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

Abstract

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-gamma, 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 alpha4beta7 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.

Type Journal
ISBN 2379-3708 (Electronic) 2379-3708 (Linking)
Authors Engel, J. A.; Lee, H. J.; Williams, C. G.; Kuns, R.; Olver, S.; Lansink, L. I.; Soon, M. S.; Andersen, S. B.; Powell, J. E.; Svensson, V.; Teichmann, S. A.; Hill, G. R.; Varelias, A.; Koyama, M.; Haque, A.
Responsible Garvan Author A/Prof Joseph Powell
Publisher Name Journal of Clinical Investigation Insight
Published Date 2020-07-31
Published Volume 5
Published Issue 13
Published Pages e137990
Status Published in-print
DOI 10.1172/jci.insight.137990
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/32484791