Massive inflammatory syndrome and lymphocytic immunodeficiency in KARAP/DAP12-transgenic mice

Lucas, Mathias; Daniel, Laurent; Tomasello, Elena; Guia, Sophie; Horschowski, N; Aoki, Naoko; Figarella‐Branger, Dominique; Gomez, Sophie; Vivier, Éric

doi:10.1002/1521-4141(200209)32:9<2653::aid-immu2653>3.0.co;2-v

Cited by 40 publications

(30 citation statements)

References 36 publications

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“…DAP12 gain-of-function Tg female mice, which express multiple integrated transgene copies of human DAP12 cDNA under the control of an MHC class I promoter/Ig enhancer expression cassette, have been described [25]. Loss-of-function DAP12 homozygous knockin mice were also as described [19].…”

Section: Methodsmentioning

confidence: 84%

“…Tg mice that overexpress DAP12 in both myeloid and lymphoid compartments are characterized by severe lymphopenia and massive inflammatory syndrome associated with neutrophilia and lung infiltration by multinucleated macrophages [25]. These myeloid abnormalities suggest that DAP12-driven signals are critically involved in inflammation, representing an essential target to control the resolution of inflammatory disorders based on monocytes/macrophages and neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…The addition of as few as 3% CD8 + DC to a population of CD8 -DC inhibits priming by the latter cells in this model of MHC class Irestricted reactivity to synthetic peptides [21,24]. DAP12-Tg mice, which overexpress DAP12 in myeloid and lymphoid cells, develop a massive inflammatory syndrome and lymphocytic immunodeficiency [25]. We compared CD8 + DC from control and DAP12-Tg mice for their ability to suppress priming to the HY peptide by CD8 -DC from control mice (Fig.…”

Section: Cd8mentioning

confidence: 91%

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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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Section: Methodsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Cd8mentioning

confidence: 91%

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Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

et al. 2005

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“…Secretion of soluble TREM-1 has been reported in LPS-stimulated human monocytes as well as during mouse bacterial infection, suggesting endogen- ous regulation of inflammatory processes [39]. Mice transgenic for human KARAP/DAP12 present a hyperresponsiveness to LPS-induced experimental septic shock [40]. Altogether, these data indicate that KARAP/DAP12-dependent signals amplify TLR-dependent inflammatory reactions.…”

Section: Karap/dap12 In T and B Lymphocytesmentioning

confidence: 88%

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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“…In addition, the biological functions of proinflammatory macrophages are redirected to alternate functions including humoral immunity and wound healing [10]. Although regulation is predominantly under control of cytokines [11], regulation by myeloid cells is important in "fine tuning" [12,13], and altered integration of the composite of activating/inhibitory signaling through such receptors is thought to contribute to many autoimmune processes [14][15][16].…”

Section: Structure: Function Analysis Of Cd200:cd200rmentioning

confidence: 99%

CD200:CD200R-Mediated Regulation of Immunity

Gorczynski

2012

ISRN Immunology

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The type 1 membrane glycoprotein CD200, widely expressed on multiple cells/tissues, uses a structurally similar receptor (CD200R1), whose expression is more restricted to cells of the myeloid and lymphoid lineages, to transmit signals affecting responses in multiple physiological systems. Thus CD200 expression is reported to exert effects on cancer growth, autoimmune and allergic disorders, infection, transplantation, bone development and homeostasis, and reproductive biology. It was initially thought, based on the idea that CD200R1 was mostly expressed on cells of myeloid origin, that CD200:CD200R1 interactions were primarily dedicated to controlling myeloid cell function. However additional members of the CD200R family have now also been identified, although their function(s) remain unclear, and CD200R1 itself is now known to be expressed by subsets of T cells and other cells. Together these observations add layers of complexity to our understanding of CD200-related regulation. In common with a number of physiological systems, the mechanism(s) of CD200-induced signaling seem to fit within a similar framework of opposing actions of kinases and phosphatases. This paper highlights the advances in our knowledge of immunoregulation achieved following CD200:CD200R interaction and the potential clinical applicability of that information.

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Massive inflammatory syndrome and lymphocytic immunodeficiency in KARAP/DAP12-transgenic mice

Cited by 40 publications

References 36 publications

Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12

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

CD200:CD200R-Mediated Regulation of Immunity

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