Our work in this period has particularly focused on understanding mechanisms implicated in the development of Th17 immune responses at the gingival barrier. The development of Th17 responses at other barriers, such as the skin and gastrointestinal (GI) tract, has been linked to tissue-specific factors, particularly colonization by niche-specific commensals. However, little is known regarding the development of tissue immunity at the oral barrier. Consequently, it is not known how Th17 cells are induced in the oral environment. Our work reveals that Th17 cells expand with age in the gingiva independent of microbial colonization, since the number of gingival Th17 cells in germ-free mice (GF) is comparable numbers to that in specific pathogen free (SPF) mice. These data starkly contrast with the developmental pathway for Th17 cells at other barrier sites such as the skin and gut, where Th17 cell development is dependent upon commensal colonization. Thus, residence of Th17 cells in the gingiva takes place via mechanisms distinct from those employed at other barrier sites. In the gingiva, accumulation of Th17 cells occurred in response to the physiological barrier damage that results from mastication/chewing. Therefore, ongoing mechanical damage is a tissue-specific cue that triggers immune responsiveness. Underscoring the vital role of mastication-induced barrier damage in local immune function, mice placed on a soft diet, and, that have reduced gingival barrier damage, had reduced numbers of gingival Th17 cells. By contrast, mice on a hardened diet, or following acute but mild gingival injury/abrasion, exhibited elevated frequencies of gingival Th17 cells. Damage-induced Th17 cells were shown to arise in an IL6- and antigen-dependent manner, through amplification of local resident Th17 cells. Importantly, physiologic damage-induced Th17 cells promoted the induction of protective innate barrier defenses. These data demonstrate the pivotal role of a physiological function such as mastication as a central regulator of barrier immunity, and highlight the importance of understanding unique local cues in the study of tissue immunity. Our ongoing work is currently interrogating mechanisms by which Th17 cells become expanded in the setting of periodontal disease and their role in the process of disease pathology.
Showing the most recent 10 out of 17 publications
