γδT cells are a major component of epithelial tissues and play a role in tissue homeostasis and host defense. γδT cells also reside in the gingiva, an oral tissue covered with specialized epithelium that continuously monitors the challenging dental biofilm. Whereas most research on intraepithelial γδT cells focuses on the skin and intestine epithelia, our knowledge on these cells in the gingiva is still incomplete. In this study, we demonstrate that even though the gingiva develops after birth, the majority of gingival γδT cells are fetal thymus-derived Vγ6+ cells, and to a lesser extent Vγ1+ and Vγ4+ cells. Furthermore, we show that γδT cells are motile and locate preferentially in the epithelium adjacent to the biofilm. Vγ6+ cells represent the major source of IL-17–producing cells in the gingiva. Chimeric mice and parabiosis experiments indicated that the main fraction of gingival γδT cells is radioresistant and tissue-resident, persisting locally independent of circulating γδT cells. Notably, gingival γδT cell homeostasis is regulated by the microbiota as the ratio of Vγ6+ and Vγ4+ cells was reversed in germ-free mice, and their activation state was decreased. As a consequence, conditional ablation of γδT cells results in elevated gingival inflammation and subsequent alterations of oral microbial diversity. Taken together, these findings suggest that oral mucosal homeostasis is shaped by reciprocal interplays between γδT cells and local microbiota.

. HIF-1␣-targeted pathways are activated by heat acclimation and contribute to acclimation-ischemic cross-tolerance in the heart. Physiol Genomics 23: 79-88, 2005. First published July 26, 2005 10.1152/physiolgenomics.00279.2004.-Hypoxiainducible factor-1 (HIF-1) is a key regulator of the cellular hypoxic response. We previously showed that HIF-1 activation is essential for heat acclimation (AC) in Caenorhabditis elegans. Metabolic changes in AC rat hearts indicate HIF-1␣ activation in mammals as well. Here we characterize the HIF-1␣ profile and the transcriptional activation of its target genes following AC and following heat stress (HS) in hearts from nonacclimated (C; 24°C) and AC (34°C, 1 mo) rats. We used Western blot and immunohistochemistry to measure HIF-1␣ levels and EMSA and RT-PCR/quantitative RT-PCR to detect expression of the HIF-1␣-targeted genes, including vascular endothelial growth factor (Vegf), heme oxygenase-1 (HO1), erythropoietin (Epo), and Epo receptor (EpoR). EpoR and Epo mRNA levels were measured to determine systemic effects in the kidneys and cross-tolerance effects in C and AC ischemic hearts (Langendorff, 75% ischemia, 40 min). The results demonstrated that 1) after AC, HIF-1␣ protein levels were increased, 2) HS alone induced transient HIF-1␣ upregulation, and 3) VEGF and HO1 mRNA levels increased after HS, with greater magnitude in the AC hearts. Epo mRNA in AC kidneys and EpoR mRNA in AC hearts were also elevated. In AC hearts, EpoR expression was markedly higher after HS or ischemia. Hearts from AC rats were dramatically protected against infarction after ischemiaperfusion. We conclude that HIF-1 contributes to the acclimation-ischemia cross-tolerance mechanism in the heart by induction of both chronic and inducible adaptive components.hypoxia-inducible factor-

Excessive bone resorption is frequently associated with chronic infections and inflammatory diseases. Whereas T cells were demonstrated to facilitate osteoclastogenesis in such diseases, the role of dendritic cells, the most potent activators of naive T cells, remains unclear. Using a model involving inflammation-driven alveolar bone loss attributable to infection, we showed that in vivo ablation of Langerhans cells (LCs) resulted in enhanced bone loss. An increased infiltration of B and T lymphocytes into the tissue surrounding the bone was observed in LC-ablated mice, including receptor activator of NF-κB ligand (RANKL)-expressing CD4 + T cells with known capabilities of altering bone homeostasis. In addition, the absence of LCs significantly reduced the numbers of CD4 + Foxp3 + T-regulatory cells in the tissue. Further investigation revealed that LCs were not directly involved in presenting antigens to T cells. Nevertheless, despite their low numbers in the tissue, the absence of LCs resulted in an elevated activation of CD4 + but not CD8 + T cells. This activation involved elevated production of IFN-γ but not IL-17 or IL-10 cytokines. Our data, thus, reveal a protective immunoregulatory role for LCs in inflammation-induced alveolar bone resorption, by inhibiting IFN-γ secretion and excessive activation of RANKL + CD4 + T cells with a capability of promoting osteoclastogenesis.

Acclimation to heat is a biphasic process involving a transient perturbed phase followed by a long lasting period during which acclimatory homeostasis is developed. In this investigation, we used cDNA stress microarray (Clontech Laboratory) to characterize the stress-related genomic response during the course of heat acclimation and to test the hypotheses that 1) heat acclimation influences the threshold of activation of protective molecular signaling, and 2) heat-acclimation-mediated ischemic-reperfusion (I/R) protection is coupled with reprogrammed gene expression leading to altered capacity or responsiveness of protective-signaling pathways shared by heat and I/R cytoprotective systems. Rats were acclimated at 34 degrees C for 0, 2, and 30 days. 32P-labeled RNA samples prepared from the left ventricles of rats before and after subjection to heat stress (HS; 2 h, 41 degrees C) or after I/R insult (ischemia: 75%, 45 min; reperfusion: 30 min) were hybridized onto the array membranes. Confirmatory RT-PCR of selected genes conducted on samples taken at 0, 30, and 60 min after HS or total ischemia was used to assess the promptness of the transcriptional response. Cluster analysis of the expressed genes indicated that acclimation involves a "two-tier" defense strategy: an immediate transient response peaking at the initial acclimating phase to maintain DNA and cellular integrity, and a sustained response, correlated with slowly developed adaptive, long-lasting cytoprotective signaling networks involving genes encoding proteins that are essential for the heat-shock response, antiapoptosis, and antioxidation. Gene activation was stress specific. Faster activation and suppression of signaling pathways shared by HS and I/R stressors probably contribute to heat-acclimation I/R cross-tolerance.

Capucha et al. demonstrate that mucosal Langerhans cell (LC) differentiation from pre–dendritic cells and monocytes involves consecutive BMP7 and TGF-β1 signaling in separate anatomical locations. Moreover, mucosal microbiota regulates the development of LCs that in turn shape microbial and immunological homeostasis.