Abstract
Leukocyte immunoglobulin-like receptor (LILR)B3 and LILRA6 represent a pair of inhibitory/activating receptors with identical extracellular domains and unknown ligands. LILRB3 can mediate inhibitory signaling via immunoreceptor tyrosine-based inhibition motifs in its cytoplasmic tail whereas LILRA6 can signal through association with an activating adaptor molecule, FcRγ, which bears a cytoplasmic tail with an immunoreceptor tyrosine-based activation motif. The receptors are encoded by two highly polymorphic neighboring genes within the leukocyte receptor complex on human chromosome 19. Here, we report that the two genes display similar levels of single nucleotide polymorphisms with the majority of polymorphic sites being identical. In addition, the LILRA6 gene exhibits copy number variation (CNV) whereas LILRB3 does not. A screen of healthy Caucasians indicated that 32 % of the subjects possessed more than two copies of LILRA6, whereas 4 % have only one copy of the gene per diploid genome. Analysis of mRNA expression in the major fractions of PBMCs showed that LILRA6 is primarily expressed in monocytes, similarly to LILRB3, and its expression level correlates with copy number of the gene. We suggest that the LILRA6 CNV may influence the level of the activating receptor on the cell surface, potentially affecting signaling upon LILRB3/A6 ligation.
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References
Allen RL, Raine T, Haude A, Trowsdale J, Wilson MJ (2001) Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures. J Immunol 167:5543–5547
Anderson KJ, Allen RL (2009) Regulation of T cell immunity by leucocyte immunoglobulin-like receptors: innate immune receptors for self on antigen-presenting cells. Immunology 127:8–17
Banchereau J, Zurawski S, Thompson-Snipes L, Blanck JP, Clayton S, Munk A, Cao Y, Wang Z, Khandelwal S, Hu J, McCoy WH, Palucka KA, Reiter Y, Fremont DH, Zurawski G, Colonna M, Shaw AS, Klechevsky E (2012) Immunoglobulin-like transcript receptors on human dermal CD14+ dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming. Proc Natl Acad Sci U S A 109:18885–18890
Borges L, Hsu ML, Fanger N, Kubin M, Cosman D (1997) A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J Immunol 159:5192–5196
Cao W, Bover L, Cho M, Wen X, Hanabuchi S, Bao M, Rosen DB, Wang YH, Shaw JL, Du Q, Li C, Arai N, Yao Z, Lanier LL, Liu YJ (2009) Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J Exp Med 206:1603–1614
Colonna M, Navarro F, Bellon T, Llano M, Garcia P, Samaridis J, Angman L, Cella M, Lopez-Botet M (1997) A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp Med 186:1809–1818
Colonna M, Samaridis J, Cella M, Angman L, Allen RL, O'Callaghan CA, Dunbar R, Ogg GS, Cerundolo V, Rolink A (1998) Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol 160:3096–3100
Colonna M, Nakajima H, Navarro F, Lopez-Botet M (1999) A novel family of Ig-like receptors for HLA class I molecules that modulate function of lymphoid and myeloid cells. J Leukoc Biol 66:375–381
Daeron M, Jaeger S, Du Pasquier L, Vivier E (2008) Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol Rev 224:11–43
D'Haene B, Vandesompele J, Hellemans J (2010) Accurate and objective copy number profiling using real-time quantitative PCR. Methods 50:262–270
Gu W, Zhang F, Lupski JR (2008) Mechanisms for human genomic rearrangements. PathoGenetics 1:4
Huang J, Burke PS, Cung TD, Pereyra F, Toth I, Walker BD, Borges L, Lichterfeld M, Yu XG (2010) Leukocyte immunoglobulin-like receptors maintain unique antigen-presenting properties of circulating myeloid dendritic cells in HIV-1-infected elite controllers. J Virol 84:9463–9471
Humphrey MB, Lanier LL, Nakamura MC (2005) Role of ITAM-containing adapter proteins and their receptors in the immune system and bone. Immunol Rev 208:50–65
Jones DC, Kosmoliaptsis V, Apps R, Lapaque N, Smith I, Kono A, Chang C, Boyle LH, Taylor CJ, Trowsdale J, Allen RL (2011) HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding. J Immunol 186:2990–2997
Kuroki K, Furukawa A, Maenaka K (2012) Molecular recognition of paired receptors in the immune system. Front Microbiol 3:429
Mori Y, Tsuji S, Inui M, Sakamoto Y, Endo S, Ito Y, Fujimura S, Koga T, Nakamura A, Takayanagi H, Itoi E, Takai T (2008) Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development. J Immunol 181:4742–4751
Nakayama M, Underhill DM, Petersen TW, Li B, Kitamura T, Takai T, Aderem A (2007) Paired Ig-like receptors bind to bacteria and shape TLR-mediated cytokine production. J Immunol 178:4250–4259
Pfistershammer K, Lawitschka A, Klauser C, Leitner J, Weigl R, Heemskerk MH, Pickl WF, Majdic O, Bohmig GA, Fischer GF, Greinix HT, Steinberger P (2009) Allogeneic disparities in immunoglobulin-like transcript 5 induce potent antibody responses in hematopoietic stem cell transplant recipients. Blood 114:2323–2332
Ryu M, Chen Y, Qi J, Liu J, Fan Z, Nam G, Shi Y, Cheng H, Gao GF (2011) LILRA3 binds both classical and non-classical HLA class I molecules but with reduced affinities compared to LILRB1/LILRB2: structural evidence. PLoS One 6:e19245
Sambrook JG, Bashirova A, Andersen H, Piatak M, Vernikos GS, Coggill P, Lifson JD, Carrington M, Beck S (2006) Identification of the ancestral killer immunoglobulin-like receptor gene in primates. BMC Genomics 7:209
Sloane DE, Tedla N, Awoniyi M, Macglashan DW Jr, Borges L, Austen KF, Arm JP (2004) Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition. Blood 104:2832–2839
Tedla N, Bandeira-Melo C, Tassinari P, Sloane DE, Samplaski M, Cosman D, Borges L, Weller PF, Arm JP (2003) Activation of human eosinophils through leukocyte immunoglobulin-like receptor 7. Proc Natl Acad Sci U S A 100:1174–1179
Torkar M, Haude A, Milne S, Beck S, Trowsdale J, Wilson MJ (2000) Arrangement of the ILT gene cluster: a common null allele of the ILT6 gene results from a 6.7-kbp deletion. Eur J Immunol 30:3655–3662
Willcox BE, Thomas LM, Bjorkman PJ (2003) Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nat Immunol 4:913–919
Acknowledgments
This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. X.G.Y. was supported by NIH/NIAID R01 AI078799. We would like to thank Colm O'huigin, Daniel McVicar, and Ludmila Lyakh for helpful discussions and the BSP CCR Genetics Core for technical assistance.
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The authors declare that they have no conflict of interest.
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Bashirova, A.A., Apps, R., Vince, N. et al. Diversity of the human LILRB3/A6 locus encoding a myeloid inhibitory and activating receptor pair. Immunogenetics 66, 1–8 (2014). https://doi.org/10.1007/s00251-013-0730-9
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DOI: https://doi.org/10.1007/s00251-013-0730-9