SummaryLevels of inflammatory mediators in circulation are known to increase with age, but the underlying cause of this age-associated inflammation is debated. We find that, when maintained under germ-free conditions, mice do not display an age-related increase in circulating pro-inflammatory cytokine levels. A higher proportion of germ-free mice live to 600 days than their conventional counterparts, and macrophages derived from aged germ-free mice maintain anti-microbial activity. Co-housing germ-free mice with old, but not young, conventionally raised mice increases pro-inflammatory cytokines in the blood. In tumor necrosis factor (TNF)-deficient mice, which are protected from age-associated inflammation, age-related microbiota changes are not observed. Furthermore, age-associated microbiota changes can be reversed by reducing TNF using anti-TNF therapy. These data suggest that aging-associated microbiota promote inflammation and that reversing these age-related microbiota changes represents a potential strategy for reducing age-associated inflammation and the accompanying morbidity.

The authors would like to clarify that several experiments in the paper as detailed here were performed simultaneously. Specifically, the histology slides represented in Figures 1G, 2E, and 3H were analyzed by a blinded reviewer and quantified using the same pathology scale. The experiments yielding data on intestinal permeability (Figures 3D and 5B) and ELISA data (Figures 1E, 1F, 2B, 3G, and 3I) were performed simultaneously to minimize inter-experimental error. The relevant comparisons (e.g., age, genotype, SPF/germ-free) were presented in separate figures/panels to facilitate the narrative of the manuscript, but the statistical analysis was performed and presented based on analysis of the entire dataset. Additionally, the sentence ''Mice were deprived of food 4 hr prior to and both food and water 4 hr following an oral gavage using 200 ml of 0.8 mg/ml FITC-dextran'' should state ''80 mg/ml FITC-dextran.'' The authors apologize for this error, and it has been corrected online.

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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.