Microbiota drive concomitant expression of IL-17 and the inhibitory receptor PD-1 to regulate effector functions of γδ17 cells in the intestine

Abstract

Abstract While developmental programming of innate-like γδT cells generates dedicated IFN-γ-producing (γδIFN-γ) or IL-17-producing (γδ17) subsets, emerging evidence suggests these are further shaped by environmental cues. Such cues include the intestinal microbiota, although the nature of microbiota-dependent regulation is poorly understood since some reports hold that microbiota exert strictly activating signals, while other reports show microbiota are strictly suppressive. Whether the impact of microbiota on γδT cells is indeed exclusively binary, and whether regulatory modules stemming from the microbiota can be dynamic in response to changing physiologic conditions remains unknown. Here we identify a microbiota-dependent regulatory module for γδ17 cells in which microbiota concomitantly upregulate IL-17-production and the inhibitory receptor programmed cell death protein 1 (PD-1). Concomitant expression of these two modules, the requirements for microbiota, and preferential upregulation of a PD-1high phenotype is conserved for γδ17 cells resident within multiple mucosal barriers. Importantly, microbiota-driven PD-1 inhibits IL-17 production by endogenous γδ17 effectors. We further show that these two microbiota-dependent modules are dynamic, wherein both PD-1 and IL-17 producing functions are downregulated upon depletion of microbiota, and concomitantly upregulated in response to intestinal inflammation. We also identify enhanced capacity for lipid uptake as an inflammation-associated metabolic response specific to the γδ17 subset, thus linking augmented γδ17 effector functions to dynamic subset-specific metabolic remodeling within the intestine. Supported by NIH R01-AI088100 awarded to MLS