Gut CD4 + T cell phenotypes are a continuum molded by microbes, not by T H archetypes

Nat Immunol. 2021 Feb;22(2):216-228. doi: 10.1038/s41590-020-00836-7. Epub 2021 Jan 18.

Abstract

CD4+ effector lymphocytes (Teff) are traditionally classified by the cytokines they produce. To determine the states that Teff cells actually adopt in frontline tissues in vivo, we applied single-cell transcriptome and chromatin analyses to colonic Teff cells in germ-free or conventional mice or in mice after challenge with a range of phenotypically biasing microbes. Unexpected subsets were marked by the expression of the interferon (IFN) signature or myeloid-specific transcripts, but transcriptome or chromatin structure could not resolve discrete clusters fitting classic helper T cell (TH) subsets. At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as TH markers were distributed in a polarized continuum, which was functionally validated. Clones derived from single progenitors gave rise to both IFN-γ- and interleukin (IL)-17-producing cells. Most of the transcriptional variance was tied to the infecting agent, independent of the cytokines produced, and chromatin variance primarily reflected activities of activator protein (AP)-1 and IFN-regulatory factor (IRF) transcription factor (TF) families, not the canonical subset master regulators T-bet, GATA3 or RORγ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / immunology
  • Bacteria / pathogenicity*
  • Bacterial Infections / genetics
  • Bacterial Infections / immunology
  • Bacterial Infections / metabolism
  • Bacterial Infections / microbiology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / microbiology*
  • CD4-Positive T-Lymphocytes / parasitology*
  • Chromatin / genetics
  • Chromatin / metabolism
  • Citrobacter rodentium / immunology
  • Citrobacter rodentium / pathogenicity
  • Colon / immunology
  • Colon / metabolism
  • Colon / microbiology*
  • Colon / parasitology*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gastrointestinal Microbiome*
  • Gene Expression Profiling
  • Heligmosomatoidea / immunology
  • Heligmosomatoidea / pathogenicity*
  • Host-Pathogen Interactions
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Intestinal Diseases, Parasitic / genetics
  • Intestinal Diseases, Parasitic / immunology
  • Intestinal Diseases, Parasitic / metabolism
  • Intestinal Diseases, Parasitic / parasitology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nematospiroides dubius / immunology
  • Nematospiroides dubius / pathogenicity
  • Nippostrongylus / immunology
  • Nippostrongylus / pathogenicity
  • Phenotype
  • Salmonella enterica / immunology
  • Salmonella enterica / pathogenicity
  • Single-Cell Analysis
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Transcriptome

Substances

  • Chromatin
  • Cytokines
  • Interferon Regulatory Factors
  • Transcription Factor AP-1