Protein Tyrosine Phosphatases in Autoimmunity

Vang, Torkel; Miletic, Ana V.; Arimura, Yutaka; Tautz, Lutz; Rickert, Robert C.; Mustelin, Tomas

doi:10.1146/annurev.immunol.26.021607.090418

Cited by 159 publications

(151 citation statements)

References 151 publications

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“…3B), suggesting that MR-mediated T-cell impairment shares mechanisms operative in T-cell tolerance. Next, we applied a combined approach to identify and prioritize candidate effector molecules responsible for MR-mediated T-cell impairment as defined by differential expression at least at one time point (first criterion), being part of the tolerance gene set (second criterion), and being part of a set of genes (n = 45) that were previously associated with T-cell anergy or tolerance (third criterion) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). For genes within the intersection of these three gene groups, a sum rank was determined based on most significant differential expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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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Section: Resultsmentioning

confidence: 99%

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

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…One would expect this R620W substitution to result in increased T-cell signaling and activation; however, experimental evidence suggests the opposite with TCR signaling actually reduced in cells carrying the tryptophan variant protein (Vang, 2005). A number of explanations have been proposed including an effect of the mutation on the tyrosine phosphatase activity of LYP, or an effect on the binding of other ligands or the conformation of LYP in response to these ligands (Vang, 2008). At a cellular level the mechanism by which reduced T-cell activation may actually increase the potential for autoimmunity remains a matter for speculation, although the suppression of regulatory T-cells is a possibility (Vang, 2008).…”

Section: Protein Tyrosine Phosphatase Non-receptor 22 (Ptpn22) (1p13)mentioning

confidence: 99%

“…A number of explanations have been proposed including an effect of the mutation on the tyrosine phosphatase activity of LYP, or an effect on the binding of other ligands or the conformation of LYP in response to these ligands (Vang, 2008). At a cellular level the mechanism by which reduced T-cell activation may actually increase the potential for autoimmunity remains a matter for speculation, although the suppression of regulatory T-cells is a possibility (Vang, 2008). A connection between PtPn22 and the type I IFN pathway has been suggested on the basis of elevated serum IFN-activity and decreased tumor necrosis factor (TNF) levels in patients with SLE carrying the rs2476601 risk allele (Kariuki, 2008).…”

Section: Protein Tyrosine Phosphatase Non-receptor 22 (Ptpn22) (1p13)mentioning

confidence: 99%

Genetics and Epigenetic in Systemic Lupus Erythematosus

AlFadhli¹

2012

Systemic Lupus Erythematosus

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“…PTK signaling is the major mechanism for receptor signal transduction, which mediates cell growth, differentiation, host defense, and metabolic regulation [3,4]. In humans, there are about 80 active protein phosphatases, which can be divided into four distinct classes.…”

Section: Introductionmentioning

confidence: 99%

PTPN4 negatively regulates CrkI in human cell lines

Zhou

Wan

Shan

et al. 2013

Cellular and Molecular Biology Letters

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PTPN4 is a widely expressed non-receptor protein tyrosine phosphatase. Although its overexpression inhibits cell growth, the proteins with which it interacts to regulate cell growth are unknown. In this study, we identified CrkI as a PTPN4-interacting protein using a yeast two-hybrid, and confirmed this interaction using in vitro GST pull-down and coimmunoprecipitation and co-localization assays. We further determined the interactional regions as the SH3 domain of CrkI and the proline-rich region between amino acids 462 and 468 of PTPN4. Notably, overexpression of PTPN4 inhibits CrkI-mediated proliferation and wound healing of HEK293T cells, while knockdown of PTPN4 by siRNA in Hep3B cells enhances CrkI-mediated cell growth and motility. Moreover, our data show that ectopic expression of PTPN4 reduces the phosphorylation level of CrkI in HEK293T cells. These findings suggest that PTPN4 negatively regulates cell proliferation and motility through dephosphorylation of CrkI.

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Protein Tyrosine Phosphatases in Autoimmunity

Cited by 159 publications

References 151 publications

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

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

Genetics and Epigenetic in Systemic Lupus Erythematosus

PTPN4 negatively regulates CrkI in human cell lines

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