Single-cell transcriptomics of alloreactive CD4+ T cells over time reveals divergent fates during gut graft-versus-host disease.

Autor:	Engel JA; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia., Lee HJ; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia., Williams CG; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia., Kuns R; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia., Olver S; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia., Lansink LI; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia., Soon MS; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia., Andersen SB; Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia., Powell JE; Garvan-Weizmann Centre for Cellular Genomics, Sydney, New South Wales, Australia.; UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia., Svensson V; Flagship Labs 60 Inc., Cambridge, Massachusetts, USA., Teichmann SA; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom., Hill GR; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.; Division of Medical Oncology, University of Washington, Seattle, Washington, USA., Varelias A; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.; Faculty of Medicine, University of Queensland, St. Lucia, Queensland, Australia., Koyama M; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Haque A; QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.; Department of Microbiology and Immunology, University of Melbourne, located at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2020 Jul 09; Vol. 5 (13). Date of Electronic Publication: 2020 Jul 09.
DOI:	10.1172/jci.insight.137990
Abstrakt:	Acute gastrointestinal (GI) graft-versus-host disease (GVHD) is a primary determinant of mortality after allogeneic hematopoietic stem cell transplantation (alloSCT). The condition is mediated by alloreactive donor CD4+ T cells that differentiate into pathogenic subsets expressing IFN-γ, IL-17A, or GM-CSF and is regulated by subsets expressing IL-10 and/or Foxp3. Developmental relationships between Th cell states during priming in mesenteric lymph nodes (mLNs) and effector function in the GI tract remain undefined at genome scale. We applied scRNA-Seq and computational modeling to a mouse model of donor DC-mediated GVHD exacerbation, creating an atlas of putative CD4+ T cell differentiation pathways in vivo. Computational trajectory inference suggested emergence of pathogenic and regulatory states along a single developmental trajectory in mLNs. Importantly, we inferred an unexpected second trajectory, categorized by little proliferation or cytokine expression, reduced glycolysis, and high tcf7 expression. TCF1hi cells upregulated α4β7 before gut migration and failed to express cytokines. These cells exhibited recall potential and plasticity following secondary transplantation, including cytokine or Foxp3 expression, but reduced T cell factor 1 (TCF1). Thus, scRNA-Seq suggested divergence of alloreactive CD4+ T cells into quiescent and effector states during gut GVHD exacerbation by donor DC, reflecting putative heterogeneous priming in vivo. These findings, which are potentially the first at a single-cell level during GVHD over time, may assist in examination of T cell differentiation in patients undergoing alloSCT.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu