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Front. Immunol. | doi: 10.3389/fimmu.2019.00024

Conservation, extensive heterozygosity, and convergence of signaling potential all indicate a critical role for KIR3DL3 in higher primates.

 Laura A. Leaton1, 2, Jonathan Shortt1, Katherine M. Kichula1, 2, Sudan Tao1, 2, 3, Neda Nemat-Gorgani4, 5, Alexander J. Mentzer6, 7, Stephen J. Oppenheimer8, Zhi H. Deng9,  Jill A. Hollenbach10, Christopher R. Gignoux1, Lisbeth A. Guethlein4, 5, Peter Parham4, 5,  Mary N. Carrington11 and  Paul J. Norman1, 2*
  • 1Division of Bioinformatics and Personalized Medicine, School of Medicine, University of Colorado, United States
  • 2Department of Immunology and Microbiology, School of Medicine, University of Colorado, United States
  • 3Blood Center of Zhejiang Province, China
  • 4Department of Structural Biology, School of Medicine, Stanford University, United States
  • 5Department of Microbiology and Immunology, School of Medicine, Stanford University, United States
  • 6Jenner Institute, Nuffield Department of Medicine, University of Oxford, United Kingdom
  • 7Wellcome Trust Centre for Human Genetics (WT), United Kingdom
  • 8University of Oxford, United Kingdom
  • 9Shenzhen Blood Center, China
  • 10Department of Neurology, University of California, San Francisco, United States
  • 11Frederick National Laboratory for Cancer Research (NIH), United States

Natural killer 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.

Keywords: KIR, KIR3DL3, NK cells, HLA class 1, Comparative evolutionary analysis, Reproduction, Infectious Disease

Received: 10 Dec 2018; Accepted: 07 Jan 2019.

Edited by:

Ronald Bontrop, Biomedical Primate Research Centre, Netherlands

Reviewed by:

Ralf Dressel, University Medical Center Göttingen, Germany
John Trowsdale, University of Cambridge, United Kingdom  

Copyright: © 2019 Leaton, Shortt, Kichula, Tao, Nemat-Gorgani, Mentzer, Oppenheimer, Deng, Hollenbach, Gignoux, Guethlein, Parham, Carrington and Norman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Paul J. Norman, School of Medicine, University of Colorado, Division of Bioinformatics and Personalized Medicine, Aurora, 80045, Colorado, United States,