Single-cell immune profiling reveals a developmentally distinct CD4+ GM-CSF+ 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). CD4+ T cells that produce 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 there exists a unique CD4+ GM-CSF+ subset that differs from other defined T helper (TH) subtypes. Using single cell RNA sequencing analysis, we identified two CD4+ GM-CSF+ T cell populations that arose during GVHD and were distinguishable by the presence or absence of IFN-γ co-expression. CD4+ GM-CSF+ IFN-γ- T cells which emerged preferentially in the colon had a distinct transcriptional profile, employed unique gene regulatory networks, and possessed a non-overlapping TCR repertoire when compared to 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 pathological damage in the GI tract which was critically dependent upon signaling through the 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 TH GM-CSF+ subset that mediates immunopathology.

TRPV4 mRNA is elevated in the caudate nucleus with NPH but not in Alzheimer’s disease

“…There are immunological cells such as T lymphocytes in the CSF ( Evans et al, 2019 ) that can be analyzed by single cell techniques ( Esaulova et al, 2020 ; Guan et al, 2022 ; Piper et al, 2022 ; You et al, 2022 ). To study CSF and compare that with the brain tissue finding is thus highly relevant.…”

Integrated Analysis of T cell Repertoire and Transcriptome Identifies Mechanisms of Regulatory T cell (Treg) Suppression of Acute Graft-versus-Host-Disease

“…Our study has several limitations. First, we performed our analysis on Treg and Tcon recovered from secondary lymphoid organs (SLO) and not on GvHD-target tissues as previously reported by other groups who focused on Tcon [42][43][44][45] . We decided to study SLO because this is the site where Treg suppression of Tcon mediating GvHD is believed to take place 6,46 .…”

Role of cross-reactivity in cellular immune targeting of influenza A M158-66 variant peptide epitopes

“…The existing singlecell data for the M1 response ( 5) is not large enough to determine the relation between band a-chain pairing. However, we examined two larger single-cell data sets (~2K cells), one from colon-resident CD8 cells (43), and the other splenic CD4 cells specific for an LCMV peptide (44). The percent of clonotypes that were accounted for by cells sharing a b-chain and showing exclusive a-chain pairing was 2.3% for the CD8 and 2.4% for the CD4 repertoires (Supplemental Figure S2).…”

“…Estimating the frequency of clonotypes with identical b-chain rearrangements and unique exclusive a-chain rearrangements. Singlecell T cell analysis from published data (43,44) was analyzed for the occurrence of clonotypes with the same b-chain gene rearrangement but different a-chain gene rearrangements. Data on the left is from colonderived CD8 T cells, and that on the right for tetramer selected CD4 T cells participating in a response to LCMV.…”