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S Kollnberger - One of the best experts on this subject based on the ideXlab platform.
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the leukocyte immunoglobulin like receptor family member lilrb5 binds to hla class i heavy chains
PLOS ONE, 2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, J Shaw, Marloes Olde Nordkamp, Guosheng Jiang, S KollnbergerAbstract:Objective The leukocyte immunoglobulin-like receptor (LILR) family includes inhibitory and stimulatory members which bind to classical and non-classical HLA-class I. The ligands for many LILR including LILRB5 have not yet been identified. Methods We generated C-terminal eGFP and N-terminal FLAG-tagged fusion constructs for monitoring LILR expression. We screened for LILR binding to HLA-class I by tetramer staining of 293T cells transfected with LILRA1, A4, A5 A6 and LILRB2 and LILRB5. We also studied HLA class I tetramer binding to LILRB5 on peripheral monocyte cells. LILRB5 binding to HLA-class I heavy chains was confirmed by co-immunoprecipitation. Results HLA-B27 (B27) free heavy chain (FHC) dimer but not other HLA-class I stained LILRB5-transfected 293T cells. B27 dimer binding to LILRB5 was blocked with the class I heavy chain antibody HC10 and anti-LILRB5 antisera. B27 dimers also bound to LILRB5 on peripheral monocytes. HLA-B7 and B27 heavy chains co-immunoprecipitated with LILRB5 in transduced B and rat basophil RBL cell lines. Conclusions Our findings show that class I free heavy chains are ligands for LILRB5. The unique binding specificity of LILRB5 for HLA-class I heavy chains probably results from differences in the D1 and D2 immunoglobulin-like binding domains which are distinct from other LILR which bind to β2m-associated HLA-class I.
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HLA-B27 free heavy chain dimers bind to LILRB5.
2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, Marloes Olde Nordkamp, Guosheng Jiang, Jacqueline Shaw, S KollnbergerAbstract:FACS staining of 293 T cells transfected with eGFP and FLAG-tagged constructs of LILRA1, LILRA4, LILRA5, LILRA6, LILRB2 and LILRB5 stained with Extravidin-PE (left panels) or Extravidin PE-conjugated HLA-B27 free heavy chain dimer tetramers (centre panels). FACS plots show PE fluorescence from tetramer or Extravidin staining plotted against eGFP expression of each of the fusion experiments. (Right panels) FACS staining of 293 T cells transfected with eGFP and FLAG-tagged constructs of LILRA1, LILRA4, LILRA5, LILRA6, and LILRB5 stained with allophycocyanin (APC) conjugated anti-FLAG antibody. FACS plots show APC fluorescence from anti-FLAG staining plotted against eGFP expression of each of the fusion constructs. Representative FACS stain from 1 of 4 independent experiments.
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The Leukocyte Immunoglobulin-Like Receptor Family Member LILRB5 Binds to HLA-Class I Heavy Chains - Fig 2
2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, Marloes Olde Nordkamp, Guosheng Jiang, Jacqueline Shaw, S KollnbergerAbstract:LILRB5 binds specifically to HLA-B27 free heavy chain dimers but does not bind to β2m and peptide associated HLA-A3, HLA-B7 and HLA-B27 heterodimers A. FACS staining of 293 T cells transfected with eGFP and FLAG-tagged constructs of LILRB2 and LILRB5 and stained with Extravidin-PE, orExtravidin-PE conjugated tetramers of HLA-A3, HLA-B7, and HLA-B27 heterodimer or HLA-B27 free heavy chain (FHC) dimers. FACS plots show PE fluorescence from tetramer or Extravidin staining plotted against eGFP expression of each of the fusion experiments. Representative FACS stain from 1 of 3 independent experiments B. FACS staining of LILRB5 transfected 293T cells with HLA-B27 FHC dimer tetramer or Extravidin PE with or without isotype control antibody (IgG2a) or free heavy chain antibody HC10 as indicated. FACS plots show PE fluorescence from tetramer or Extravidin staining plotted against eGFP expression of each of the fusion experiments. Representative FACS stain from 1 of 3 independent experiments.
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B27 dimer binding to LILRB5 is inhibited by LILRB5 specific antiserum.
2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, Marloes Olde Nordkamp, Guosheng Jiang, Jacqueline Shaw, S KollnbergerAbstract:A. FACS staining of LILRB5, LILRA1 and B2 transfected 293T cells with HLA-B27 FHC dimer tetramer or Extravidin PE with or without isotype control antisera (ISOT) or anti-LILRB5 antisera (αLILRB5) as indicated. FACS plots show PE fluorescence from tetramer or Extravidin staining plotted against eGFP expression of each of the respective fusion constructs. Representative FACS stain from 1 of 3 independent experiments. B. Representative FACS staining of 293T cells transfected with the indicated LILR constructs and stained with anti-LILRB5 or normal goat antisera (NGS). Representative stain from 1 of 3 independent experiments.
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LILRB5 is expressed on the surface of peripheral monocytes.
2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, Marloes Olde Nordkamp, Guosheng Jiang, Jacqueline Shaw, S KollnbergerAbstract:B27 heavy chain dimers bind to monocyte LILRB5. A. Forward scatter (FSC-A) and side scatter (SSC-A) FACS plot of peripheral blood mononuclear cells (PBMC) showing gating strategy for monocytes (Mθ) and lymphocyte (Lθ) populations. The relative proportions of monocyte and lymphocyte populations are indicated to the side of each gate. B. FACS staining of peripheral CD14+ (CD3-, CD19-, CD56-) monocytes with anti-LILRB5 antiserum (bold line) or normal goat serum (NGS, shaded histogram). C. FACS staining of (left panel) CD19+ (CD3-,CD14-CD56-) peripheral B, (centre panel) CD56+ (CD3-,CD14-,CD19-) natural killer (NK) or (right panel) CD3+ (CD14-,CD19-) T cell populations with anti-LILRB5 antiserum (bold line) or NGS (shaded histogram). Representative staining from 1 of 3 independent experiments. D. B27 dimer tetramer staining of peripheral monocytes without antiserum (dashed line) or in the presence of NGS (light line) or LILRB5 antiserum (bold line). FACS staining with extravidin PE (ExPE, shaded histogram) is included as a background staining control. The respective geometric mean fluorescent intensities (MFI) for staining without antiserum, with NGS and with anti-LILRB5 antiserum were 2498, 2827 and 881 respectively. The geometric MFI for staining with extravidin PE was 236. Representative staining from 1 of 3 independent experiments.
Mathias Lichterfeld - One of the best experts on this subject based on the ideXlab platform.
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Stable LILRB1 expression on T cells after “bystander activation”.
2013Co-Authors: Ilona Toth, Florencia Pereyra, Julian Schulze Zur Wiesch, Jennifer Rychert, Eric S. Rosenberg, Jan Van Lunzen, Mathias LichterfeldAbstract:(A) Representative dot plots demonstrating proportions of LILRB1-expressing Vβ13.1+ and Vβ13.1− T cells after activation with SEB over indicated time course. (B): Fold change of LILRB1 expression on Vβ13.1+ or Vβ13.1− T cells at indicated time points. Mean and standard error from 7 different HIV-1 negative donors are shown. Significance was tested by paired T test.
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soluble hla g inhibits myeloid dendritic cell function in hiv 1 infection by interacting with leukocyte immunoglobulin like receptor b2
Journal of Virology, 2010Co-Authors: Jinghe Huang, Patrick S Burke, Thai Duong Hong Cung, Florencia Pereyra, Ildiko Toth, Yue Yang, Katherine Seiss, Jill Beamon, Mathias LichterfeldAbstract:Dendritic cells represent a specialized class of professional antigen-presenting cells that are responsible for priming and maintaining antigen-specific effector cell responses and regulating immune activation by cytokine secretion. In HIV-1 infection, myeloid dendritic cells are highly dysfunctional, but mechanisms contributing to their functional alterations are not well defined. Here, we show that soluble molecules of the nonclassical major histocompatibility complex class Ib (MHC-Ib) antigen HLA-G are highly upregulated in the plasma during progressive HIV-1 infection, while levels of membrane-bound HLA-G surface expression on dendritic cells, monocytes, and T cells only slightly differ among HIV-1 progressors, HIV-1 elite controllers, and HIV-1-negative persons. These elevated levels of soluble HLA-G in progressive HIV-1 infection likely result from increased secretion of intracellularly stored HLA-G molecules in monocytes and dendritic cells and contribute to a functional disarray of dendritic cells by inhibiting their antigen-presenting properties, while simultaneously enhancing their secretion of proinflammatory cytokines. Interestingly, we observed that these immunoregulatory effects of soluble HLA-G were mainly mediated by interactions with the myelomonocytic HLA class I receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; ILT4), while binding of soluble HLA-G to its alternative high-affinity receptor, LILRB1 (ILT2), appeared to be less relevant for its immunomodulatory functions on dendritic cells. Overall, these results demonstrate a critical role for soluble HLA-G in modulating the functional characteristics of professional antigen-presenting cells in progressive HIV-1 infection and suggest that soluble HLA-G might represent a possible target for immunotherapeutic interventions in HIV-1-infected persons.
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leukocyte immunoglobulin like receptors maintain unique antigen presenting properties of circulating myeloid dendritic cells in hiv 1 infected elite controllers
Journal of Virology, 2010Co-Authors: Jinghe Huang, Luis Borges, Patrick S Burke, Thai Duong Hong Cung, Florencia Pereyra, Ildiko Toth, Bruce D Walker, Mathias LichterfeldAbstract:Elite controllers maintain undetectable levels of HIV-1 replication in the absence of antiretroviral therapy, but the correlates of immune protection in this patient population are ill defined. Here, we demonstrate that in comparison to patients with progressive HIV-1 infection or healthy persons not infected with HIV-1, elite controllers have circulating myeloid dendritic cells with significantly increased antigen-presenting properties, while their ability to secrete proinflammatory cytokines is substantially diminished. This unique functional profile is associated with a distinct surface expression pattern of immunomodulatory leukocyte-immunoglobulin-like receptors (LILR) and a strong and selective upregulation of LILRB1 and LILRB3. Blockade of these two receptors by monoclonal antibodies or short interfering RNA (siRNA) abrogated the specific antigen-presenting properties of dendritic cells, implying an important regulatory role of these molecules. These data reveal previously unrecognized innate components of immune protection against HIV-1 in elite controllers and offer novel perspectives for the manipulation of host immunity for the prevention and treatment of HIV-1 infection.
Kouyuki Hirayasu - One of the best experts on this subject based on the ideXlab platform.
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plasmodium falciparum rifin is a novel ligand for inhibitory immune receptor LILRB2
Biochemical and Biophysical Research Communications, 2021Co-Authors: Akihito Sakoguchi, Kouyuki Hirayasu, Fumiji Saito, Tadahiro Suenaga, Kyoko Shida, Sumiko Matsuoka, Sawako Itagaki, Wataru Nakai, Masako Kohyama, Shiroh IwanagaAbstract:Abstract Plasmodium falciparum causes the most severe form of malaria. Acquired immunity against P. falciparum provides insufficient protection even after repeated infections. Therefore, P. falciparum parasites might exploit inhibitory receptors for immune evasion. P. falciparum RIFINs are products of a multigene family consisting of 150–200 genes. Previously, we demonstrated that some RIFINs downregulate the immune response through the leukocyte immunoglobulin-like receptor (LILR) family inhibitory receptor, LILRB1, and leukocyte-associated immunoglobulin-like receptor 1, LAIR1. In this study, we further analyzed the expression of inhibitory receptor ligands on P. falciparum-infected erythrocytes and found that P. falciparum-infected erythrocytes expressed ligands for another LILR family inhibitory receptor, LILRB2, that recognizes HLA class I molecules as a host ligand. Furthermore, we identified that a specific RIFIN was a ligand for LILRB2 by using a newly developed RIFIN expression library. In addition, the domain 3 of LILRB2 was involved in RIFIN binding, whereas the domains 1 and 2 of LILRB2 were involved in the binding to HLA class I molecules. These results suggest that inhibitory receptor LILRB2 is also targeted by RIFIN for immune evasion of P. falciparum similar to LILRB1 and LAIR1.
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molecular mechanism of the recognition of bacterially cleaved immunoglobulin by the immune regulatory receptor lilra2
Journal of Biological Chemistry, 2020Co-Authors: Rika Yamazaki, Kouyuki Hirayasu, Atsushi Furukawa, Kohei Yumoto, Hideo Fukuhara, Hisashi Arase, Katsumi MaenakaAbstract:Human leukocyte immunoglobulin-like receptors (LILRs) typically regulate immune activation by binding to the human leukocyte antigen class I molecules. LILRA2, a member of the LILR family, was recently reported to bind to other unique ligands, the bacterially degraded Igs (N-truncated Igs), for the activation of immune cells. Therefore, LILRA2 is currently attracting significant attention as a novel innate immune receptor. However, the detailed recognition mechanisms required for this interaction remain unclear. In this study, using several biophysical techniques, we uncovered the molecular mechanism of N-truncated Ig recognition by LILRA2. Surface plasmon resonance analysis disclosed that LILRA2 specifically binds to N-truncated Ig with weak affinity (Kd = 4.8 μm) and fast kinetics. However, immobilized LILRA2 exhibited a significantly enhanced interaction with N-truncated Ig due to avidity effects. This suggests that cell surface-bound LILRA2 rapidly monitors and identifies bi- or multivalent abnormal N-truncated Igs through specific cross-linking to induce immune activation. Van't Hoff analysis revealed that this interaction is enthalpy-driven, with a small entropy loss, and results from differential scanning calorimetry indicated the instability of the putative LILRA2-binding site, the Fab region of the N-truncated Ig. Atomic force microscopy revealed that N truncation does not cause significant structural changes in Ig. Furthermore, mutagenesis analysis identified the hydrophobic region of LILRA2 domain 2 as the N-truncated Ig-binding site, representing a novel ligand-binding site for the LILR family. These results provide detailed insights into the molecular regulation of LILR-mediated immune responses targeting ligands that have been modified by bacteria.
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corrigendum immune evasion of plasmodium falciparum by rifin via inhibitory receptors
Nature, 2018Co-Authors: Fumiji Saito, Kouyuki Hirayasu, Kyoko Shida, Sawako Itagaki, Takeshi Satoh, Christian W Wang, John Lusingu, Takao Arimori, Nirianne Marie Q Palacpac, Shiroh IwanagaAbstract:Nature 552, 101–105 (2017); doi:10.1038/nature24994 In Extended Data Fig. 1 of this Letter, the flow cytometry data panel showing uninfected erythrocytes stained with LILRB5-Fc was inadvertently duplicated from the panel showing uninfected erythrocytes stained with LILRB4-Fc. This figure has been corrected online, and the original incorrect panel is provided as Supplementary Information to this Corrigendum, for transparency.
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immune evasion of plasmodium falciparum by rifin via inhibitory receptors
Nature, 2017Co-Authors: Fumiji Saito, Kouyuki Hirayasu, Kyoko Shida, Takeshi Satoh, Christian W Wang, John Lusingu, Takao Arimori, Nirianne Marie Q Palacpac, Sawako ItagakiAbstract:Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths each year. Plasmodium falciparum causes most life-threatening cases of malaria. Acquired immunity to malaria is inefficient, even after repeated exposure to P. falciparum, but the immune regulatory mechanisms used by P. falciparum remain largely unknown. Here we show that P. falciparum uses immune inhibitory receptors to achieve immune evasion. RIFIN proteins are products of a polymorphic multigene family comprising approximately 150-200 genes per parasite genome that are expressed on the surface of infected erythrocytes. We found that a subset of RIFINs binds to either leucocyte immunoglobulin-like receptor B1 (LILRB1) or leucocyte-associated immunoglobulin-like receptor 1 (LAIR1). LILRB1-binding RIFINs inhibit activation of LILRB1-expressing B cells and natural killer (NK) cells. Furthermore, P. falciparum-infected erythrocytes isolated from patients with severe malaria were more likely to interact with LILRB1 than erythrocytes from patients with non-severe malaria, although an extended study with larger sample sizes is required to confirm this finding. Our results suggest that P. falciparum has acquired multiple RIFINs to evade the host immune system by targeting immune inhibitory receptors.
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microbially cleaved immunoglobulins are sensed by the innate immune receptor lilra2
Nature microbiology, 2016Co-Authors: Kouyuki Hirayasu, Fumiji Saito, Tadahiro Suenaga, Kyoko Shida, Noriko Arase, Keita Oikawa, Toshifumi Yamaoka, Hiroyuki Murota, Hiroji Chibana, Ichiro NakagawaAbstract:The innate immune receptor, LILRA2, specifically senses microbially cleaved host immunoglobulins.
Zhiyong Zhang - One of the best experts on this subject based on the ideXlab platform.
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the leukocyte immunoglobulin like receptor family member lilrb5 binds to hla class i heavy chains
PLOS ONE, 2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, J Shaw, Marloes Olde Nordkamp, Guosheng Jiang, S KollnbergerAbstract:Objective The leukocyte immunoglobulin-like receptor (LILR) family includes inhibitory and stimulatory members which bind to classical and non-classical HLA-class I. The ligands for many LILR including LILRB5 have not yet been identified. Methods We generated C-terminal eGFP and N-terminal FLAG-tagged fusion constructs for monitoring LILR expression. We screened for LILR binding to HLA-class I by tetramer staining of 293T cells transfected with LILRA1, A4, A5 A6 and LILRB2 and LILRB5. We also studied HLA class I tetramer binding to LILRB5 on peripheral monocyte cells. LILRB5 binding to HLA-class I heavy chains was confirmed by co-immunoprecipitation. Results HLA-B27 (B27) free heavy chain (FHC) dimer but not other HLA-class I stained LILRB5-transfected 293T cells. B27 dimer binding to LILRB5 was blocked with the class I heavy chain antibody HC10 and anti-LILRB5 antisera. B27 dimers also bound to LILRB5 on peripheral monocytes. HLA-B7 and B27 heavy chains co-immunoprecipitated with LILRB5 in transduced B and rat basophil RBL cell lines. Conclusions Our findings show that class I free heavy chains are ligands for LILRB5. The unique binding specificity of LILRB5 for HLA-class I heavy chains probably results from differences in the D1 and D2 immunoglobulin-like binding domains which are distinct from other LILR which bind to β2m-associated HLA-class I.
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HLA-B27 free heavy chain dimers bind to LILRB5.
2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, Marloes Olde Nordkamp, Guosheng Jiang, Jacqueline Shaw, S KollnbergerAbstract:FACS staining of 293 T cells transfected with eGFP and FLAG-tagged constructs of LILRA1, LILRA4, LILRA5, LILRA6, LILRB2 and LILRB5 stained with Extravidin-PE (left panels) or Extravidin PE-conjugated HLA-B27 free heavy chain dimer tetramers (centre panels). FACS plots show PE fluorescence from tetramer or Extravidin staining plotted against eGFP expression of each of the fusion experiments. (Right panels) FACS staining of 293 T cells transfected with eGFP and FLAG-tagged constructs of LILRA1, LILRA4, LILRA5, LILRA6, and LILRB5 stained with allophycocyanin (APC) conjugated anti-FLAG antibody. FACS plots show APC fluorescence from anti-FLAG staining plotted against eGFP expression of each of the fusion constructs. Representative FACS stain from 1 of 4 independent experiments.
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The Leukocyte Immunoglobulin-Like Receptor Family Member LILRB5 Binds to HLA-Class I Heavy Chains - Fig 2
2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, Marloes Olde Nordkamp, Guosheng Jiang, Jacqueline Shaw, S KollnbergerAbstract:LILRB5 binds specifically to HLA-B27 free heavy chain dimers but does not bind to β2m and peptide associated HLA-A3, HLA-B7 and HLA-B27 heterodimers A. FACS staining of 293 T cells transfected with eGFP and FLAG-tagged constructs of LILRB2 and LILRB5 and stained with Extravidin-PE, orExtravidin-PE conjugated tetramers of HLA-A3, HLA-B7, and HLA-B27 heterodimer or HLA-B27 free heavy chain (FHC) dimers. FACS plots show PE fluorescence from tetramer or Extravidin staining plotted against eGFP expression of each of the fusion experiments. Representative FACS stain from 1 of 3 independent experiments B. FACS staining of LILRB5 transfected 293T cells with HLA-B27 FHC dimer tetramer or Extravidin PE with or without isotype control antibody (IgG2a) or free heavy chain antibody HC10 as indicated. FACS plots show PE fluorescence from tetramer or Extravidin staining plotted against eGFP expression of each of the fusion experiments. Representative FACS stain from 1 of 3 independent experiments.
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B27 dimer binding to LILRB5 is inhibited by LILRB5 specific antiserum.
2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, Marloes Olde Nordkamp, Guosheng Jiang, Jacqueline Shaw, S KollnbergerAbstract:A. FACS staining of LILRB5, LILRA1 and B2 transfected 293T cells with HLA-B27 FHC dimer tetramer or Extravidin PE with or without isotype control antisera (ISOT) or anti-LILRB5 antisera (αLILRB5) as indicated. FACS plots show PE fluorescence from tetramer or Extravidin staining plotted against eGFP expression of each of the respective fusion constructs. Representative FACS stain from 1 of 3 independent experiments. B. Representative FACS staining of 293T cells transfected with the indicated LILR constructs and stained with anti-LILRB5 or normal goat antisera (NGS). Representative stain from 1 of 3 independent experiments.
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LILRB5 is expressed on the surface of peripheral monocytes.
2015Co-Authors: Zhiyong Zhang, Hiroko Hatano, Marloes Olde Nordkamp, Guosheng Jiang, Jacqueline Shaw, S KollnbergerAbstract:B27 heavy chain dimers bind to monocyte LILRB5. A. Forward scatter (FSC-A) and side scatter (SSC-A) FACS plot of peripheral blood mononuclear cells (PBMC) showing gating strategy for monocytes (Mθ) and lymphocyte (Lθ) populations. The relative proportions of monocyte and lymphocyte populations are indicated to the side of each gate. B. FACS staining of peripheral CD14+ (CD3-, CD19-, CD56-) monocytes with anti-LILRB5 antiserum (bold line) or normal goat serum (NGS, shaded histogram). C. FACS staining of (left panel) CD19+ (CD3-,CD14-CD56-) peripheral B, (centre panel) CD56+ (CD3-,CD14-,CD19-) natural killer (NK) or (right panel) CD3+ (CD14-,CD19-) T cell populations with anti-LILRB5 antiserum (bold line) or NGS (shaded histogram). Representative staining from 1 of 3 independent experiments. D. B27 dimer tetramer staining of peripheral monocytes without antiserum (dashed line) or in the presence of NGS (light line) or LILRB5 antiserum (bold line). FACS staining with extravidin PE (ExPE, shaded histogram) is included as a background staining control. The respective geometric mean fluorescent intensities (MFI) for staining without antiserum, with NGS and with anti-LILRB5 antiserum were 2498, 2827 and 881 respectively. The geometric MFI for staining with extravidin PE was 236. Representative staining from 1 of 3 independent experiments.
Rachel L Allen - One of the best experts on this subject based on the ideXlab platform.
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ral ssBioMed Cent Open Acce
2016Co-Authors: Bmc Immunology, Robin A Buerki, John Trowsdale, Rachel L AllenAbstract:Research article The inhibitory receptor LILRB4 (ILT3) modulates antigen presenting cell phenotype and, along with LILRB2 (ILT4), is upregulated in response to Salmonella infectio
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crystal structure of leukocyte ig like receptor lilrb4 ilt3 lir 5 cd85k a myeloid inhibitory receptor involved in immune tolerance
Journal of Biological Chemistry, 2011Co-Authors: Hao Cheng, Yong Chen, Rachel L Allen, Fiyaz Mohammed, Jianxun Qi, Lee I Garner, Benjamin E WillcoxAbstract:Abstract The myeloid inhibitory receptor LILRB4 (also called ILT3, LIR-5, CD85k), a member of the leukocyte immunoglobulin-like receptors (LILRs/LIRs), is an important mediator of immune tolerance. Up-regulated on tolerogenic dendritic cells, it has been shown to modulate immune responses via induction of T cell anergy and differentiation of CD8+ T suppressor cells and may play a role in establishing immune tolerance in cancer. Consequently, characterizing the molecular mechanisms involved in LILRB4 function and in particular its structure and ligands is a key aim but has remained elusive to date. Here we describe the production, crystallization, and structure of the LILRB4 ectodomain to 1.7 A using an expression strategy involving engineering of an additional disulfide bond in the D2 domain to enhance protein stability. LILRB4 comprises two immunoglobulin domains similar in structure to other LILRs; however, the D2 domain, which is most closely related to the D4 domains of other family members, contains 310 helices not previously observed. At the D1-D2 interface, reduced interdomain contacts resulted in an obtuse interdomain angle of ∼107°. Comparison with MHC class I binding Group 1 LILRs suggests LILRB4 is both conformationally and electrostatically unsuited to MHC ligation, consistent with LILRB4 status as a Group 2 LILR likely to bind novel non-MHC class I ligands. Finally, examination of the LILRB4 surface highlighted distinctive surface patches on the D1 domain and D1D2 hinge region, which may be involved in ligand binding. These findings will facilitate our attempts to precisely define the role of LILRB4 in the regulation of immune tolerance.
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the inhibitory receptor lilrb4 ilt3 modulates antigen presenting cell phenotype and along with LILRB2 ilt4 is upregulated in response to salmonella infection
BMC Immunology, 2009Co-Authors: Damien P Brown, Robin A Buerki, John Trowsdale, Desmond Jones, Katie J Anderson, Nicolas Lapaque, Rachel L AllenAbstract:Background Leukocyte Ig-like receptors (LILR) are a family of innate immune receptors with immunomodulatory functions. High-level expression of the receptors LILRB2 (ILT4) and LILRB4 (ILT3) is a feature of tolerogenic antigen presenting cells and has been observed in cancer and transplant situations. There are relatively few studies regarding these receptors in the context of infection and it is not yet clear how LILRB4 exerts its inhibitory effects.