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1.
J Clin Invest ; 128(4): 1523-1537, 2018 04 02.
Article in English | MEDLINE | ID: mdl-29528338

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.


Subject(s)
Antigens, CD , Capsid Proteins , Cytomegalovirus Infections , Cytomegalovirus , Genetic Predisposition to Disease , HLA-G Antigens , Leukocyte Immunoglobulin-like Receptor B1 , Organ Transplantation , Polymorphism, Genetic , Antigens, CD/genetics , Antigens, CD/immunology , Capsid Proteins/genetics , Capsid Proteins/immunology , Cell Line , Cytomegalovirus/genetics , Cytomegalovirus/immunology , Cytomegalovirus Infections/genetics , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/pathology , Female , HLA-G Antigens/genetics , HLA-G Antigens/immunology , Humans , Killer Cells, Natural/immunology , Leukocyte Immunoglobulin-like Receptor B1/genetics , Leukocyte Immunoglobulin-like Receptor B1/immunology , Male
2.
Int Immunol ; 26(1): 21-33, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24038602

ABSTRACT

Leukocyte immunoglobulin-like receptor 1 (LILRB1) is an inhibitory receptor that binds classical and non-classical MHC-I as well as UL18, a viral MHC-I homolog. LILRB1 is encoded within the leukocyte receptor complex and is widely expressed on immune cells. Two distinct promoters used differentially by lymphoid and myeloid cells were previously identified, but little is known regarding molecular regulation of each promoter or cell-type-specific usage. Here, we have investigated the transcriptional regulation of human LILRB1 focusing on elements that drive expression in NK cells. We found that while both the distal and proximal promoter regions are active in reporter plasmids in lymphoid and myeloid cells, the proximal promoter is used minimally to transcribe LILRB1 in NK cells compared with monocytes. We defined a 120-bp core region of transcriptional activity in the distal promoter that can bind several factors in NK cell nuclear extracts. Within this region, we investigated overlapping putative AP-1 sites. An inhibitor of JNK decreased LILRB1 transcript in a LILRB1⁺ NK cell line. Upon examining binding of specific AP-1 factors, we found JunD associated with the LILRB1 distal promoter. Finally, depletion of JunD led to a decrease in distal promoter transcript, indicating an activating role for JunD in regulation of LILRB1 transcription. This study presents the first description of regions/factors required for activity of the LILRB1 distal promoter, the first description of a role for JunD in NK cells and suggests a potential mechanism for dynamic regulation of LILRB1 by cytokines.


Subject(s)
Antigens, CD/genetics , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins c-jun/genetics , Receptors, Immunologic/genetics , Transcription Factor AP-1/genetics , Cell Line , Gene Expression Regulation/genetics , Humans , Killer Cells, Natural/metabolism , Leukocyte Immunoglobulin-like Receptor B1 , MAP Kinase Kinase 4/genetics , Monocytes/metabolism , Transcription, Genetic/genetics
3.
J Immunol ; 188(10): 4980-91, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22491247

ABSTRACT

Innate immune recognition of virus-infected cells includes NK cell detection of changes to endogenous cell-surface proteins through inhibitory receptors. One such receptor system is the NK cell receptor protein-1B (NKR-P1B) and its ligand C-type lectin-related-b (Clr-b). NKR-P1B and Clr-b are encoded within the NK cell gene complex, a locus that has been linked to strain-dependent differences in susceptibility to infection by poxviruses. In this study, we report the impact of vaccinia virus (VV) and ectromelia virus infection on expression of Clr-b and Clr-b-mediated protection from NK cells. We observed a loss of Clr-b cell-surface protein upon VV and ectromelia virus infection of murine cell lines and bone marrow-derived macrophages. The reduction of Clr-b is more rapid than MHC class I, the prototypic ligand of NK cell inhibitory receptors. Reduction of Clr-b requires active viral infection but not expression of late viral genes, and loss of mRNA appears to lag behind loss of Clr-b surface protein. Clr-b-mediated protection from NK cells is lost following VV infection. Together, these results provide the second example of Clr-b modulation during viral infection and suggest reductions of Clr-b may be involved in sensitizing poxvirus-infected cells to NK cells.


Subject(s)
Down-Regulation/immunology , Killer Cells, Natural/immunology , Lectins, C-Type/antagonists & inhibitors , NK Cell Lectin-Like Receptor Subfamily B/physiology , Receptors, Immunologic/physiology , Vaccinia virus/immunology , Vaccinia virus/metabolism , Animals , CHO Cells , Cell Line , Cell Line, Tumor , Cricetinae , Humans , Hypersensitivity/immunology , Killer Cells, Natural/metabolism , Killer Cells, Natural/virology , Lectins, C-Type/metabolism , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Signal Transduction/immunology
4.
Front Immunol ; 2: 46, 2011.
Article in English | MEDLINE | ID: mdl-22566836

ABSTRACT

Leukocyte Ig-like receptor 1 (LIR-1) is an inhibitory Ig superfamily receptor with broad specificity for MHC-I expressed on leukocytes including natural killer (NK) and T cells. The extent of LIR-1 expression on NK cells is quite disparate between donors but the regulation of LIR-1 in NK cells is poorly understood. We examined expression profiles of LIR-1 on NK and T lymphocytes in 11 healthy donors over 1 year. Four of the 11 donors demonstrated substantial increases in LIR-1⁺ NK cells. High levels of LIR-1 expression were not correlated with exposure to human cytomegalovirus or the fraction of CD57⁺ NK cells in the donor. LIR-1 levels on ex vivo NK and CD56⁺ T cells were increased in vitro by short term exposure to IL-2 or IL-15 compared to control but not with various other cytokines tested. Sorted CD56(bright) NK cells also increased LIR-1 expression when cultured in IL-2. Maintenance of LIR-1 on longer term NK cells was also dependent on continuous stimulation by IL-15 or IL-2. While we could not detect increases in total LIR-1 mRNA in response to cytokine treatment by qPCR, we observed a shift in activity of LIR-1 promoter reporter constructs in the presence of IL-2 favoring the more translationally active transcript from the proximal promoter. Together these results show LIR-1 on NK cells is under the control of cytokines known to drive NK cell maturation and activation and suggest availability of such cytokines may alter the NK repertoire in vivo as we observed in several donors with fluctuating levels of LIR-1 on their NK cells.

5.
Hum Immunol ; 71(10): 942-9, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20600445

ABSTRACT

Leukocyte Ig-like receptor (LIR)-1 is an inhibitory receptor that binds a broad range of class I HLA molecules and is encoded by the LILRB1 gene within the leukocyte receptor complex. In contrast to uniform expression on monocytes and B cells, LIR-1 expression on natural killer (NK) cells varies considerably between individuals. To investigate how polymorphism is related to the observed patterns of expression, we analyzed the LILRB1 gene and its transcriptional activity in a group of individuals with various levels of expression on NK cells. We found that LILRB1 transcription is correlated with surface protein expression on NK cells. In a cohort of 24 donors, we found high expression on NK cells to be associated with three linked SNPs (AGG verses GAA) within the putative regulatory region. We also identified several new protein variants and observed variants with P, T, T, and I at positions 68, 95, 142, and 155, respectively, more frequently in donors with low expression on NK cells. These results suggest that there is a significant degree of diversity within the LILRB1 locus and that it influences expression patterns on NK cells. These genetic differences may underpin variation in individual immune responses involving LIR-1 on NK cells.


Subject(s)
Antigens, CD/genetics , Antigens, CD/metabolism , Killer Cells, Natural/metabolism , Lymphocyte Subsets/metabolism , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Alleles , Amino Acid Sequence , Antigens, CD/immunology , Cell Line , Cell Separation , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation/immunology , Genetic Association Studies , Humans , Immunophenotyping , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Leukocyte Immunoglobulin-like Receptor B1 , Lymphocyte Subsets/cytology , Lymphocyte Subsets/immunology , Molecular Sequence Data , Polymorphism, Genetic , Receptors, Immunologic/immunology
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