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

Immuno-surveillance networks operating at barrier sites are tuned by local tissue cues to ensure effective immunity. Site-specific commensal bacteria provide key signals ensuring host defense in the skin and gut. However, how the oral microbiome and tissue-specific signals balance immunity and regulation at the gingiva, a key oral barrier, remains minimally explored. In contrast to the skin and gut, we demonstrate that gingiva-resident T helper 17 (Th17) cells developed via a commensal colonization-independent mechanism. Accumulation of Th17 cells at the gingiva was driven in response to the physiological barrier damage that occurs during mastication. Physiological mechanical damage, via induction of interleukin 6 (IL-6) from epithelial cells, tailored effector T cell function, promoting increases in gingival Th17 cell numbers. These data highlight that diverse tissue-specific mechanisms govern education of Th17 cell responses and demonstrate that mechanical damage helps define the immune tone of this important oral barrier.

Amphiregulin-producing γδ T cells are vital for safeguarding oral barrier immune homeostasis.

γδ T cells are enriched at barrier sites such as the gut, skin, and lung, where their roles in maintaining barrier integrity are well established. However, how these cells contribute to homeostasis at the gingiva, a key oral barrier and site of the common chronic inflammatory disease periodontitis, has not been explored. Here we demonstrate that the gingiva is policed by γδ T cells with a T cell receptor (TCR) repertoire that diversifies during development. Gingival γδ T cells accumulated rapidly after birth in response to barrier damage, and strikingly, their absence resulted in enhanced pathology in murine models of the oral inflammatory disease periodontitis. Alterations in bacterial communities could not account for the increased disease severity seen in γδ T cell-deficient mice. Instead, gingival γδ T cells produced the wound healing associated cytokine amphiregulin, administration of which rescued the elevated oral pathology of tcrδ-/- mice. Collectively, our results identify γδ T cells as critical constituents of the immuno-surveillance network that safeguard gingival tissue homeostasis.

Macrophages in gastrointestinal homeostasis and inflammation.

Monocyte-derived mononuclear phagocytes, particularly macrophages, are crucial to maintain gastrointestinal homeostasis in the steady state but are also important for protection against certain pathogens. However, when uncontrolled, they can promote immunopathology. Broadly two subsets of macrophages can be considered to perform the vast array of functions to complete these complex tasks: resident macrophages that dominate in the healthy gut and inflammation-elicited (inflammatory) macrophages that derive from circulating monocytes infiltrating inflamed tissue. Here, we discuss the features of resident and inflammatory intestinal macrophages, complexities in identifying and defining these populations and the mechanisms involved in their differentiation. In particular, focus will be placed on describing their unique ontogeny as well as local gastrointestinal signals that instruct specialisation of resident macrophages in healthy tissue. We then explore the very different roles of inflammatory macrophages and describe new data suggesting that they may be educated not only by the gut microenvironment but also by signals they receive during development in the bone marrow. Given the high degree of plasticity of gut macrophages and their multifaceted roles in both healthy and inflamed tissue, understanding the mechanisms controlling their differentiation could inform development of improved therapies for inflammatory diseases such as inflammatory bowel disease (IBD).

Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression.

A defining feature of resident gut macrophages is their high replenishment rate from blood monocytes attributed to tonic commensal stimulation of this site. In contrast, almost all other tissues contain locally maintained macrophage populations, which coexist with monocyte-replenished cells at homeostasis. In this study, we identified three transcriptionally distinct mouse gut macrophage subsets that segregate based on expression of Tim-4 and CD4. Challenging current understanding, Tim-4+CD4+ gut macrophages were found to be locally maintained, while Tim-4-CD4+ macrophages had a slow turnover from blood monocytes; indeed, Tim-4-CD4- macrophages were the only subset with the high monocyte-replenishment rate currently attributed to gut macrophages. Moreover, all macrophage subpopulations required live microbiota to sustain their numbers, not only those derived from blood monocytes. These findings oppose the prevailing paradigm that all macrophages in the adult mouse gut rapidly turn over from monocytes in a microbiome-dependent manner; instead, these findings supplant it with a model of ontogenetic diversity where locally maintained subsets coexist with rapidly replaced monocyte-derived populations.