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Spatiotemporal single-cell profiling of gastrointestinal GVHD reveals invasive and resident memory T cell states

View ORCID ProfileVictor Tkachev, James Kaminski, E. Lake Potter, Scott N. Furlan, Alison Yu, Daniel J. Hunt, Connor McGuckin, Hengqi Zheng, Lucrezia Colonna, Ulrike Gerdemann, Judith Carlson, Michelle Hoffman, Joe Olvera, Chris English, Audrey Baldessari, Angela Panoskaltsis-Mortari, Benjamin Watkins, Muna Qayed, Yvonne Suessmuth, Kayla Betz, Brandi Bratrude, Amelia Langston, John Horan, Jose Ordovas-Montanes, Alex K. Shalek, Bruce R. Blazar, Mario Roederer, Leslie S. Kean
doi: https://doi.org/10.1101/2020.07.20.212399
Victor Tkachev
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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  • ORCID record for Victor Tkachev
  • For correspondence: victor.tkachev@childrens.harvard.edu leslie.kean@childrens.harvard.edu
James Kaminski
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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E. Lake Potter
2Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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Scott N. Furlan
3Fred Hutchinson Cancer Research Center and Department of Pediatrics, University of Washington, Seattle, WA
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Alison Yu
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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Daniel J. Hunt
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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Connor McGuckin
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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Hengqi Zheng
4University of Washington, Seattle WA
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Lucrezia Colonna
3Fred Hutchinson Cancer Research Center and Department of Pediatrics, University of Washington, Seattle, WA
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Ulrike Gerdemann
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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Judith Carlson
4University of Washington, Seattle WA
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Michelle Hoffman
3Fred Hutchinson Cancer Research Center and Department of Pediatrics, University of Washington, Seattle, WA
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Joe Olvera
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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Chris English
5Washington National Primate Research Center, Seattle, WA
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Audrey Baldessari
5Washington National Primate Research Center, Seattle, WA
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Angela Panoskaltsis-Mortari
6Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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Benjamin Watkins
7Emory University School of Medicine, Atlanta GA
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Muna Qayed
7Emory University School of Medicine, Atlanta GA
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Yvonne Suessmuth
7Emory University School of Medicine, Atlanta GA
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Kayla Betz
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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Brandi Bratrude
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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Amelia Langston
7Emory University School of Medicine, Atlanta GA
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John Horan
7Emory University School of Medicine, Atlanta GA
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Jose Ordovas-Montanes
8Division of Gastroenterology, Boston Children’s Hospital and Program in Immunology Harvard Medical School Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA
9Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Alex K. Shalek
9Broad Institute of MIT and Harvard, Cambridge, MA, USA
10Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA
11Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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Bruce R. Blazar
6Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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Mario Roederer
2Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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Leslie S. Kean
1Division of Pediatric Hematology/Oncology, Boston Children’s Hospital; Department of Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA
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  • For correspondence: victor.tkachev@childrens.harvard.edu leslie.kean@childrens.harvard.edu
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ABSTRACT

One of the central challenges in the field of allo-immunity is deciphering the mechanisms driving T cells to infiltrate and subsequently occupy target organs to cause disease. The act of CD8-dominated T cell infiltration is critical to acute graft-versus-host disease (aGVHD), wherein donor T cells become activated, tissue-infiltrating and highly cytotoxic, causing wide-spread tissue damage after allogeneic hematopoietic stem cell transplant (allo-HCT). However, in human and non-human primate studies, deconvolving the transcriptional programs of newly recruited relative to resident memory T cells in the gastrointestinal (GI) tract has remained a challenge. In this study, we combined the novel technique of Serial Intravascular Staining (SIVS) with single-cell RNA-Seq (scRNA-seq) to enable detailed dissection of the tightly connected processes by which T cells first infiltrate tissues and then establish a pathogenic tissue residency program after allo-HCT in non-human primates. Our results have enabled the creation of a spatiotemporal map of the transcriptional drivers of CD8 T cell infiltration into the primary aGVHD target-organ, the GI tract. We identify the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphdepletion-driven T cell infiltration. The donor CD8 T cells that infiltrate the GI tract demonstrate a highly activated, cytotoxic phenotype while simultaneously rapidly developing canonical tissue-resident memory (TRM) protein expression and transcriptional signatures, driven by IL-15/IL-21 signaling. Moreover, by combining SIVS and transcriptomic analysis, we have been able to work backwards from this pathogenic TRM programing, and, for the first time, identify a cluster of genes directly associated with tissue invasiveness, prominently including specific chemokines and adhesion molecules and their receptors, as well as a central cytoskeletal transcriptional node. The clinical relevance of this new tissue invasion signature was validated by its ability to discriminate the CD8 T cell transcriptome of patients with GI aGVHD. These results provide new insights into the mechanisms controlling tissue infiltration and pathogenic CD8 TRM transcriptional programing, uncovering critical transitions in allo-immune tissue invasion and destruction.

One sentence summary Flow cytometric and transcriptomic analysis reveals coordinated tissue-infiltration and tissue-residency programs driving gastrointestinal aGVHD.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 21, 2020.
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Spatiotemporal single-cell profiling of gastrointestinal GVHD reveals invasive and resident memory T cell states
Victor Tkachev, James Kaminski, E. Lake Potter, Scott N. Furlan, Alison Yu, Daniel J. Hunt, Connor McGuckin, Hengqi Zheng, Lucrezia Colonna, Ulrike Gerdemann, Judith Carlson, Michelle Hoffman, Joe Olvera, Chris English, Audrey Baldessari, Angela Panoskaltsis-Mortari, Benjamin Watkins, Muna Qayed, Yvonne Suessmuth, Kayla Betz, Brandi Bratrude, Amelia Langston, John Horan, Jose Ordovas-Montanes, Alex K. Shalek, Bruce R. Blazar, Mario Roederer, Leslie S. Kean
bioRxiv 2020.07.20.212399; doi: https://doi.org/10.1101/2020.07.20.212399
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Spatiotemporal single-cell profiling of gastrointestinal GVHD reveals invasive and resident memory T cell states
Victor Tkachev, James Kaminski, E. Lake Potter, Scott N. Furlan, Alison Yu, Daniel J. Hunt, Connor McGuckin, Hengqi Zheng, Lucrezia Colonna, Ulrike Gerdemann, Judith Carlson, Michelle Hoffman, Joe Olvera, Chris English, Audrey Baldessari, Angela Panoskaltsis-Mortari, Benjamin Watkins, Muna Qayed, Yvonne Suessmuth, Kayla Betz, Brandi Bratrude, Amelia Langston, John Horan, Jose Ordovas-Montanes, Alex K. Shalek, Bruce R. Blazar, Mario Roederer, Leslie S. Kean
bioRxiv 2020.07.20.212399; doi: https://doi.org/10.1101/2020.07.20.212399

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