infused differently labeled antibodies at different time points to reveal distinct leukocyte population kinetics in healthy macaques and those infected with Mycobacterium tuberculosis. Tkachev et al. then applied SIVS to shed light on donor T cell trafficking in macaques that developed acute graft-versus-host disease (GVHD) after transplant. They found that donor cytotoxic CD8+ T cells infiltrated the gastrointestinal tract and developed the transcriptional signature of tissue-resident memory T cells. SIVS will be useful for revealing leukocyte trafficking kinetics not only in GVHD and infection but in a variety of other diseases as well.


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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