Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut

• Published in: Immunity (Cambridge, Mass.) Mass.), 2021-03, Vol.54 (3), p.499-513.e5
• Main Authors: Yan, Yiqing, Ramanan, Deepshika, Rozenberg, Milena, McGovern, Kelly, Rastelli, Daniella, Vijaykumar, Brinda, Yaghi, Omar, Voisin, Tiphaine, Mosaheb, Munir, Chiu, Isaac, Itzkovitz, Shalev, Rao, Meenakshi, Mathis, Diane, Benoist, Christophe
• Format: Article
• Language: English
• Subjects: Ablation; Animal models; Apposition; Cell activation; Cell differentiation; Circuits; Colon; Colonization; Commensals; Cytokines; Density; Depletion; Enteric nervous system; Fibers; Foxp3 protein; Gene expression; Germfree; gut-brain axis; Homeostasis; Immunological tolerance; Immunology; Immunoregulation; Interleukin 6; Lamina propria; Lymphocytes; Lymphocytes T; Microbiota; Microorganisms; Motility; neuro-immune interactions; Neurons; Neurotransmitters; Phenotypes; regulatory T cells; Transcription factors; Treg-neuron interactions
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.02.002

The immune and enteric nervous (ENS) systems monitor the frontier with commensal and pathogenic microbes in the colon. We investigated whether FoxP3+ regulatory T (Treg) cells functionally interact with the ENS. Indeed, microbe-responsive RORγ+ and Helios+ subsets localized in close apposition to nitrergic and peptidergic nerve fibers in the colon lamina propria (LP). Enteric neurons inhibited in vitro Treg (iTreg) differentiation in a cell-contact-independent manner. A screen of neuron-secreted factors revealed a role for interleukin-6 (IL-6) in modulating iTreg formation and their RORγ+ proportion. Colonization of germfree mice with commensals, especially RORγ+ Treg inducers, broadly diminished colon neuronal density. Closing the triangle, conditional ablation of IL-6 in neurons increased total Treg cells but decreased the RORγ+ subset, as did depletion of two ENS neurotransmitters. Our findings suggest a regulatory circuit wherein microbial signals condition neuronal density and activation, thus tuning Treg cell generation and immunological tolerance in the gut. [Display omitted] •Treg cells in the colon lamina propria reside close to neuron projections•Neurons modulate the differentiation and phenotype of iTreg cells in culture via IL-6•Neuron-specific ablation of Il6 increases the number of RORγ+ Treg cells in vivo•Microbial colonization affects a subset of neurons in the enteric nervous system Regulatory T (Treg) cells lie in proximity to nerve fibers in the colon lamina propria. Yan et al. reveal a regulatory circuit wherein microbial signals condition neuronal density and activation, which in turn, via neuron-produced IL-6, tunes Treg cell generation, which has implications for intestinal tolerance.