Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Abstract

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 ...

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“…Moreover, MR can interact with other canonical pattern recognition receptors to mediate intracellular signaling. [32][33][34] We found that inhibition of MR by its specific siRNA can block AOS function. The data suggested that AOS might act its function through MR signaling pathway.…”

“…The MR is an endocytic receptor containing eight C-type lectinlike domains (CTLDs) which can bind to glycoconjugates terminated in mannose, fucose, or glucose. We hypothesized that the function of AOS may be through MR. 32,33 Then siRNAs of MR were used in this study in vitro with IPEC-J2 cells (swine intestinal cell line) to explore the mechanism of AOS effects on the recovering of mouse small intestinal. It was very interesting that AOS 10, and 100 μg/ml significantly increased the protein levels of CX43, claudin, DSG2, and APOA1 in IPEC-J2 cells which was constant with the in vivo data in mouse, however, AOS 10, and 100 μg/ml cannot increase the levels of these three proteins in the present of MR siRNA (Fig.…”

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“…Blocking the MR modulated the differentiation, maturation, and functions of DCs resulting in a reduced severity of induced autoimmune arthritis [11]. Moreover, deleting or blocking CD206 on DCs decreased the proliferation and cytotoxic activity of urine CD8 + T cells in vitro [10]. The expression of surface molecules on DCs is dynamic and changes according to tissue localization and maturation state.…”

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“…Recent studies have further supported the role of MR in controlling inflammation. For instance, MR has been shown to induce T-cell reprogramming and subsequent tolerance via inhibition of CD45 and upregulation of the inhibitory molecule CTLA-4, which was responsible for the impaired cytotoxic activity of T cells [44]. …”