Inhibition of natural killer cell activation signals by killer cell immunoglobulin‐like receptors (CD158)

Long, Eric O.; Barber, Domingo F.; Burshtyn, Deborah N.; Faure, Mathias; Peterson, Mary; Rajagopalan, Sumati; Renard, Valéry; Sandusky, Mina; Stebbins, Christopher; Wagtmann, Nicolai; Watzl, Carsten

doi:10.1034/j.1600-065x.2001.1810119.x

Cited by 129 publications

(99 citation statements)

References 3 publications

(3 reference statements)

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“…However, none of the aforementioned receptors has signaling properties or distributions similar to those reported for KIR2DL4 [11,14,[22][23][24]. By contrast, KIR3DL3, whose ligand and functionality are unknown, shares with KIR2DL4 having a single ITIM and being well conserved in different individuals of several primate species [32][33][34][48][49][50]. Therefore, although the structures of these two receptors are otherwise divergent, this convergent feature makes it worth considering whether they might substitute for some of each other's functions.…”

Section: Discussionmentioning

confidence: 94%

Recognition of HLA‐G by the NK cell receptor KIR2DL4 is not essential for human reproduction

et al. 2003

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A central issue of reproductive immunology in mammals is why a semi-allogeneic embryo is not rejected by the pregnant mother. This is particularly intriguing since, in different species, the early pregnant uterus is infiltrated by numerous maternal lymphocytes, predominantly NK cells. The human NK cell receptor KIR2DL4 has been implicated in the maternal tolerance to the embryo due to its recognition of HLA-G, a non-classical MHC molecule expressed preferentially in the placenta. Killer cell Ig-like receptors (KIR) are believed to participate in the natural immunity to infection and tumors, but KIR2DL4 has unique structural, functional and genetic features that could confer it a different role. However, we demonstrate here that the KIR2DL4:HLA-G interaction is not essential for human reproduction by showing that a multiparous woman lacks a KIR2DL4 gene.

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Section: Discussionmentioning

confidence: 94%

Recognition of HLA‐G by the NK cell receptor KIR2DL4 is not essential for human reproduction

et al. 2003

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“…Based on these data, the observed low or nonexistent expression of KIR3DL3 (29) is possibly due to a lack of core promoter elements. In the upstream region of this gene, the sequence between Ϫ40 bp and the ATG is identical with that of KIR3DL1.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the two KIR genes showing divergence in expression pattern (KIR3DL3 and KIR2DL4) belong to those framework loci with upstream sequences present in unique or divergent regions of the KIR cluster. KIR3DL3 (otherwise known as KIR3DL7 or KIRC1) does not appear to be expressed by the circulating NK cell pool in many donors (29). Most reports indicate that all NK clones and KIR-positive T cell clones express KIR2DL4 transcripts (16,23,24,30,31).…”

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confidence: 99%

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

Stewart

Bergen

Trowsdale

2003

The Journal of Immunology

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The killer Ig-like receptors (KIR) are a family of highly related MHC class I receptors that show extreme genetic polymorphism both within the human population and between closely related primate species, suggestive of rapid evolutionary diversification. Most KIR are expressed in a variegated fashion by the NK population, giving rise to an NK repertoire of specificities for MHC class I. We compared the promoter for KIR3DL1, which exhibits variegated gene expression, with that for KIR2DL4, which is expressed by all NK cell clones. Maximum transcriptional activity of each was encoded within ∼270 bp upstream of the translation initiation codon. The KIR2DL4 promoter drove reporter gene expression only in NK cells, while the KIR3DL1 promoter was active in a range of cell types, suggesting that the latter requires other regulatory elements for physiological expression. In NK cells, reporter gene expression driven by the KIR2DL4 promoter was greater than that driven by the KIR3DL1 promoter. DNase I footprinting revealed that transcription factor binding sites differ between the two promoters. The data indicate that while the promoters of these two KIR genes share 67% nucleotide identity, they have evolved distinct properties consistent with different roles in regulating the generation of NK repertoire.

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“…ITIM motifs usually couple to phosphatases to promote inhibitory signaling (19). We therefore transfected 293T cells with His-tagged WT or mutant human CLEC12B in combination with SHP-1 or SHP-2.…”

Section: Resultsmentioning

confidence: 99%

Identification of CLEC12B, an Inhibitory Receptor on Myeloid Cells

Hoffmann

Schellack

Textor

et al. 2007

Journal of Biological Chemistry

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Activation of immune cells has to be tightly controlled to prevent detrimental hyperactivation. In this regulatory process molecules of the C-type lectin-like family play a central role. Here we describe a new member of this family, CLEC12B. The extracellular domain of CLEC12B shows considerable homology to the activating natural killer cell receptor NKG2D, but unlike NKG2D, CLEC12B contains an immunoreceptor tyrosine-based inhibition motif in its intracellular domain. Despite the homology, CLEC12B does not appear to bind NKG2D ligands and therefore does not represent the inhibitory counterpart of NKG2D. However, CLEC12B has the ability to counteract NKG2D-mediated signaling, and we show that this function is dependent on the immunoreceptor tyrosine-based inhibition motif and the recruitment of the phosphatases SHP-1 and SHP-2. Using monoclonal anti-CLEC12B antibodies we found de novo expression of this receptor on in vitro generated human macrophages and on the human myelo-monocytic cell line U937 upon phorbol 12-myristate 13-acetate treatment, suggesting that this receptor plays a role in myeloid cell function.Activation of the immune system has to be tightly regulated to prevent the attack of self-antigens and the development of autoimmunity (1). This is in part accomplished by a sophisticated system of various receptors that create a delicate balance of activating and inhibitory signals (2, 3). These receptors are present on different immune cells but play a major role for the innate immune system.Many receptors share common signaling motifs to transmit their signal into the cell. Activating receptors usually signal via the immunoreceptor tyrosine-based activation motif containing tyrosine residues that can be phosphorylated upon receptor engagement and can recruit Syk family kinases (4). Inhibitory receptors often possess an Immunoreceptor Tyrosine-based Inhibition Motif (ITIM), 4 which can recruit phosphatases upon phosphorylation (5). These phosphatases, like SHP-1 or SHP-2, are able to de-phosphorylate and therefore inhibit intracellular factors that otherwise would promote cellular activation (6).Interestingly, many activating and inhibitory receptors come in pairs, with a strong homology of the extracellular domains and partially overlapping ligand specificity but opposite signaling capacities (2). One reason for the existence of these receptor pairs might be to avoid extreme immune reactions to minor threats. Examples for these paired receptors are killer cell Iglike receptors on natural killer (NK) cells, which comprise inhibitory and activating receptors, both recognizing the same major histocompatibility complex class I ligand (5, 7). Also in the family of lectin-like receptors can be found antithetic pairs that are specific for the same ligand but transmit opposing signals (8). For example, the NKG2A-CD94 heterodimer transmits an inhibitory signal and NKG2C-CD94 signals in an activating fashion while both receptors recognize the same ligand, HLA-E.NKG2D is a C-type lectin-like receptor and plays a...

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Inhibition of natural killer cell activation signals by killer cell immunoglobulin‐like receptors (CD158)

Cited by 129 publications

References 3 publications

Recognition of HLA‐G by the NK cell receptor KIR2DL4 is not essential for human reproduction

Recognition of HLA‐G by the NK cell receptor KIR2DL4 is not essential for human reproduction

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

Identification of CLEC12B, an Inhibitory Receptor on Myeloid Cells

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