Tissue-specific Control of Th17 Responses in the Oral Mucosa

At barrier sites maintenance of immune tolerance and generation of immunity relies on specialized immune-cell networks. These barrier resident cells integrate local cues to generate responses that preserve barrier integrity, maintain host-commensal interactions, and fight infection. Although mediators of immune-homeostasis are characterized at other barrier sites, the factors governing immune-cell education at the oral barrier remain minimally explored. To understand oral barrier tailoring of immune responses we examined the immuno-surveillance network of both humans and mice. We focused on the development of oral barrier IL-17 responses, as although IL-17 is an important mediator of muco-cutaneous defense, it is also a key driver of pathology in a highly prevalent inflammatory disease of the oral barrier; Periodontitis. Our data show that the frequencies of oral barrier IL-17-producing CD4⁺ T-cells (Th17) increase with age. Exploring this increase in Th17 cells in older mice, we find that the mechanisms controlling CD4⁺ T-cell differentiation in the oral cavity are different to those operating at other barrier sites. Our data demonstrate that differentiation of Th17 cells at the oral barrier was not dependent on commensal colonization, with Th17 cell frequency being unchanged in germ free mice. Interrogation of the cytokine cues promoting oral barrier Th17 cell development, further outlined divergent control compared to other barrier sites; with IL-1 signals playing no role, yet IL-6 being critical for oral barrier Th17 development. Collectively our data show that diverse mechanisms govern tissue-specific education of Th17 responses and highlight the unique rules defining immune-homeostasis at the oral barrier.