Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

Cerboni, Cristina; Achour, Adnane; Wärnmark, Anette; Mousavi‐Jazi, Mehrdad; Sandalova, T.; Hsu, Mei Ling; Cosman, David; Kärre, Klas; Carbone, Ennio

doi:10.1002/eji.200425220

Cited by 39 publications

(39 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2), superposition of the UL18 and HLA-A2 ␣1-␣2 domains (Fig. 1C) (rmsd ϭ 0.5 Å for 50 C␣ atoms) revealed that the changes were usually accommodated without generating the protruding loops that had been suggested by computational modeling of the UL18 structure (25,26,28).…”

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

confidence: 79%

“…2 and Fig. S1), were predicted to contact LIR-1 (25,26); however, there are no UL18-␣1-domain residues within 4 Å of LIR-1 D1-D2. Although LIR-1 D3-D4, which is not present in the crystals, could contact this region of UL18, analytical ultracentrifugation data suggested an extended structure for LIR-1 D1-D4 (18), whereas a substantial bend would be required to achieve D3-D4 contacts with UL18 ␣1.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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.

View full text Add to dashboard Cite

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...

show abstract

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

confidence: 79%

Section: Resultsmentioning

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.

View full text Add to dashboard Cite

show abstract

“…One node of this network is represented by the interaction between the viral glycoprotein UL18 on HCMV-infected cells and CD85j expressed by T and NK cells, as suggested by the high affinity of UL18 for CD85j (K d in the nanomolar range (30,49)), and by the fact that no other ligands for UL18 have been identified. Also, UL18 is not necessary for infection (15), but the gene was found in all HCMV genomes analyzed so far, namely in four laboratory strains and in 26 samples from clinical isolates or seropositive donors (49,50).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Regulates Surface Expression of the Viral Protein UL18 by Means of Two Motifs Present in the Cytoplasmic Tail

Maffei¹,

Ghiotto²,

Occhino³

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

UL18 is a trans-membrane viral protein expressed on human cytomegalovirus (HCMV)-infected cells, and its surface expression determines the interaction of infected cells with lymphocytes expressing the CD85j (LIR-1/ILT2) receptor. We previously showed that the UL18–CD85j interaction elicits activation of T lymphocytes. However, in in vitro cell models UL18 displays mostly undetectable surface expression. Thus, we asked how surface expression of UL18 is regulated. Domain-swapping experiments and construction of specific mutants demonstrated that two motifs on its cytoplasmic tail, homologous to YXXΦ and KKXX consensus sequences, respectively, are responsible for impairing UL18 surface expression. However, the presence of the whole HCMV genome, granted by HCMV infection of human fibroblasts, restored surface expression of either UL18 or chimeric proteins carrying the UL18 cytoplasmic tail, starting from the third day after infection. It is of note that the two motifs responsible for cytoplasmic retention are identical in all 17 HCMV strains examined. We disclosed a control mechanism used by the HCMV to regulate the availability of UL18 on the infected-cell surface to allow interaction with its ligand on T and NK cells.

show abstract

“…The incubation time was chosen to allow even late viral transcripts like UL18 to be sufficiently expressed while infected fibroblasts were still viable. The clinical strain 4636 was included to detect a possible role of UL18 on LIR-1 regulation, because the 4636 strain encodes a UL18 protein with higher affinity for LIR-1 than AD169 (36). There was no consistent effect on the expression of LIR-1 on NK cells, neither in percentage of cells nor in level of expression (MFI) in this setting, using AD169-infected HL (Fig.…”

Section: Induction Of Lir-1 On Nk Cellsmentioning

confidence: 92%

Increased Expression of Leukocyte Ig-Like Receptor-1 and Activating Role of UL18 in the Response to Cytomegalovirus Infection

Wagner

Riise²,

Bergström

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

NK and T cells are important for combating CMV infection. Some NK and T cells express leukocyte Ig-like receptor-1 (LIR-1), an inhibitory receptor recognizing MHC class I and the CMV-encoded homolog UL18. We previously demonstrated an early increase in LIR-1-expressing blood lymphocytes in lung-transplanted patients later developing CMV disease. We now show that NK and T cells account for the observed LIR-1 augmentation. Coincubation of PBMC from CMV-seropositive donors with virus-infected lung fibroblasts led to a T cell-dependent secretion of IFN-γ, produced mainly by LIR-1+ T cells and by NK cells. Cytokine production during coculture with fibroblasts infected with virus containing the UL18 gene was augmented compared with the UL18 deletion virus, suggesting a stimulatory role for UL18. However, purified UL18Fc proteins inhibited IFN-γ production of LIR-1+ T cells. We propose that cytokine production in the transplant induces NK and T cells to express LIR-1, which may predispose to CMV disease by MHC/LIR-1-mediated suppression. Although the UL18/LIR-1 interaction could inhibit T cell responses, this unlikely plays a role in response to infected cells. Instead, our data point to an activating role for viral UL18 during infection, where indirect intracellular effects cannot be excluded.

show abstract

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

Cited by 39 publications

References 43 publications

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

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

Human Cytomegalovirus Regulates Surface Expression of the Viral Protein UL18 by Means of Two Motifs Present in the Cytoplasmic Tail

Increased Expression of Leukocyte Ig-Like Receptor-1 and Activating Role of UL18 in the Response to Cytomegalovirus Infection

Contact Info

Product

Resources

About