On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier

摘要

class="head no_bottom_margin" id="sec1title">IntroductionBarrier-resident immune populations integrate local cues to generate responses that preserve barrier integrity, maintain host-commensal interactions, and aid in fighting infection (, ). In recent years our understanding of barrier-tailoring of immune responses has dramatically expanded. This is particularly true in the gastrointestinal (GI) tract and skin, where tissue-specific and microbial-derived signals have been shown to shape the immune surveillance network and immune responsiveness (, , ). Yet, little is known regarding the development of tissue-specific immunity at the gingiva, an essential oral barrier that supports the dentition, harbors a complex commensal microbiome, and is a site where food antigens are first encountered prior to GI tract entry. Indeed, how effective immunity and regulation are balanced at this oral barrier is poorly understood. Expanding our understanding of the basic mechanisms controlling immunity at this barrier is important because the breakdown of controlled immune responses at the gingiva leads to periodontitis, a common inflammatory disease of humans. Additionally, periodontitis has been linked to the potentiation of a plethora of inflammatory conditions, such as cardiovascular disease and rheumatoid arthritis (). Therefore, understanding the mediators of health and disease at the gingiva may have broad-reaching implications for systemic inflammation.T helper 17 (Th17) cells are key mediators of barrier immunity, participating in immune surveillance and maintenance of barrier integrity (). Importantly, this T cell subset has been implicated in mediating protective immunity as well as pathogenic inflammation at the oral barrier. The development of Th17-cell-mediated responses at barriers such as the skin and GI tract is linked to tissue-specific factors, particularly colonization by site-specific commensals (, ). However, in the gingiva the factors controlling tissue-specific immunity remain ill defined, and as such it is not known how Th17 cells are induced in this environment. The critical role of Th17 cells in mediating protection at the oral barrier is evident in patients with genetic defects in Th17 cell differentiation and function; these patients present with severe and recurrent oral fungal infections (, ). However, exaggerated Th17 cell responses at the gingiva are detrimental and have been shown to promote inflammatory bone loss and tissue damage in periodontitis (, ). How Th17 cells are induced in the gingiva and subsequently become deregulated in periodontitis is poorly understood. Therefore, elucidating the factors involved in the induction and regulation of Th17 cells in this environment will shed light on the tissue-specific cues that regulate immunity in the gingiva.Here we delineated the mechanisms controlling accumulation of Th17 cells in the gingiva. Our data show that the gingival interleukin 17 (IL-17)-producing CD4⁺ T cell population increased with age. Exploring this increase in Th17 cells in older mice, we found that the mechanisms controlling CD4⁺ T cell effector function in the gingiva were different to those operating at other barrier sites. Our data demonstrate that gingival Th17 cells were not dependent on colonization by commensal bacteria, as the Th17 cell population was unchanged in germ-free mice. However, gingival Th17 cells were dependent upon IL-6-mediated signals. We identified that mechanical damage, which induces IL-6 and occurs physiologically in the oral cavity through mastication and abrasion, promoted accumulation of gingival Th17 cells. Thus, damage, as opposed to commensal colonization, helps define the immune tone of the gingiva, clearly demonstrating that unique rules shape gingival immune-homeostasis.