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Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Although largely deprived from exogenous stimuli in utero, the mucosal barriers of the neonate after birth are bombarded by environmental, nutritional, and microbial exposures. The microbiome is established concurrently with the developing immune system. The nature and timing of discrete interactions between these two factors underpins the long-term immune characteristics of these organs, and can set an individual on a trajectory towards or away from disease. Microbial exposures in the gastrointestinal and respiratory tracts are some of the key determinants of the overall immune tone at these mucosal barriers and represent a leading target for future intervention strategies. In this review, we discuss immune maturation in the gut and lung and how microbes have a central role in this process.

The integrity of the intestinal epithelium is constantly surveyed by a peculiar subset of innate-like T lymphocytes embedded in the epithelial cell layer, hence called intestinal intraepithelial lymphocytes (IELs). IELs are thought to act as "first-line" sentinels sensing the state of adjacent epithelial cells via both T-cell receptors and auxiliary receptors. Auxiliary receptors modulating IEL activity include C-type lectin-like receptors encoded in the natural killer gene complex such as NKG2D. Here, we report that the CTLR Nkrp1g is expressed by a subpopulation of mouse CD103(+) IELs allowing immunosensing of the intestinal epithelium through ligation of the genetically coupled CTLR Clr-f that is almost exclusively expressed on differentiated intestinal epithelial cells (IECs). Most of these Nkrp1g-expressing IELs exhibit a γδTCR(bright)Nkg2a(-) phenotype and are intimately associated with the intestinal epithelium. As Clr-f expression strongly inhibits effector functions of Nkrp1g-expressing cells and is upregulated upon poly(I:C) challenge, Clr-f molecules may quench reactivity of these IELs towards the epithelial barrier that is constantly provoked by microbial and antigenic stimuli. Altogether, we here newly characterize a genetically linked C-type lectin-like receptor/ligand pair with a highly restricted tissue expression that apparently evolved to allow for a dedicated immunosurveillance of the mouse intestinal epithelium.

Innate immune recognition of the bacterial cell wall constituent peptidoglycan by the cytosolic nucleotide-binding oligomerization domain 2 (Nod2) receptor has a pivotal role in the maintenance of intestinal mucosal homeostasis. Whereas peptidoglycan cleavage by gut-derived lysozyme preserves the recognition motif, the N-acetylmuramoyl-L-alanine amidase activity of the peptidoglycan recognition protein 2 (PGLYRP-2) destroys the Nod2-detected muramyl dipeptide structure. PGLYRP-2 green fluorescent protein (GFP) reporter and wild-type mice were studied by flow cytometry and quantitative RT-PCR to identify Pglyrp-2 expression in cells of the intestinal mucosa and reveal a potential regulatory function on epithelial peptidoglycan recognition. CD3(+)/CD11c(+) T lymphocytes revealed significant Pglyrp-2 expression, whereas epithelial cells and intestinal myeloid cells were negative. The mucosal Pglyrp-2-expressing lymphocyte population demonstrated a mixed T-cell receptor (TCR) αβ or γδ phenotype with predominant CD8α and less so CD8β expression, as well as significant staining for the activation markers B220 and CD69, presenting a typical intraepithelial lymphocyte phenotype. Importantly, exposure of peptidoglycan to PGLYRP-2 significantly reduced Nod2/Rip2-mediated epithelial activation. Also, moderate but significant alterations of the intestinal microbiota composition were noted in Pglyrp-2-deficient animals. PGLYRP-2 might thus have a significant role in regulation of the enteric host-microbe homeostasis.

Gastric malignancies have been closely linked to infection of the gastric mucosa with Helicobacter pylori, but the individual factors involved in the multistage process of tumor development are still poorly understood. H. pylori evades the host defense system and causes persistent infection and chronic inflammation. Immune activation leads to DNA damage by the release of oxygen and nitrogen radicals. Ongoing tissue repair mechanisms and the secretion of cytokines and growth factors, as well as bacterial effector molecules, cause disturbances in the balance between epithelial cell proliferation and apoptosis, promote the accumulation of potential oncogenic mutations, and support neovascularization and tumor growth. In addition, H. pylori might hamper the development of an efficient antitumor immunity and provoke immune-mediated pathology. This review summarizes the recent progress in the understanding of the intimate bacteria-host relationship and the mechanisms by which H. pylori may promote the process of tumor development.

Epstein-Barr virus (EBV) has been shown to establish latency in resting B lymphocytes of the peripheral blood. This creates a virus reservoir in contrast to lytic virus replication, which is thought to be restricted to differentiated epithelial cells in vivo. So far, the route of transmission between B cells and the production of progeny virus in the epithelial tissue has remained unclear. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry analysis of 16 patients with acute infectious mononucleosis (IM) and 25 healthy seropositive donors was performed to detect lytic replication gene products in B lymphocytes of the peripheral blood. Transcriptional activity was found in peripheral blood B lymphocytes (PBLs) for BZLF1 in 88%, BALF2 in 50%, and BcLF1 in 25% of the tested IM patients. All positive results were further confirmed in enriched B-cell populations by antigen determination using immunostaining with the APAAP technique. Furthermore, we detected transcripts for BZLF1 in 72% and for BALF2 in 16% of peripheral B lymphocytes of healthy seropositive donors. In contrast to patients with IM, no signals for BcLF1 were ever found in healthy seropositive donors. In these individuals, lytic replication of EBV is probably restricted by immunologic and gene regulatory mechanisms, whereas in the absence of immunologic control, reflected here by IM patients, the production of infectious virus becomes visible in PBLs.