Paired Activating and Inhibitory Immunoglobulin-like Receptors, MAIR-I and MAIR-II, Regulate Mast Cell and Macrophage Activation

Yotsumoto, Katsumi; Okoshi, Yasushi; Shibuya, Kazuko; Yamazaki, Satoshi; Tahara‐Hanaoka, Satoko; Honda, Shin‐ichiro; Osawa, Mitsujiro; Kuroiwa, Asato; Matsuda, Yoichi; Tenen, Daniel G.; Iwama, Atsushi; Nakauchi, Hiromitsu; Shibuya, Akira

doi:10.1084/jem.20021825

Cited by 96 publications

(143 citation statements)

References 42 publications

(50 reference statements)

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“…In humans, KARAP/DAP12 and KIR-S are expressed by CD4 + CD28 -T cells, which expand in patients suffering from chronic inflammatory diseases [25,26]. The activating NK cell receptor Ly49D can be expressed in immature mouse B lymphocytes, whereas myeloid associated immunoglobulin-like receptor II (MAIR-II), also known as leukocyte mono-Ig-like receptor 2 (LMIR-2), is present in LPSstimulated mouse B cells as well as in a subset of mouse peritoneal macrophages [27][28][29]. In T and B lymphocytes, KARAP/DAP12 is preferentially expressed by cells with an activated phenotype that is often related to inflammatory conditions.…”

Section: Karap/dap12 In T and B Lymphocytesmentioning

confidence: 99%

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

2005

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The signaling adaptor protein KARAP/DAP12/TYROBP (killer cell activating receptorassociated protein / DNAX activating protein of 12 kDa / tyrosine kinase binding protein) belongs to the family of transmembrane polypeptides bearing an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). This adaptor, initially characterized in NK cells, is associated with multiple cell-surface activating receptors expressed in both lymphoid and myeloid lineages. We review here the main features of KARAP/DAP12, describing findings from its identification to recently published data, showing its involvement in a broad array of biological functions. KARAP/DAP12 is a wiring component for NK cell anti-viral function (e.g. mouse cytomegalovirus via its association with mouse Ly49H) and NK cell anti-tumoral function (e.g. via its association with mouse NKG2D or human NKp44). KARAP/DAP12 is also involved in inflammatory reactions via its coupling to myeloid receptors, such as the triggering receptors expressed by myeloid cells (TREM) displayed by neutrophils, monocytes/ macrophages and dendritic cells. Finally, bone remodeling and brain function are also dependent upon the integrity of KARAP/DAP12 signals, as shown by the analysis of KARAP/DAP12-deficient mice and KARAP/DAP12-deficient Nasu-Hakola patients. IntroductionPolypeptides that bear at least one immunoreceptor tyrosine-based activation motif (ITAM; YxxL-x 7 -YxxL) in their intracytoplasmic domain constitute family of various signaling molecules ( Fig. 1A and B). ITAM were first identified in the immune system, where they are required for the expression and signaling of several activating immunoreceptors, thus playing a key role in immune responses. ITAM-bearing proteins can also be detected in non-hematopoietic tissues, such as the brain, and they can also be produced by several viruses (Fig. 1A and B). The latest ITAM-bearing polypeptide to be identified [1][2][3][4][5] protein (TYROBP); here we refer to it as KARAP/DAP12. As previously described for other ITAM-bearing polypeptides, tyrosine residues present in KARAP/DAP12 ITAM, once phosphorylated, are both required for the recruitment and the activation of Syk and ZAP70, which are SH2-domain-containing protein tyrosine kinases (PTK) [3]. KARAP/DAP12 transcripts are present in bony fishes, rodents, swine and humans, showing the broad conservation of this signaling component in vertebrates [2, 3, 6, 7]. KARAP/DAP12 expression is detectable in both lymphoid and myeloid cells, where it can associate with several activating immunoreceptors, contributing to several biological functions [8].In this review, we will correlate KARAP/DAP12 broad expression in both hematopoietic and non-hematopoietic tissues with pleiotropic functions of this signaling , protein G1 of hantavirus (sequence indicated corresponds to substrain NY1, but G1 proteinITAM sequences of several other hantavirus substrains' have also been reported) [59]. All the ITAM motifs reported here, except for viral molecules, are derived from human sequenc...

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Section: Karap/dap12 In T and B Lymphocytesmentioning

confidence: 99%

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

2005

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“…Granulocytes, mast cells, monocytes, and DC all express DAP12 [9]. MDL-1 (myeloid DAP12 associating lectin-1) [10], SIRPb1 (signal-regulatory protein b1) [11], TREM-1 (triggering receptor expressed on myeloid cells-1 ), TREM-2 [1], MAIR-II (myeloid-associated immunoglobulin-like receptor-II) [12], and PILRb [2] have been identified as cell surface receptors that associate with DAP12 in myeloid cells. Recently, members of a novel family of receptors, the CD200R-like receptors, have been found to associate with DAP12 [13].…”

Section: Introductionmentioning

confidence: 99%

Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

et al. 2005

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DAP12 is an immunoreceptor tyrosine-based activation motif-bearing membrane adapter molecule expressed by different cell types. Although several receptors associate with DAP12 in murine dendritic cells (DC), the function of these receptors is as yet unknown. Here we report that splenic mature DC with DAP12 overexpression are characterized by an impaired tolerogenic potential. In contrast, inhibition of DAP12 function results in enhanced tolerogenesis and constitutive expression of immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO). Increased resistance to experimental encephalomyelitis is observed in DAP12 knockin mice, which is dependent on IDO expression. Therefore, DAP12-related receptors act as negative regulators of IDO-mediated tolerance in vivo.

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“…Paired immune receptors are generally composed of several activating and inhibitory receptors with high homology in the extracellular domains (1,2). We have previously characterized leukocyte mono-Ig-like receptors 1-5 (LMIR1-5) 3 among a novel paired receptor family called LMIR/CMRF-35-like molecules (CLMs)/myeloid-associated Ig-like receptor (MAIR)/ dendritic cell-derived Ig-like receptor (DIgR)/CD300 (3)(4)(5)(6)(7)(8)(9). LMIR3/CLM-1/MAIR-V/DIgR2/CD300LF is an inhibitory receptor that possesses an ITIM in the cytoplasmic region (4,6,7,10,11).…”

mentioning

confidence: 99%

An Activating and Inhibitory Signal from an Inhibitory Receptor LMIR3/CLM-1: LMIR3 Augments Lipopolysaccharide Response through Association with FcRγ in Mast Cells

Izawa

Kitaura

Yamanishi

et al. 2009

The Journal of Immunology

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Leukocyte mono-Ig-like receptor 3 (LMIR3) is an inhibitory receptor mainly expressed in myeloid cells. Coengagement of FcεRI and LMIR3 impaired cytokine production in bone marrow-derived mast cells (BMMCs) induced by FcεRI crosslinking alone. Mouse LMIR3 possesses five cytoplasmic tyrosine residues (Y241, Y276, Y289, Y303, Y325), among which Y241 and Y289 (Y241/289) or Y325 fit the consensus sequence of ITIM or immunotyrosine-based switch motif (ITSM), respectively. The inhibitory effect was abolished by the replacement of Y325 in addition to Y241/289 with phenylalanine (Y241/189/325/F) in accordance with the potential of Y241/289/325 to cooperatively recruit Src homology region 2 domain-containing phosphatase 1 (SHP)-1 or SHP-2. Intriguingly, LMIR3 crosslinking alone induced cytokine production in BMMCs expressing LMIR3 (Y241/276/289/303/325F) mutant as well as LMIR3 (Y241/289/325F). Moreover, coimmunoprecipitation experiments revealed that LMIR3 associated with ITAM-containing FcRγ. Analysis of FcRγ-deficient BMMCs demonstrated that both Y276/303 and FcRγ played a critical role in the activating function of this inhibitory receptor. Importantly, LMIR3 crosslinking enhanced cytokine production of BMMCs stimulated by LPS, while suppressing production stimulated by other TLR agonists or stem cell factor. Thus, an inhibitory receptor LMIR3 has a unique property to associate with FcRγ and thereby functions as an activating receptor in concert with TLR4 stimulation.

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Paired Activating and Inhibitory Immunoglobulin-like Receptors, MAIR-I and MAIR-II, Regulate Mast Cell and Macrophage Activation

Cited by 96 publications

References 42 publications

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

An Activating and Inhibitory Signal from an Inhibitory Receptor LMIR3/CLM-1: LMIR3 Augments Lipopolysaccharide Response through Association with FcRγ in Mast Cells

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