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

• Published in: Nature immunology Vol. 22; no. 2; pp. 216 - 228
• Main Authors: Kiner, Evgeny, Willie, Elijah, Vijaykumar, Brinda, Chowdhary, Kaitavjeet, Schmutz, Hugo, Chandler, Jodie, Schnell, Alexandra, Thakore, Pratiksha I., LeGros, Graham, Mostafavi, Sara, Mathis, Diane, Benoist, Christophe
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2021; Nature Publishing Group
• Subjects: 631/250; 631/250/2152; 631/337; Biomedical and Life Sciences; Biomedicine; CD4 antigen; Chromatin; Cytokines; GATA-3 protein; Gene expression; Germfree; Immunology; Infectious Diseases; Lymphocytes; Lymphocytes T; Microorganisms; Phenotypes; Transcriptomes; γ-Interferon
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-020-00836-7

CD4 + effector lymphocytes (T eff ) are traditionally classified by the cytokines they produce. To determine the states that T eff cells actually adopt in frontline tissues in vivo, we applied single-cell transcriptome and chromatin analyses to colonic T eff 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 (T H ) subsets. At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as T H 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. Helper T cell subsets are characterized functionally by the cytokines they produce. Benoist and colleagues demonstrate that in vivo helper T cells do not manifest as discrete helper subsets but rather form a continuum shaped by microbial exposure.