Paired opposing leukocyte receptors recognizing rapidly evolving ligands are subject to homogenization of their ligand binding domains

Fossum, Sigbjørn; Saether, Per C.; Vaage, John T.; Daws, Michael R.; Dissen, Erik

doi:10.1007/s00251-011-0553-5

Cited by 8 publications

(10 citation statements)

References 56 publications

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“…The inhibitory NKR-P1D receptor in C57BL/6 mice appears to be the functional homolog of the rat NKR-P1B receptor, and this receptor has been associated with a subset of NK cells with reduced expression of Ly49 receptors and elevated expression of NKG2 receptors (20). It should be noted that with the exception of NKR-P1F and -G, it is difficult to establish orthologous relationships between mouse and rat NKR-P1 receptors, presumably because of extensive homogenization of their ligand-binding parts (24,25). The separation of KIR/Ly49 and NKG2 into overlapping subsets thus appears to be a common phenomenon across the species.…”

Section: N Atural Killer Cells Are Important Contributors To the Earlmentioning

confidence: 99%

A Novel NKR-P1Bbright NK Cell Subset Expresses an Activated CD25+CX3CR1+CD62L−CD11b−CD27− Phenotype and Is Prevalent in Blood, Liver, and Gut-Associated Lymphoid Organs of Rats

Inngjerdingen

Kveberg

Vaage

2012

The Journal of Immunology

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The inhibitory NKR-P1B receptor identifies a subset of rat splenic NK cells that is low in Ly49 receptors but enriched for CD94/NKG2 receptors. We report in this study a novel NKR-P1Bbright NK subpopulation that is prevalent in peripheral blood, liver, and gut-associated lymphoid organs and scarce in the spleen, peripheral lymph nodes, bone marrow, and lungs. This NKR-P1Bbright NK subset displays an activated phenotype, expressing CD25, CD93, CX3CR1 and near absence of CD62-L, CD11b, and CD27. Functionally, NKR-P1Bbright NK cells are highly responsive in terms of IFN-γ production and exert potent cytolytic activity. They show little spontaneous proliferation, are reduced in numbers upon in vivo activation with polyinosinic:polycytidylic acid, and have poor survival in ex vivo cytokine cultures. Our findings suggest that NKR-P1Bbright NK cells are fully differentiated effector cells that rapidly die upon further activation. The identification of this novel rat NK cell subset may facilitate future translational research of the role of distinct NK cell subsets under normal physiological conditions and during ongoing immune responses.

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Section: N Atural Killer Cells Are Important Contributors To the Earlmentioning

confidence: 99%

A Novel NKR-P1Bbright NK Cell Subset Expresses an Activated CD25+CX3CR1+CD62L−CD11b−CD27− Phenotype and Is Prevalent in Blood, Liver, and Gut-Associated Lymphoid Organs of Rats

Inngjerdingen

Kveberg

Vaage

2012

The Journal of Immunology

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“…We and others have previously discussed the origin and evolution of pairs of activating and inhibitory NK cells receptors (62,63). It seems likely that KIR2DS2 might have evolved from a KIR2DL2/ 3-like ancestor, and one hypothesis suggests that activating NK receptors in evolution have undergone cycles of birth and death, always arising from an inhibitory ancestor by recombination events (62).…”

Section: Discussionmentioning

confidence: 99%

“…It seems likely that KIR2DS2 might have evolved from a KIR2DL2/ 3-like ancestor, and one hypothesis suggests that activating NK receptors in evolution have undergone cycles of birth and death, always arising from an inhibitory ancestor by recombination events (62). Although not yet completely understood, most if not all pairs of activating/inhibitory NK cell receptors seem to be under a selective pressure to maintain some similarity in their ligand-binding domains, occurring by exchange of genetic material (gene conversion or unequal crossing-over) between activating and inhibitory receptor loci (63). Although incompletely understood in the absence of identified ligands for activating KIR, this suggests that the functions of activating and inhibitory receptors such as KIR2DS2 and -2DL2/-2DL3 are interrelated, in some instances possibly regulating NK cell responses to the same ligand.…”

Section: Discussionmentioning

confidence: 99%

The Activating Human NK Cell Receptor KIR2DS2 Recognizes a β2-Microglobulin–Independent Ligand on Cancer Cells

Thiruchelvam-Kyle

Hoelsbrekken

Saether

et al. 2017

The Journal of Immunology

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The functions of activating members of the killer cell Ig-like receptor (KIR) family are not fully understood, as the ligands for these receptors are largely unidentified. In this study, we report that KIR2DS2 reporter cells recognize a ligand expressed by cancer cell lines. All cancer targets recognized by KIR2DS2 were also recognized by KIR2DL2 and KIR2DL3 reporters. Trogocytosis of membrane proteins from the cancer targets was observed with responding reporter cells, indicating the formation of KIR2DS2 ligand-specific immunological synapses. HLA-C typing of target cells showed that KIR2DS2 recognition was independent of the HLA C1 or C2 group, whereas targets cells that were only recognized by KIR2DL3 expressed C1 group alleles. Anti-HLA class I Abs blocked KIR2DL3 responses toward C1-expressing targets, but they did not block KIR2DS2 recognition of cancer cells. Small interfering RNA knockdown of β-microglobulin reduced the expression of class I H chain on the cancer targets by >97%, but it did not reduce the KIR2DS2 reporter responses, indicating a β-microglobulin-independent ligand for KIR2DS2. Importantly, KIR2DL3 responses toward some KIR2DS2 ligand-expressing cells were also undiminished after β-microglobulin knockdown, and they were not blocked by anti-HLA class I Abs, suggesting that KIR2DL3, in addition to the traditional HLA-C ligands, can bind to the same β-microglobulin-independent ligand as KIR2DS2. These observations indicate the existence of a novel, presently uncharacterized ligand for the activating NK cell receptor KIR2DS2. Molecular identification of this ligand may lead to improved KIR-HLA mismatching in hematopoietic stem cell transplantation therapy for leukemia and new, more specific NK cell-based cancer therapies.

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“…In paired receptors, pathogen-binding regions have to stay similar thus allowing the host to counterbalance the immune suppressive signal elicited by engagement of the inhibitory receptor through the pathogen by providing an activating receptor as a mimic [33,34]. In other paired receptor gene families this is often achieved by recombination or gene conversion between genes encoding inhibitory and activating receptors, restricted to the gene region encoding the ligand binding domains [33]. We, therefore, screened the potential Xenopus paired receptor genes for recombination/gene conversion events.…”

Section: Similarity Of Receptor Binding Domains Of Paired Receptors Imentioning

confidence: 99%

Coevolution of paired receptors in Xenopus carcinoembryonic antigen-related cell adhesion molecule families suggests appropriation as pathogen receptors

Zimmermann

Kammerer

2016

BMC Genomics

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BackgroundIn mammals, CEACAM1 and closely related members represent paired receptors with similar extracellular ligand-binding regions and cytoplasmic domains with opposing functions. Human CEACAM1 and CEACAM3 which have inhibitory ITIM/ITSM and activating ITAM-like motifs, respectively, in their cytoplasmic regions are such paired receptors. Various bacterial pathogens bind to CEACAM1 on epithelial and immune cells facilitating both entry into the host and down-regulation of the immune response whereas interaction with granulocyte-specific CEACAM3 leads to their uptake and destruction. It is unclear whether paired CEACAM receptors also exist in other vertebrate clades.ResultsWe identified more than 80 ceacam genes in Xenopus tropicalis and X. laevis. They consist of two subgroups containing one or two putative paired receptor pairs each. Analysis of genomic sequences of paired receptors provide evidence that their highly similar ligand binding domains were adjusted by recent gene conversion events. In contrast, selection for diversification is observed among inhibitory receptor orthologs of the two frogs which split some 60 million years ago. The allotetraploid X. laevis arose later by hybridization of two closely related species. Interestingly, despite the conservation of the genomic landscape surrounding the homeologous ceacam loci only one locus resembles the one found in X. tropicalis. From the second X. laevis locus more than 80 % of the ceacam genes were lost including 5 of the 6 paired receptor genes. This suggests that once the gene for one of the paired receptors is lost the remaining gene cluster degrades rapidly probably due to lack of selection pressure exerted by pathogens.ConclusionsThe presence of paired receptors and selection for diversification suggests that also in amphibians CEACAM1-related inhibitory proteins are or were used as pathogen receptors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3279-9) contains supplementary material, which is available to authorized users.

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Paired opposing leukocyte receptors recognizing rapidly evolving ligands are subject to homogenization of their ligand binding domains

Cited by 8 publications

References 56 publications

A Novel NKR-P1Bbright NK Cell Subset Expresses an Activated CD25+CX3CR1+CD62L−CD11b−CD27− Phenotype and Is Prevalent in Blood, Liver, and Gut-Associated Lymphoid Organs of Rats

A Novel NKR-P1Bbright NK Cell Subset Expresses an Activated CD25+CX3CR1+CD62L−CD11b−CD27− Phenotype and Is Prevalent in Blood, Liver, and Gut-Associated Lymphoid Organs of Rats

The Activating Human NK Cell Receptor KIR2DS2 Recognizes a β2-Microglobulin–Independent Ligand on Cancer Cells

Coevolution of paired receptors in Xenopus carcinoembryonic antigen-related cell adhesion molecule families suggests appropriation as pathogen receptors

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