Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates
Natural killer (NK) cell functions are modulated by polymorphic killer cell immunoglobulin-like receptors (KIR). Among 13 human KIR genes, which vary by presence and copy number, KIR3DL3 is ubiquitously present in every individual across diverse populations. No ligand or function is known for KIR3DL...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00024/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Laura A. Leaton Laura A. Leaton Jonathan Shortt Katherine M. Kichula Katherine M. Kichula Sudan Tao Sudan Tao Sudan Tao Neda Nemat-Gorgani Neda Nemat-Gorgani Alexander J. Mentzer Stephen J. Oppenheimer Zhihui Deng Jill A. Hollenbach Christopher R. Gignoux Lisbeth A. Guethlein Lisbeth A. Guethlein Peter Parham Peter Parham Mary Carrington Mary Carrington Paul J. Norman Paul J. Norman |
| spellingShingle |
Laura A. Leaton Laura A. Leaton Jonathan Shortt Katherine M. Kichula Katherine M. Kichula Sudan Tao Sudan Tao Sudan Tao Neda Nemat-Gorgani Neda Nemat-Gorgani Alexander J. Mentzer Stephen J. Oppenheimer Zhihui Deng Jill A. Hollenbach Christopher R. Gignoux Lisbeth A. Guethlein Lisbeth A. Guethlein Peter Parham Peter Parham Mary Carrington Mary Carrington Paul J. Norman Paul J. Norman Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates Frontiers in Immunology KIR3DL3 NK cells KIR HLA class I comparative evolution infectious disease |
| author_facet |
Laura A. Leaton Laura A. Leaton Jonathan Shortt Katherine M. Kichula Katherine M. Kichula Sudan Tao Sudan Tao Sudan Tao Neda Nemat-Gorgani Neda Nemat-Gorgani Alexander J. Mentzer Stephen J. Oppenheimer Zhihui Deng Jill A. Hollenbach Christopher R. Gignoux Lisbeth A. Guethlein Lisbeth A. Guethlein Peter Parham Peter Parham Mary Carrington Mary Carrington Paul J. Norman Paul J. Norman |
| author_sort |
Laura A. Leaton |
| title |
Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates |
| title_short |
Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates |
| title_full |
Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates |
| title_fullStr |
Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates |
| title_full_unstemmed |
Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates |
| title_sort |
conservation, extensive heterozygosity, and convergence of signaling potential all indicate a critical role for kir3dl3 in higher primates |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2019-01-01 |
| description |
Natural killer (NK) cell functions are modulated by polymorphic killer cell immunoglobulin-like receptors (KIR). Among 13 human KIR genes, which vary by presence and copy number, KIR3DL3 is ubiquitously present in every individual across diverse populations. No ligand or function is known for KIR3DL3, but limited knowledge of expression suggests involvement in reproduction, likely during placentation. With 157 human alleles, KIR3DL3 is also highly polymorphic and we show heterozygosity exceeds that of HLA-B in many populations. The external domains of catarrhine primate KIR3DL3 evolved as a conserved lineage distinct from other KIR. Accordingly, and in contrast to other KIR, we show the focus of natural selection does not correspond exclusively to known ligand binding sites. Instead, a strong signal for diversifying selection occurs in the D1 Ig domain at a site involved in receptor aggregation, which we show is polymorphic in humans worldwide, suggesting differential ability for receptor aggregation. Meanwhile in the cytoplasmic tail, the first of two inhibitory tyrosine motifs (ITIM) is conserved, whereas independent genomic events have mutated the second ITIM of KIR3DL3 alleles in all great apes. Together, these findings suggest that KIR3DL3 binds a conserved ligand, and a function requiring both receptor aggregation and inhibitory signal attenuation. In this model KIR3DL3 resembles other NK cell inhibitory receptors having only one ITIM, which interact with bivalent downstream signaling proteins through dimerization. Due to the extensive conservation across species, selection, and other unusual properties, we consider elucidating the ligand and function of KIR3DL3 to be a pressing question. |
| topic |
KIR3DL3 NK cells KIR HLA class I comparative evolution infectious disease |
| url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.00024/full |
| work_keys_str_mv |
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doaj-444209174b3f4e9882d65728b9988a4f2020-11-25T02:46:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-01-011010.3389/fimmu.2019.00024442089Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher PrimatesLaura A. Leaton0Laura A. Leaton1Jonathan Shortt2Katherine M. Kichula3Katherine M. Kichula4Sudan Tao5Sudan Tao6Sudan Tao7Neda Nemat-Gorgani8Neda Nemat-Gorgani9Alexander J. Mentzer10Stephen J. Oppenheimer11Zhihui Deng12Jill A. Hollenbach13Christopher R. Gignoux14Lisbeth A. Guethlein15Lisbeth A. Guethlein16Peter Parham17Peter Parham18Mary Carrington19Mary Carrington20Paul J. Norman21Paul J. Norman22Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO, United StatesDepartment of Microbiology & Immunology, University of Colorado, Aurora, CO, United StatesDivision of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO, United StatesDivision of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO, United StatesDepartment of Microbiology & Immunology, University of Colorado, Aurora, CO, United StatesDivision of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO, United StatesDepartment of Microbiology & Immunology, University of Colorado, Aurora, CO, United StatesBlood Center of Zhejiang Province, Hangzhou, ChinaDepartment of Structural Biology, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, United StatesWellcome Trust Centre for Human Genetics, and Jenner Institute, University of Oxford, Oxford, United KingdomInstitute of Social and Cultural Anthropology, School of Anthropology and Museum Ethnography, University of Oxford, Oxford, United KingdomImmunogenetics Laboratory, Shenzhen Blood Center, Shenzhen, ChinaDepartment of Neurology, University of California, San Francisco, San Francisco, CA, United StatesDivision of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO, United StatesDepartment of Structural Biology, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Structural Biology, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, United States0Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States1Ragon Institute of the Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA, United StatesDivision of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO, United StatesDepartment of Microbiology & Immunology, University of Colorado, Aurora, CO, United StatesNatural killer (NK) cell functions are modulated by polymorphic killer cell immunoglobulin-like receptors (KIR). Among 13 human KIR genes, which vary by presence and copy number, KIR3DL3 is ubiquitously present in every individual across diverse populations. No ligand or function is known for KIR3DL3, but limited knowledge of expression suggests involvement in reproduction, likely during placentation. With 157 human alleles, KIR3DL3 is also highly polymorphic and we show heterozygosity exceeds that of HLA-B in many populations. The external domains of catarrhine primate KIR3DL3 evolved as a conserved lineage distinct from other KIR. Accordingly, and in contrast to other KIR, we show the focus of natural selection does not correspond exclusively to known ligand binding sites. Instead, a strong signal for diversifying selection occurs in the D1 Ig domain at a site involved in receptor aggregation, which we show is polymorphic in humans worldwide, suggesting differential ability for receptor aggregation. Meanwhile in the cytoplasmic tail, the first of two inhibitory tyrosine motifs (ITIM) is conserved, whereas independent genomic events have mutated the second ITIM of KIR3DL3 alleles in all great apes. Together, these findings suggest that KIR3DL3 binds a conserved ligand, and a function requiring both receptor aggregation and inhibitory signal attenuation. In this model KIR3DL3 resembles other NK cell inhibitory receptors having only one ITIM, which interact with bivalent downstream signaling proteins through dimerization. Due to the extensive conservation across species, selection, and other unusual properties, we consider elucidating the ligand and function of KIR3DL3 to be a pressing question.https://www.frontiersin.org/article/10.3389/fimmu.2019.00024/fullKIR3DL3NK cellsKIRHLA class Icomparative evolutioninfectious disease |