Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d)

Shiroishi, Mitsunori; Kuroki, Kazuhiko; Rasubala, Linda; Tsumoto, Kouhei; Koyanagi, Izumi; Kurimoto, Eiji; Kato, Koichi; Kohda, Daisuke; Maenaka, Katsumi

doi:10.1073/pnas.0605228103

Cited by 236 publications

(271 citation statements)

References 37 publications

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“…ILT2 is expressed on NK cells, dendritic cells, and all T cells (37), whereas ILT4 is found mainly in monocytes (38). ILT2 and ILT4 bind preferentially to the nonclassic MHC molecule HLA-G, with a higher affinity than to classic MHC-I, suggesting that these molecules can regulate the immune response in the maternal-fetal interface (38)(39)(40). ILT3 is a receptor expressed on dendritic cells, monocytes, and endothelial cells (41).…”

Section: Introductionmentioning

confidence: 99%

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

et al. 2009

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One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer (NK) cells and CD8 + T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor (TNF) and TNF receptor pathway. We discussed three models of possible molecular interaction between lytic molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis. Cellular & Molecular Immunology. 2009;6(1):15-25.

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Section: Introductionmentioning

confidence: 99%

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

et al. 2009

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“…3B). In addition, one of the loops in LIR-1 D1 that makes contacts with UL18 ␣3 in site 1 (LIR-1 residues 77-86; LIR-2 residues 77-85) showed an altered conformation in the LIR-2 structures (21,23), such that a loop with this conformation would not contact UL18 in a LIR-2/ UL18 complex. A LIR-2 mutant in which LIR-1 residues were introduced into this loop (Q76Y/R80D/W83R LIR-2) bound UL18 10-to 30-fold more tightly than did wild-type LIR-2 (20), suggesting the potential for flexibility and demonstrating that the wild-type LIR-2 sequence is not optimal for UL18 binding.…”

Section: Comparison Of Ul18 With Classical Class I Mhc and Mhc Homologmentioning

confidence: 99%

Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor

Yang

Björkman

2008

Proc. Natl. Acad. Sci. U.S.A.

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UL18 is a human cytomegalovirus class I MHC (MHCI) homolog that binds the host inhibitory receptor LIR-1 and the only known viral MHC homolog that presents peptides. The 2.2-Å structure of a LIR-1/UL18/peptide complex reveals increased contacts and optimal surface complementarity in the LIR-1/UL18 interface compared with LIR/MHCI interfaces, resulting in a >1,000-fold higher affinity. Despite sharing only Ϸ25% sequence identity, UL18's structure and peptide binding are surprisingly similar to host MHCI. The crystal structure suggests that most of the UL18 surface, except where LIR-1 and the host-derived light chain bind, is covered by carbohydrates attached to 13 potential N-glycosylation sites, thereby preventing access to bound peptide and association with most MHCI-binding proteins. The LIR-1/UL18 structure demonstrates how a viral protein evolves from its host ancestor to impede unwanted interactions while preserving and improving its receptor-binding site.cytomegalovirus ͉ immune evasion ͉ LIR-1 ͉ x-ray crystallography H uman cytomegalovirus (HCMV) is prevalent among all human populations, infecting 70-90% of adults (1). HCMV infection is usually asymptomatic in immunocompetent individuals, but the virus causes a latent infection that can be reactivated during immune suppression. To maintain persistence in the presence of a primed immune system, HCMV has developed mechanisms to subvert the host immune response (2). One strategy is to downregulate cell surface expression of host class I MHC molecules, thereby allowing HCMV-infected cells to avoid recognition by virus-specific cytotoxic T cells. However, cells that lack surface class I MHC molecules are susceptible to lysis by natural killer (NK) cells (3). NK cells express both activating receptors and inhibitory receptors, many of which recognize class I MHC molecules (4). Stimulation of the activating receptors leads to lysis of target cells when expression of class I MHC proteins is down-regulated (5); however, clinical isolates of HCMV can evade NK lysis (6) by down-regulation (7) or inhibition (8) of the activating ligands for NK cells; up-regulation of HLA-E (9), which binds the NK cell inhibitory receptor NKG2A/CD94; and potentially through the expression of two virally encoded class I MHC homologs, UL142 (10) and UL18 (11).UL18 is a heavily glycosylated transmembrane protein that shares Ϸ25% sequence identity with class I MHC molecules (11). It associates with the class I MHC light chain, ␤2-microglobulin (␤2m) (12), and with endogenous peptides derived from cytoplasmic proteins that resemble those bound to host class I proteins (13). Peptide binding renders UL18 unique among viral MHC homologs and unusual among host MHC homologs. The role of UL18 in NK cell recognition is controversial; it has been reported to inhibit NK-cell-mediated lysis in some experimental conditions but not others (14).The only host receptor identified for UL18 is LIR-1 (15) (also known as ILT2, CD85j, or LILRB1) (16). LIR-1 is expressed on most or all monocytes, dendritic and...

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“…These sites are readily accessible to receptors, explaining the increased avidity (26). However, no crystal structure of an HLA-G homodimer complexed with a LILRB protein has been published, although one for the HLA-G monomer-LILRB2 complex was reported (28). The HLA-G dimer modulates the function of LILRB1-expressing antigen-presenting cells (macrophages) by principally binding to LILRB1.…”

mentioning

confidence: 99%

HLA-G homodimer-induced cytokine secretion through HLA-G receptors on human decidual macrophages and natural killer cells

Houser²,

Nicotra³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

177

150

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Human decidual CD14 ؉ macrophages and CD56 ؉ NK cells were isolated from material obtained after first-trimester pregnancy terminations. Each cell type expressed a specific surface receptor for histocompatibility leukocyte antigen (HLA)-G (an MHC class Ib protein that is expressed on extravillous trophoblasts), LILRB1 on CD14 ؉ macrophages and KIR2DL4 on CD56 ؉ NK cells. Cross-linking with anti-LILRB1 or anti-KIR2DL4 resulted in up-regulation of a small subset of mRNAs including those for IL-6, IL-8, and TNF␣ detected using a microarray representing 114 cytokines. Incubation with transfectants expressing the HLA-G homodimer (but not with transfectants expressing the HLA-G monomer) resulted in secretion of the same cytokine proteins from both leukocyte sets. Moreover, cytokine secretion from both leukocyte sets was blocked by both the appropriate anti-receptor mAb and by anti-HLA-G. The amount of these cytokines secreted by decidual macrophages was substantially greater than that secreted by decidual NK cells. VEGF was constitutively secreted by both cell types. LILRB1, which contains an immunoreceptor tyrosine-based switch motif, functions here as an activating receptor, although it has been known as an inhibitory receptor. KIR2DL4 also functions as an activating receptor, although it also has the potential to function as an inhibitory receptor. Secretion of proinflammatory and proangiogenic proteins supports a role for these leukocytes in important processes that are essential for successful pregnancy, but they may represent only a portion of the proteins that are secreted.IL-6 ͉ IL-8 ͉ pregnancy ͉ trophoblast ͉ VEGF

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Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d)

Cited by 236 publications

References 37 publications

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor

HLA-G homodimer-induced cytokine secretion through HLA-G receptors on human decidual macrophages and natural killer cells

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