Combined Natural Killer Cell and Dendritic Cell Functional Deficiency in KARAP/DAP12 Loss-of-Function Mutant Mice

Tomasello, Elena; Desmoulins, Pierre-Olivier; Chemin, Karine; Guia, Sophie; Cremer, Harold; Ortaldo, John R.; Love, Paul E.; Kaiserlian, Dominique; Vivier, Éric

doi:10.1016/s1074-7613(00)00035-2

Cited by 149 publications

(160 citation statements)

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“…(17) ITAM-deficient DAP12 knock-in mice, with nonfunctional DAP12, have an accumulation of dendritic cells in the mucocutaneous epithelia, and these dendritic cells fail to migrate to draining lymph nodes in response to a hapten skin challenge. (21) Thus, TREM2-DAP12 signaling may contribute to chemotaxis in both dendritic cells and OCs. Further studies are needed to elucidate the mechanisms of these effects, but TREM2 stimulation of OCs leading to enhanced migration of OC precursors would be of particular importance in the setting of pro-inflammatory signals generated in areas of inflammation, such as in rheumatoid arthritis erosions.…”

Section: Discussionmentioning

confidence: 99%

TREM2, a DAP12-Associated Receptor, Regulates Osteoclast Differentiation and Function

Humphrey

Daws

Spusta

et al. 2006

Journal of Bone and Mineral Research

143

146

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Deficiency of the signaling adapter protein DAP12 or its associated receptor TREM2 is associated with abnormal OC development in humans. Here we examine the role of TREM2 in mouse OC development and function, including migration and resorption in vitro. These results provide new evidence that TREM2 regulates OC function independent of its effects on multinucleated OC differentiation.Introduction: TREM2 (triggering receptor expressed in myeloid cells-2) associates with the signaling adapter DAP12 in osteoclasts (OCs). Genetic mutation or deletion of either the TYROBP (DAP12) or TREM2 gene is associated with the human disorder of brain and bone, Nasu-Hakola disease. We and others recently showed the critical requirement for immunoreceptor tyrosine-based activation motif (ITAM) signals through DAP12 and the Fc Receptor ␥ chain (FcR␥) during OC development. Here, we further define the role of TREM2 in OC differentiation and describe a role for TREM2 in OC migration and bone resorption. Materials and Methods:We generated monoclonal anti-mouse TREM2 antibodies (mAb), analyzed preosteoclasts and mature OCs for TREM2 surface expression, and determined the effect of antibody ligation on in vitro OC differentiation, resorption, and migration. TREM2 RNA interference (RNAi) was used to disrupt expression of TREM2 in pre-osteoclasts. Results: Using flow cytometry, our studies reveal that TREM2 is weakly expressed on C57BL/6 bone marrow macrophages (BMMs) and is upregulated during culture with RANKL and macrophage-colony stimulating factor (M-CSF). The expression of TREM2 is unaltered in DAP12-deficient OCs. Using C57BL/6 BMMs or RAW264.7 precursors, anti-TREM2 mAb treatment with RANKL and M-CSF enhances the formation of multinuclear TRACP + OCs compared with control mAb treatment. In contrast, these agents have no effect on DAP12-deficient precursors. Monoclonal Ab blockade of TREM2 on OCs generated from C57BL/6 BMMs results in decreased resorption of artificial calcium-phosphate substrate and dentine. Reduction of TREM2 expression in RAW264.7 cells by RNAi results in loss of OC formation in response to RANKL and M-CSF. Anti-TREM2 cross-linking enhances migration of C57BL/6 OCs and RAW246.7 OCs in response to M-CSF. Conclusions: Our studies indicate that the TREM2 receptor regulates OC multinucleation as well as resorption and migration of mature OCs. Thus, TREM2-DAP12 signals regulate both OC formation and function.

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Section: Discussionmentioning

confidence: 99%

TREM2, a DAP12-Associated Receptor, Regulates Osteoclast Differentiation and Function

Humphrey

Daws

Spusta

et al. 2006

Journal of Bone and Mineral Research

143

146

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“…The presence of a charged arginine residue in the transmembrane domain of DCAR encouraged us to investigate the possibility that DCAR acts as an activating receptor in association with an adaptor molecule. The most widely used ITAM- bearing adaptor molecule would be DAP12 (38), and its critical role in DC antigen-priming capacity as well as in NK cell activation was demonstrated by the analysis of DAP12-deficient mice (39,40). In fact, myeloid DAP12-associating lectin-1 (41), triggering receptor expressed on myeloid cells-2 (42), and signal-regulatory protein ␤ (43, 44) have been identified as DAP12-associating immunoreceptors expressed in myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell Immunoactivating Receptor, a Novel C-type Lectin Immunoreceptor, Acts as an Activating Receptor through Association with Fc Receptor γ Chain

Kanazawa

Tashiro

Inaba

et al. 2003

Journal of Biological Chemistry

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An increasing number of C-type lectin receptors are being discovered on dendritic cells, but their signaling abilities and underlying mechanisms require further definition. Among these, dendritic cell immunoreceptor (DCIR) induces negative signals through an inhibitory immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail. Here we identify a novel C-type lectin receptor, dendritic cell immunoactivating receptor (DCAR), whose extracellular lectin domain is highly homologous to that of DCIR. DCAR is expressed similarly in tissues to DCIR, but its short cytoplasmic portion lacks signaling motifs like ITIM. However, a positively charged arginine residue is present in the transmembrane region of the DCAR, which may explain its association with Fc receptor ␥ chain and its stable expression on the cell surface. Furthermore, cross-linking of DCAR in the presence of ␥ chain activates calcium mobilization and tyrosine phosphorylation of cellular proteins. These signals are mediated by the immunoreceptor tyrosine-based activating motif (ITAM) of the ␥ chain. Thus, DCAR is closely related to DCIR, but it introduces activating signals into antigen-presenting cells through its physical and functional association with ITAM-bearing ␥ chain. The identification of this activating immunoreceptor provides an example of signaling via a dendritic cell-expressed C-type lectin receptor.Paired immunoreceptors (1-4) are composed of an immunoreceptor tyrosine-based inhibitory motif (ITIM) 1 -bearing inhibitory receptor and an immunoreceptor tyrosine-based activating motif (ITAM)-bearing activating receptor. Such pairs of receptors, when expressed on the same cell, allow for a balance between positive and negative cell signaling. In most cases, activating receptors are formed as complexes of a ligand-binding subunit with a short cytoplasmic tail and an ITAM-bearing signal-transducing subunit. This signal-transducing subunit can be shared by several receptors. These activating receptors were first identified on effector cells such as natural killer (NK), T, B, and mast cells and subsequently detected on myeloid cells including granulocytes, macrophages, and dendritic cells (DC). Now it is evident that such receptors are used rather ubiquitously, including in platelets (5) and even nonhematopoietic cells (6). Based on their domain structures, these receptors are divided into two subgroups, Ig superfamily and Ca 2ϩ -dependent (C-type) lectin family. Besides their structural similarity, the genes for these families are clustered (e.g. the Ig superfamily in the leukocyte receptor complex on human chromosome 19 or syntenic mouse chromosome 7, and the C-type lectin family in the NK gene complex (NKC) on human chromosome 12 or syntenic mouse chromosome 6, respectively) (7).On the other hand, there have been many C-type lectin receptors detected on DC. Based on their molecular structures, they include two types of receptors: type I C-type lectin as a type I transmembrane protein with several carbohydrate recognition domains ...

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“…62 Interestingly, genetic mutations in human DAP12 or TREM-2 result in a bone-fracture syndrome called Nasu-Hakola disease, further suggesting that plexin-A1 physiologically associates with the TREM/ DAP12 complex and that this interaction is relevant to these diseases.…”

Section: Regulation Of Immune Cell Responses H Takamatsu Et Al 85mentioning

confidence: 99%

Regulation of immune cell responses by semaphorins and their receptors

2010

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Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called 'immune semaphorins', are crucially involved in various phases of immune responses. These semaphorins regulate both immune cell interactions and immune cell trafficking during physiological and pathological immune responses. Here, we review the following two functional aspects of semaphorins and their receptors in immune responses: their functions in cell-cell interactions and their involvement in immune cell trafficking.

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Combined Natural Killer Cell and Dendritic Cell Functional Deficiency in KARAP/DAP12 Loss-of-Function Mutant Mice

Cited by 149 publications

References 50 publications

TREM2, a DAP12-Associated Receptor, Regulates Osteoclast Differentiation and Function

TREM2, a DAP12-Associated Receptor, Regulates Osteoclast Differentiation and Function

Dendritic Cell Immunoactivating Receptor, a Novel C-type Lectin Immunoreceptor, Acts as an Activating Receptor through Association with Fc Receptor γ Chain

Regulation of immune cell responses by semaphorins and their receptors

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