A binary module for microbiota-mediated regulation of γδ17 cells, hallmarked by microbiota-driven expression of programmed cell death protein 1

Little is known about how microbiota regulate innate-like y8 T cells or how these restrict their effector functions within mucosal barriers, where microbiota provide chronic stimulation. Here, we show that microbiotamediated regulation of y817 cells is binary, where microbiota instruct in situ interleukin-17 (IL-17) production and concomitant expression of the inhibitory receptor programmed cell death protein 1 (PD-1). Microbiotadriven expression of PD-1 and IL-17 and preferential adoption of a PD-1high phenotype are conserved for y817 cells across multiple mucosal barriers. Importantly, microbiota-driven PD-1 inhibits in situ IL-17 production by mucosa-resident y817 effectors, linking microbiota to their simultaneous activation and suppression. We further show the dynamic nature of this microbiota-driven module and define an inflammation-associated activation state for y817 cells marked by augmented PD-1, IL-17, and lipid uptake, thus linking the microbiota to dynamic subset-specific activation and metabolic remodeling to support y817 effector functions in a microbiota-dense tissue environment.

Automated summary

This study reveals the binary regulation of y817 cells by microbiota, where microbiota instruct in situ IL-17 production and concomitant expression of the inhibitory receptor PD-1. Microbiota-driven PD-1 inhibits in situ IL-17 production by mucosa-resident y817 effectors, linking microbiota to their simultaneous activation and suppression.