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LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions
Kang Yu, … , Swiss Transplant Cohort Study, Deborah N. Burshtyn
Kang Yu, … , Swiss Transplant Cohort Study, Deborah N. Burshtyn
Published March 12, 2018
Citation Information: J Clin Invest. 2018;128(4):1523-1537. https://doi.org/10.1172/JCI96174.
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Research Article Immunology Infectious disease

LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions

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Abstract

UL18 is a human CMV (HCMV) MHC class I (MHCI) homolog that efficiently inhibits leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1)+ NK cells. We found an association of LILRB1 polymorphisms in the regulatory regions and ligand-binding domains with control of HCMV in transplant patients. Naturally occurring LILRB1 variants expressed in model NK cells showed functional differences with UL18 and classical MHCI, but not with HLA-G. The altered functional recognition was recapitulated in binding assays with the binding domains of LILRB1. Each of 4 nonsynonymous substitutions in the first 2 LILRB1 immunoglobulin domains contributed to binding with UL18, classical MHCI, and HLA-G. One of the polymorphisms controlled addition of an N-linked glycan, and that mutation of the glycosylation site altered binding to all ligands tested, including enhancing binding to UL18. Together, these findings indicate that specific LILRB1 alleles that allow for superior immune evasion by HCMV are restricted by mutations that limit LILRB1 expression selectively on NK cells. The polymorphisms also maintained an appropriate interaction with HLA-G, fitting with a principal role of LILRB1 in fetal tolerance.

Authors

Kang Yu, Chelsea L. Davidson, Agnieszka Wójtowicz, Luiz Lisboa, Ting Wang, Adriana M. Airo, Jean Villard, Jeremie Buratto, Tatyana Sandalova, Adnane Achour, Atul Humar, Katia Boggian, Alexia Cusini, Christian van Delden, Adrian Egli, Oriol Manuel, Nicolas Mueller, Pierre-Yves Bochud, Swiss Transplant Cohort Study, Deborah N. Burshtyn

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Figure 5

Mutation of the putative glycosylation site alters binding.

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Mutation of the putative glycosylation site alters binding.
(A) The sequ...
(A) The sequence surrounding the putative N-linked glycosylation site NVT at position 117 is shown for both variants. The region boxed in red illustrates the target sequence NVT, present only in the variants with T at position 119. (B) LILRB1-PTTI and -LAIS variants treated with N-glycosidase analyzed by SDS-PAGE and Western blot. Lanes 1–2 are KIR3DL1-Fc, 3–4 are LILRB1-PTTI-Fc, 5–6 are LILRB1-LAIS-Fc, and 7 is the molecular weight marker. (C) Representative SDS-PAGE and Coomassie blue staining of the LILRB1-Fc N117Q-PTTI and N117Q-LAIS mutants. Lanes from left to right indicate the protein ladder, LILRB1-PTTI-Fc, N117Q-PTTI-Fc, LILRB1-LAIS-Fc, and N117Q-LAIS-Fc. (D) Reactivity with α-LILRB1 (HPF1) for the mutated LILRB1 by ELISA. Results shown are the average of 3 independent tests for the same batch of protein; error bars represent SD. (E) Fc fusion protein binding to cells expressing the ligands at the top was measured by flow cytometry as before. Significance testing was performed between the binding of each artificial mutants and PTTI. *P < 0.05, ns = P ≥ 0.05 using 1-way ANOVA. The plots are the normalized binding results aggregated from at least 3 independent tests (4 and 5 independent tests for HLA-G and UL18, respectively).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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