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

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.