Single-cell immune profiling reveals a developmentally distinct CD41 GM-CSF1 T-cell lineage that induces GI tract GVHD

Abstract

Gastrointestinal (GI) tract involvement is a major determinant for subsequent morbidity and mortality arising during graft-versus-host disease (GVHD). CD41 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 CD41 GM-CSF1 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 CD41 GM-CSF1 subset exists that differs from other defined T helper subtypes. Using single-cell RNA sequencing analysis (scRNAseq), we identified two CD41 GM-CSF1 T-cell populations that arose during GVHD and were distinguishable according to the presence or absence of interferon-g (IFN-g) coexpression. CD41 GM-CSF1 IFN-g2 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 CD41 GM-CSF1 IFN-g1 T cells as well as all other transcriptionally defined CD41 T-cell populations in the colon. Functionally, this CD41 GM-CSF1 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 CD41 GM-CSF1 T cells that arise during GVHD and define a developmentally distinct colitogenic T helper subtype GM-CSF1 subset that mediates immunopathology.