TREM-2 Mediated Signaling Induces Antigen Uptake and Retention in Mature Myeloid Dendritic Cells

Radhakrishnan, S.; Arneson, Laura N.; Upshaw, Jadee L.; Howe, Charles L.; Felts, Sara J.; Colonna, Marco; Leibson, Paul J.; Rodriguez, Moses; Pease, Larry R.

doi:10.4049/jimmunol.181.11.7863

Cited by 13 publications

(14 citation statements)

References 43 publications

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“…Therefore, we have focused on delineating the events that occur on the surface of the DCs upon binding of B7-DC XAb and to determine what membrane and intracellular molecules mediate the various DC phenotypic responses. Previously, we found that cross-linking B7-DC induced a substantial reorganization of cell surface molecules, resulting in the clustering of MHC, CD80, CD86, and CD11c molecules into a cap [3]. In this report we document that CD40 is also present within this cell surface complex on DC XAb .…”

Section: Discussionsupporting

confidence: 60%

“…Stimulation of DC via TREM-2 also induces a maturation response and activates ERK [25]. B7-DC XAb activates ERK, but ERK is not involved in the TREM-2 mediated response of DC to B7-DC XAb [3]. However, ERK activation was dependent on the expression of CD40 on the dendritic cells activated with B7-DCXAb.…”

Section: Discussionmentioning

confidence: 98%

“…We have recently shown that treatment of DCs with B7-DC XAb (DC XAb ) induces multiple membrane proteins to become organized into a cell surface cap [3]. These molecules include B7-1 (CD80), B7-2 (CD86), class-II, TREM-2 and CD11c.…”

Section: Introductionmentioning

confidence: 99%

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Indirect Recruitment of a CD40 Signaling Pathway in Dendritic Cells by B7-DC Cross-Linking Antibody Modulates T Cell Functions

et al. 2009

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The human IgM B7-DC XAb protects mice from tumors in both therapeutic and prophylactic settings. Its mechanism of action is mediated by its binding to B7-DC/PD-L2 molecules on the surface of dendritic cells (DCs) to induce a multimolecular cap and subsequent activation of signaling cascades that determine a unique combination of DC phenotypes. One such phenotype, the B7-DC XAb-induced antigen accumulation in mTLR-matured DCs, has been linked to signaling through TREM-2, but the signals required for other DC phenotypes critical for the therapeutic effects in animal models remain unclear. Here, FRET and co-immunoprecipitation studies show that CD40 is recruited to the multi-molecular complex by B7-DC XAb. Signals emanating from CD40 are important, as CD40−/− DCs treated with B7-DC XAb (DCXAb) activated DAP12, but failed to activate NFκB, and were not protected from cell death upon cytokine withdrawal or treatment with Vitamin D3. CD40−/− DCXAb also failed to secrete IL-6 and were unable to support the conversion of T regulatory cells into IL-17+ effector T cells in vitro. Importantly, the expression of CD40 was required for the overall ability of B7-DC XAb to induce anti-tumor CTL, to provide protection from a number of tumor types, and for DCXAb to be effective anti-tumor vaccines in vivo. These results indicate that B7-DC XAb modulation of DC phenotypes is through its ability to indirectly recruit common signaling molecules and elements of their endogenous signaling pathways through targeted binding to a cell-specific surface determinant.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 98%

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Indirect Recruitment of a CD40 Signaling Pathway in Dendritic Cells by B7-DC Cross-Linking Antibody Modulates T Cell Functions

et al. 2009

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“…It is possible that downstream signaling by an alternative receptor engaging B7-DC may selectively lead to the upregulation of T-bet expression and the inhibition of GATA-3 expression in responder T cells. Several studies have demonstrated that cross-linking B7-DC by human anti-mouse IgM Ab results in the activation, maturation, and migration of IL-12–producing DCs (12, 48, 49). Therefore, it is also possible that the local production of IL-12 by DCs in response to reverse signaling by B7-DC is also important in generating Th1 responses in N. brasiliensis infection.…”

Section: Discussionmentioning

confidence: 99%

Costimulator B7-DC Attenuates Strong Th2 Responses Induced by Nippostrongylus brasiliensis

Ishiwata

Watanabe

Guo

et al. 2010

The Journal of Immunology

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The caliber and magnitude of T cell responses are regulated by costimulatory molecules following the engagement of TCRs and MHC molecules. B7-DC has the highest homology with B7-H1 in the B7 family, and both of them bind an immunoregulatory molecule, programmed death 1. Previous studies have demonstrated that B7-DC stimulates T cell proliferation and CTL generation, which sharply contrasts the inhibitory role of B7-H1. Th2 cytokines prompt B7-DC expression, which in turn enhances Th1 responses. In this study, we used an intestinal nematode, Nippostrongylus brasiliensis, to induce strong Th2 responses and to evaluate B7-DC function under Th2-polarizing conditions in vivo. By either blocking B7-DC expression during N. brasiliensis infection or by examining N. brasiliensis-infected B7-DC knockout mice, we observed enhanced eosinophilia, the overproduction of serum IgE, and increased Th2 cytokine production along with decreased Th1 cytokine production (particularly IFN-γ production), indicating that B7-DC inhibits Th2 responses. Our results further demonstrate that the inhibition of Th2 responses by B7-DC occurs independently of programmed death 1 but conceivably acts through an as yet unknown alternative receptor that enhances Th1 responses. Although the deficiency of B7-DC expression that enhanced the production of IL-13 paradoxically resulted in better protection against N. brasiliensis infection, our results show that B7-DC plays an important role in bolstering a robust Th1 response that is required for effective antiviral and anticancer immunity, even under a strong Th2-polarizing environment induced by N. brasiliensis infection.

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“…Indirect activation of ITAM signaling by Semaphorin 6D is important not only in osteoclast differentiation but also in regulating cytokine production and antigen-presenting function of dendritic cells (which express TREM-2 and plexin A1). In addition, TREM-2–DAP12 signaling is activated in myeloid dendritic cells by PD-L2 (also called B7-DC), a molecule important in mediating effects of dendritic cells on T cell phenotype43. Thus, ITAM signaling can be triggered by various receptors and ligands important in immune responses, and in turn, ITAM signaling modulates the function of the TNFR family member RANK and myeloid cell activation and differentiation.…”

Section: Regulation Of Tnfr Family Responsesmentioning

confidence: 99%

Cross-regulation of signaling by ITAM-associated receptors

2009

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An important function of receptors that signal through immunoreceptor tyrosine-based activation motifs (ITAMs) is to regulate signaling by heterologous receptors. This review describes mechanisms by which ITAM-associated receptors modulate signaling by Toll-like receptors (TLRs), tumor necrosis factor receptor family members and cytokine receptors that use the Jak-STAT signaling pathway, and the biological importance of this signal transduction cross-talk. ITAM-mediated crossregulation can either augment or dampen signaling by other receptors. Conversely, TLRs and cytokines modulate ITAM-mediated signaling, by means including activation of β2 integrins that are coupled to the ITAM-containing adaptors DAP12 and FcRγ. Integration of ITAM signaling into signaling networks through cross-talk with other signal transduction pathways results in tight regulation and fine tuning of cellular responses to various extracellular stimuli and contributes to induction of specific activation and differentiation pathways.The ITAM is a conserved signaling motif preferentially used by hematopoietic cells 1 . The ITAM motif (consensus sequence YXXLX 6-8 YXXL/I) is contained in the cytoplasmic domain of transmembrane adaptor molecules that are associated with and transmit signals from various immunoreceptors. ITAM-coupled receptors include the T cell and B cell antigen receptors (TCR and BCR) and Fc receptors (FcRs), which bind immunoglobulins. In lymphocytes, ITAM-containing adaptors transmit antigen receptor signals that lead to cell activation or tolerance, depending on the intensity of receptor stimulation and the presence or absence of co-stimulatory signals 2 . Myeloid cells express approximately 20 ITAM-associated receptors, including FcRs, TREMs, ILTs (also called LILRs), MAIRs, PIR-A, MDL-1, DCAR, OSCAR, CD200 receptors and c-Fms (refs. 3,4 ). These receptors signal through two main ITAM-containing adaptors expressed by myeloid cells, termed . Except for FcRs, which bind immunoglobulins and immune complexes, the ligands for myeloid ITAM-coupled receptors are not well defined; they include MHC class I molecules and other, as yet unknown ligands that are expressed on myeloid cells or on tissue cells with which myeloid cells interact. Thus, in myeloid cells ITAM-coupled receptors are constitutively engaged, which leads to tonic low-level ITAM-mediated signaling (reviewed in ref. 5 ). More recently, it has become clear that FcRγ and DAP12 associate with β 2 and β 3 integrins and contribute to signaling by these receptors [6][7][8] . Thus, ITAM signaling is also induced by cell-cell and cell-extracellular matrix (ECM) interactions that are mediated by these integrins.The ligation of ITAM-associated receptors in myeloid cells leads to a signaling cascade that begins with phosphorylation of ITAM tyrosine residues by Src-family kinases, followed by the recruitment and activation of the spleen tyrosine kinase (Syk) 1,5 Integration with TLR responsesMany microbial products and complex inflammatory stimuli contain ligands for...

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TREM-2 Mediated Signaling Induces Antigen Uptake and Retention in Mature Myeloid Dendritic Cells

Cited by 13 publications

References 43 publications

Indirect Recruitment of a CD40 Signaling Pathway in Dendritic Cells by B7-DC Cross-Linking Antibody Modulates T Cell Functions

Indirect Recruitment of a CD40 Signaling Pathway in Dendritic Cells by B7-DC Cross-Linking Antibody Modulates T Cell Functions

Costimulator B7-DC Attenuates Strong Th2 Responses Induced by Nippostrongylus brasiliensis

Cross-regulation of signaling by ITAM-associated receptors

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