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Mathias Lichterfeld - One of the best experts on this subject based on the ideXlab platform.

  • interactions between hla b and Leukocyte immunoglobulin like Receptors b2 lilrb2 correlate with hiv 1 disease outcomes
    Retrovirology, 2012
    Co-Authors: Martin E Gayo, Florencia Pereyra, Mathias Lichterfeld, D Jones, Rachel L Allen
    Abstract:

    Background Recently, a genome-wide association study identified 3 amino acids (residues 67, 70, 97) in the HLA-B peptide binding groove that explain the classical HLA class I associations with HIV-1 immune control. However, how amino acid substitutions at these positions affect HIV-1 immune defense remains unclear. Leukocyte Immunoglobulin Like Receptors (LILR) are a class of immunoregulatory molecules that are expressed on myeloid dendritic cells and interact with HLA class I molecules as their physiologic ligands. Here, we assessed how different amino acids in the HLA-B binding groove may influence their binding to LILRs. Methods

  • Leukocyte immunoglobulin like Receptors maintain unique antigen presenting properties of circulating myeloid dendritic cells in hiv 1 infected elite controllers
    Journal of Virology, 2010
    Co-Authors: Jinghe Huang, Luis Borges, Patrick S Burke, Thai Duong Hong Cung, Florencia Pereyra, Ildiko Toth, Bruce D Walker, Mathias Lichterfeld
    Abstract:

    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.

Florencia Pereyra - One of the best experts on this subject based on the ideXlab platform.

  • interactions between hla b and Leukocyte immunoglobulin like Receptors b2 lilrb2 correlate with hiv 1 disease outcomes
    Retrovirology, 2012
    Co-Authors: Martin E Gayo, Florencia Pereyra, Mathias Lichterfeld, D Jones, Rachel L Allen
    Abstract:

    Background Recently, a genome-wide association study identified 3 amino acids (residues 67, 70, 97) in the HLA-B peptide binding groove that explain the classical HLA class I associations with HIV-1 immune control. However, how amino acid substitutions at these positions affect HIV-1 immune defense remains unclear. Leukocyte Immunoglobulin Like Receptors (LILR) are a class of immunoregulatory molecules that are expressed on myeloid dendritic cells and interact with HLA class I molecules as their physiologic ligands. Here, we assessed how different amino acids in the HLA-B binding groove may influence their binding to LILRs. Methods

  • Leukocyte immunoglobulin like Receptors maintain unique antigen presenting properties of circulating myeloid dendritic cells in hiv 1 infected elite controllers
    Journal of Virology, 2010
    Co-Authors: Jinghe Huang, Luis Borges, Patrick S Burke, Thai Duong Hong Cung, Florencia Pereyra, Ildiko Toth, Bruce D Walker, Mathias Lichterfeld
    Abstract:

    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.

Rachel L Allen - One of the best experts on this subject based on the ideXlab platform.

  • interactions between hla b and Leukocyte immunoglobulin like Receptors b2 lilrb2 correlate with hiv 1 disease outcomes
    Retrovirology, 2012
    Co-Authors: Martin E Gayo, Florencia Pereyra, Mathias Lichterfeld, D Jones, Rachel L Allen
    Abstract:

    Background Recently, a genome-wide association study identified 3 amino acids (residues 67, 70, 97) in the HLA-B peptide binding groove that explain the classical HLA class I associations with HIV-1 immune control. However, how amino acid substitutions at these positions affect HIV-1 immune defense remains unclear. Leukocyte Immunoglobulin Like Receptors (LILR) are a class of immunoregulatory molecules that are expressed on myeloid dendritic cells and interact with HLA class I molecules as their physiologic ligands. Here, we assessed how different amino acids in the HLA-B binding groove may influence their binding to LILRs. Methods

  • crystal structure of Leukocyte ig like receptor lilrb4 ilt3 lir 5 cd85k a myeloid inhibitory receptor involved in immune tolerance
    Journal of Biological Chemistry, 2011
    Co-Authors: Hao Cheng, Yong Chen, Rachel L Allen, Fiyaz Mohammed, Jianxun Qi, Lee I Garner, Benjamin E Willcox
    Abstract:

    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.

Bruce D Walker - One of the best experts on this subject based on the ideXlab platform.

  • Leukocyte immunoglobulin like Receptors maintain unique antigen presenting properties of circulating myeloid dendritic cells in hiv 1 infected elite controllers
    Journal of Virology, 2010
    Co-Authors: Jinghe Huang, Luis Borges, Patrick S Burke, Thai Duong Hong Cung, Florencia Pereyra, Ildiko Toth, Bruce D Walker, Mathias Lichterfeld
    Abstract:

    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.

Richard Apps - One of the best experts on this subject based on the ideXlab platform.

  • LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection
    2014
    Co-Authors: Arman A. Bashirova, Patrick S Burke, Enrique Martin-gayo, Des C. Jones, Richard Apps, Xiaojiang Gao, Craig J. Taylor, Jerome Rogich, Steven Wolinsky
    Abstract:

    Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human Leukocyte antigen (HLA) class I molecules with Leukocyte Immunoglobulin-Like Receptors (LILR), a group of immunoregulatory Receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10−2). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10−11–10−9) and African (p = 10−5–10−3) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.

  • a homodimeric complex of hla g on normal trophoblast cells modulates antigen presenting cells via lilrb1
    European Journal of Immunology, 2007
    Co-Authors: Richard Apps, Lucy Gardner, A M Sharkey, Nick Holmes, Ashley Moffett
    Abstract:

    In healthy individuals, the non-classical MHC molecule HLA-G is only expressed on fetal trophoblast cells that invade the decidua during placentation. We show that a significant proportion of HLA-G at the surface of normal human trophoblast cells is present as a disulphide-linked homodimer of the conventional β2m-associated HLA-I complex. HLA-G is a ligand for Leukocyte Immunoglobulin-Like Receptors (LILR), which bind much more efficiently to dimeric HLA-G than to conventional HLA-I molecules. We find that a LILRB1-Fc fusion protein preferentially binds the dimeric form of HLA-G on trophoblast cells. We detect LILRB1 expression on decidual myelomonocytic cells; therefore, trophoblast HLA-G may modulate the function of these cells. Co-culture with HLA-G+ cells does not inhibit monocyte-derived dendritic cell up-regulation of HLA-DR and costimulatory molecules on maturation, but did increase production of IL-6 and IL-10. Furthermore, proliferation of allogeneic lymphocytes was inhibited by HLA-G binding to LILRB1/2 on responding antigen-presenting cells (APC). As HLA-G is the only HLA-I molecule that forms β2m-associated dimers with increased avidity for LILRB1, this interaction could represent a placental-specific signal to decidual APC. We suggest that the placenta is modulating maternal immune responses locally in the uterus through HLA-G, a trophoblast-specific, monomorphic signal present in almost every pregnancy. See accompanying commentary: http://dx.doi.org/10.1002/eji.200737515