The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8 + T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.T he mannose receptor (MR) is an endocytic receptor belonging to the C-type lectin family and is expressed by distinct populations of dendritic cells (DCs), macrophages, and endothelial cells (1). It consists of an N-terminal cysteine-rich domain (CR), a fibronectin type II (FN II) domain, eight C-type lectinlike domains (CTLDs), a transmembrane region, and a short intracellular region. The CTLDs of the MR can bind to glycoconjugates terminated in mannose, fucose, or glucose. Despite the presence of eight CTLDs, only CTLD4 is responsible for carbohydrate binding. Additionally, the MR can bind to sulfated carbohydrates via its CR and to collagen via its FN II domain (1).In a previous study, we demonstrated that antigens internalized by the MR are processed specifically for cross-presentation (2). The correlation between the MR and cross-presentation offered the possibility that antigens targeted toward the MR could induce potent cytotoxic T-cell responses. Because the induction of a strong cytotoxic T-cell response against tumor-specific antigens is a crucial process in many tumor vaccination strategies, antigen targeting toward the MR seemed to be a promising approach. However, in in vivo tumor models, antigen targeting toward the MR did not result in a strong cytotoxic T-cell response but, instead, led to the induction of antigen-specific T-cell tolerance (3, 4). Therefore, we analyzed whether the MR has a regulatory effect on the induction of immune responses by means distinct from antigen uptake and presentation, and we investigated a direct influence of the MR on T-cell activation. We could demonstrate that the presence of the MR on the antigen-presenting cell (APC) directly impairs the cytotoxic activity of T cells in vitro and in vivo. We showed that this effect was due to a direct interaction of the MR with CD45 on the T-cell surface. This interaction inhibited CD45 activity and resulted in the up-regulation of the inhibitory molecule cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4), which was responsible for the impaired cytotoxic activity of the T cells. ResultsThe Presence of the MR on DCs Reduces Cytotoxic Activity of CD8 + T Cells. To investigate whether the MR influences T-cell ...

As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important role in immune regulation besides its requirement for xenobiotic metabolism. Transcriptional activation of AhR target genes is counterregulated by the AhR repressor (AhRR) but the exact function of the AhRR in vivo is currently unknown. We here show that the AhRR is predominantly expressed in immune cells of the skin and intestine, different from other AhR target genes. Whereas AhRR antagonizes the anti-inflammatory function of the AhR in the context of systemic endotoxin shock, AhR and AhRR act in concert to dampen intestinal inflammation. Specifically, AhRR contributes to the maintenance of colonic intraepithelial lymphocytes and prevents excessive IL-1β production and Th17/Tc17 differentiation. In contrast, the AhRR enhances IFN-γ-production by effector T cells in the inflamed gut. Our findings highlight the physiologic importance of cell-type specific balancing of AhR/AhRR expression in response to microbial, nutritional and other environmental stimuli.

For proper care of these patients excellent cooperation between gynecologists and general surgeons is desirable. A short review of the literature concerning intestinal endometriosis is given.