Single-cell immune profiling reveals a developmentally distinct CD4+ GM-CSF+ T-cell lineage that induces GI tract GVHD. Blood Adv 2022 May 10;6(9):2791-2804
Date
01/12/2022Pubmed ID
35015822Pubmed Central ID
PMC9092418DOI
10.1182/bloodadvances.2021006084Scopus ID
2-s2.0-85130140800 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Gastrointestinal (GI) tract involvement is a major determinant for subsequent morbidity and mortality arising during graft-versus-host disease (GVHD). CD4+ T cells that produce granulocyte-macrophage colony stimulating factor (GM-CSF) have emerged as central mediators of inflammation in this tissue site as GM-CSF serves as a critical cytokine link between the adaptive and innate arms of the immune system. However, cellular heterogeneity within the CD4+ GM-CSF+ T-cell population due to the concurrent production of other inflammatory cytokines has raised questions as to whether these cells have a common ontology or if a unique CD4+ GM-CSF+ subset exists that differs from other defined T helper subtypes. Using single-cell RNA sequencing analysis (scRNAseq), we identified two CD4+ GM-CSF+ T-cell populations that arose during GVHD and were distinguishable according to the presence or absence of interferon-γ (IFN-γ) coexpression. CD4+ GM-CSF+ IFN-γ- T cells, which emerged preferentially in the colon, had a distinct transcriptional profile, used unique gene regulatory networks, and possessed a nonoverlapping T-cell receptor repertoire compared with CD4+ GM-CSF+ IFN-γ+ T cells as well as all other transcriptionally defined CD4+ T-cell populations in the colon. Functionally, this CD4+ GM-CSF+ T-cell population contributed to pathologic damage in the GI tract that was critically dependent on signaling through the interleukin-17 (IL-7) receptor but was independent of type 1 interferon signaling. Thus, these studies help to unravel heterogeneity within CD4+ GM-CSF+ T cells that arise during GVHD and define a developmentally distinct colitogenic T helper subtype GM-CSF+ subset that mediates immunopathology.
Author List
Piper C, Hainstock E, Yin-Yuan C, Chen Y, Khatun A, Kasmani MY, Evans J, Miller JA, Gorski J, Cui W, Drobyski WRAuthors
William R. Drobyski MD Professor in the Medicine department at Medical College of WisconsinJames Adam Miller MD, MPH Assistant Professor in the Pathology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
CD4-Positive T-LymphocytesCell Lineage
Cytokines
Gastrointestinal Tract
Graft vs Host Disease
Granulocyte-Macrophage Colony-Stimulating Factor
Humans
Interferon-gamma
