Intestinal macrophages represent the last tissue macrophages thought to entirely adhere to van Furth's decades-old continuous monocyte replenishment model. In this study, Shaw et al. identify a population of intestinal macrophages that are long lived and maintained independently of monocyte replenishment over long periods of time.

SummaryImmuno-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.

SignificanceLoss of oral barrier homeostasis leads to the development of periodontitis, the most common chronic inflammatory condition of mankind. Therefore, it is important to better understand the immune mediators acting at this unique barrier to safeguard tissue integrity. Here we identify a vital role for γδ T cells in constraining pathological inflammation at the oral barrier, as the absence of γδ T cells resulted in enhanced pathology during periodontitis. We show that oral barrier γδ T cells produce the reparative cytokine Amphiregulin, administration of which rescued the elevated oral pathology of tcrδ−/− mice. Collectively, we identify a pathway controlling oral immunity mediated by barrier-resident γδ T cells, highlighting that these cells are crucial guards of oral barrier immune homeostasis.

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).

Signal regulatory protein alpha (SIRPα/CD172a) is a conserved transmembrane protein thought to play an inhibitory role in immune function by binding the ubiquitous ligand CD47. SIRPα expression has been used to identify dendritic cell subsets across species and here we examined its expression and function on intestinal DCs in mice. Normal mucosa contains four subsets of DCs based on their expression of CD103 and CD11b and three of these express SIRPα. However, loss of SIRPα signaling in mice leads to a selective reduction in the CD103+CD11b+ subset of DCs in the small intestine, colon, and among migratory DCs in the mesenteric lymph node. In parallel, these mice have reduced numbers of TH17 cells in steady-state intestinal mucosa, and a defective TH17 response to Citrobacter infection. Identical results were obtained in CD47KO mice. DC precursors from SIRPα mutant mice had an enhanced ability to generate CD103+CD11b+ DCs in vivo, but CD103+CD11b+ DCs from mutant mice were more prone to die by apoptosis. These data show a previously unappreciated and crucial role for SIRPα in the homeostasis of CD103+CD11b+ DCs in the intestine, as well as providing further evidence that this subset of DCs is critical for the development of mucosal TH17 responses.

The current view of lymphocyte migration states that naïve lymphocytes re-circulate between the blood and the lymph via the lymph nodes, but are not able to access non-lymphoid tissues. We examined B lymphocytes in peripheral tissues and found that the majority were phenotypically similar to naïve B cells in lymphoid tissues and were located within the parenchyma, not associated with blood vessels. The mutation rate within the Vh region of these cells was substantially less than the rate attributed to somatic hypermutation and was identical to that observed in naïve B cells isolated from the lymph nodes, showing the presence of naïve B cells in the non-lymphoid organs. Further, using FTY720-treated mice, we showed that naïve B cells migrate through the peripheral tissues and, using pertussis toxin, that the entry of B cells was not controlled by chemokinemediated signalling events. Overall, these results show that naïve B lymphocytes constitute the majority of the total B-cell population in non-lymphoid tissues and suggest that these cells may re-circulate through the periphery as part of their normal migration pathway. This has implications for the current view of the role of naïve B cells in priming and tolerance. To function effectively, the immune system must integrate complex signals from specialised immune microenvironments (such as the lymph nodes) and immune effector sites throughout the body. This allows the maintenance of a balance between priming and tolerance and ensures that disease states, such as autoimmunity, do not develop. It is now well established that the initial induction of priming or tolerance in naïve lymphocytes occurs in the organised lymphoid tissues and requires rapid migration of cells to these sites after antigen challenge. Therefore, an understanding of the migration patterns of naïve T and B lymphocytes is central in dissecting the complex mechanisms by which different types of immune responses occur.Early studies by Gowans and Knight 1 and Marchesi and Gowans 2 provided the foundations for our current understanding of naïve lymphocyte migration, indicating that these cells undergo continuous recirculation between the blood and the lymph via the lymph nodes. Further studies have reinforced these findings, showing that naïve lymphocytes are able to enter the organised lymphoid tissue by binding to high endothelial venules. [3][4][5][6] Until recently, the discovery of these mechanisms and the absence of high endothelial venules in peripheral tissues have resulted in the commonly held belief that naïve lymphocytes are not able to access non-lymphoid tissues easily or in any substantial numbers. 7,8 Studies showing heterogeneity in the expression of tissue-specific homing molecules on memory and effector (but not naïve) lymphocytes have also added weight to this argument.In contrast to this view, a recent study in normal adult mice has suggested that a significant number of CD4+ and CD8+ T lymphocytes in non-lymphoid tissues have a naïve phenotype. 9 In addition, earlier studies hav...

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At barrier sites, resident immune cell populations help to maintain tissue homeostasis and function. These cells receive and integrate key signals from the local environment including stromal/epithelial cells and the commensal microbiome. Studies of the skin and gastrointestinal tract have revealed the importance of these signals for the development of host immune response. However, which commensal or tissue-specific cues are important for the immune system at the oral barrier remains minimally explored. Th17 cells have been described as key mediators of immunity at the oral barrier but also essential for periodontitis, a highly prevalent inflammatory pathology that affects the gingiva. In this study we focused in the identification of the mechanisms controlling the induction and regulation of Th17 cells in the gingiva. Our data show that IL-17-producing CD4+ T cells increase with age and their accumulation at the oral barrier occurs independently of commensal colonization. Moreover, we demonstrate that IL-6 elicited by physiological mechanical damage during mastication shapes the function of T cells at the oral mucosa, promoting Th17 differentiation. Finally, we observe that long-term mechanical damage through mastication induces IL-17 mediated bone loss at the gingival barrier. Our data highlight the notion that a variety of signals may be essential to shape the immune responses at different barrier sites, and particularly at the oral cavity, unique mechanisms modulates homeostatic and also pathogenic Th17 responses.