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

Wagner, Claudia; Riise, Gerdt C.; Bergström, Tomas; Kärre, Klas; Carbone, Ennio; Berg, Louise

doi:10.4049/jimmunol.178.6.3536

Cited by 35 publications

(40 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whatever the mechanism, the UL18 -CD85j interaction certainly plays a pivotal role in the immune response to HCMV infection. CD85j displays an affinity for UL18 that is Ͼ1000-fold higher than for cellular MHC class I molecules (30,31), and its expression is up-regulated on HCMV-specific T cells (32,33) and on T and NK cells of lungtransplanted patients later developing HCMV disease (29,34). Binding of CD85j to UL18 requires surface expression of the viral protein.…”

mentioning

confidence: 99%

“…NK cell-mediated lysis was seen to be inhibited (4,25,26) or increased (27), depending on the experimental setting. With respect to T lymphocytes, two studies have addressed the effect of CD85j engagement by UL18, and both show that UL18 mediates an activating signal, in one case through its interaction with CD85j (28), and in the other case by still unexplained mechanisms (29). Whatever the mechanism, the UL18 -CD85j interaction certainly plays a pivotal role in the immune response to HCMV infection.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

mentioning

confidence: 99%

mentioning

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

show abstract

“…The HCMV UL18 gene product binds inhibitory LIR-1 receptor [22], while the receptor binding the MCMV class I homologue, m144, is still not identiWed. However, the role of UL18 in immune subversion must further be investigated since it may also lead to NK cell activation [23][24][25]. The diVerential regulation of MHC class I molecules could be an additional mechanism to avoid both CD8 and NK cell responses simultaneously.…”

Section: Nk Cells and CMV Controlmentioning

confidence: 99%

Murine cytomegalovirus regulation of NKG2D ligands

Lenac

Arapović

Traven

et al. 2008

Med Microbiol Immunol

View full text Add to dashboard Cite

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that causes morbidity risk in immunologically suppressed and immunodeWcient patients including congenital infections. Approaches to curb the consequences of HCMV infections are restricted by a lack of complete understanding of viral pathogenesis. The infection of mice with murine cytomegalovirus (MCMV) as a model of HCMV infection has been particularly useful in elucidating the role of innate and adaptive immune response mechanisms. A large number of cytomegalovirus genes modulate the innate and the adaptive host immune response. The products of several MCMV genes are involved in subverting the natural killer (NK) cell response by down-modulating cellular ligands for the NKG2D receptor expressed on NK cells and CD8 + T cells. Mutant viruses lacking these immunoevasion genes are attenuated with respect to virus growth in vivo. Given the importance of the NKG2D receptor in controlling both NK-and T cell-mediated immunity, it is of tremendous importance to understand the molecular mechanisms and consequences of viral regulation of the NKG2D ligands.

show abstract

“…It shares structural similarity with MHC class I molecules (1). In particular, the extracellular region is formed by three domains (␣1, ␣2, and ␣3) with a sequence identity of 21,20, and 22% with their class I counterparts (1), respectively. Moreover, its extracellular region associates with ␤ 2 -microglobulin (␤ 2 m) (4) and binds peptides derived from cytoplasmic proteins (5).…”

mentioning

confidence: 99%

“…Furthermore, UL18 has been recently described to have an activatory role on T cells (20). Whatever the mechanism, UL18 certainly plays a pivotal role in the immune response to HCMV infection, and it is therefore important to gain an understanding of the molecular properties of its complex with CD85j and, possibly, of the high affinity of the interaction.…”

mentioning

confidence: 99%

Dissecting the Structural Determinants of the Interaction between the Human Cytomegalovirus UL18 Protein and the CD85j Immune Receptor

Occhino

Ghiotto

Soro

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

UL18 is a glycoprotein encoded by the human cytomegalovirus genome and is thought to play a pivotal role during human cytomegalovirus infection, although its exact function is still a matter of debate. UL18 shares structural similarity with MHC class I and binds the receptor CD85j on immune cells. Besides UL18, CD85j binds MHC class I molecules. The binding properties of CD85j to MHC class I molecules have been thoroughly studied. Conversely, very little information is available on the CD85j/UL18 complex, namely that UL18 binds CD85j through its ␣3 domain with an affinity that is ϳ1000-fold higher than the MHC class I affinity for CD85j. Deeper knowledge of features of the UL18/CD85j complex would help to disclose the function of UL18 when it binds to CD85j. In this study we first demonstrated that the UL18␣3 domain is not sufficient per se for binding and that ␤ 2 -microglobulin is necessary for UL18 -CD85j interaction. We then dissected structural determinants of binding UL18 to CD85j. To this end, we constructed a three-dimensional model of the complex. The model was used to design mutants in selected regions of the putative interaction interface, the effects of which were measured on binding. Six regions in both the ␣2 and ␣3 domains and specific amino acids within them were identified that are potentially involved in the UL18 -CD85j interaction. The higher affinity of UL18 to CD85j, compared with MHC class I, seems to be due not to additional interaction regions but to an overall better fit of the two molecules. The Journal of Immunology, 2008, 180: 957-968. T he UL18 is a protein encoded by the human cytomegalovirus (HCMV)4 genome (1). It is a late HCMV Ag, with its transcription occurring from 54 to at least 120 h postinfection (2), and it is not essential for HCMV replication in vitro (3). It shares structural similarity with MHC class I molecules (1). In particular, the extracellular region is formed by three domains (␣1, ␣2, and ␣3) with a sequence identity of 21, 20, and 22% with their class I counterparts (1), respectively. Moreover, its extracellular region associates with ␤ 2 -microglobulin (␤ 2 m) (4) and binds peptides derived from cytoplasmic proteins (5). Similarly to class I molecules, the UL18 ␣2 and ␣3 domains each contains two cysteines characteristic of the MHC Ag-recognition domain fold and of the Ig-like fold, respectively. In contrast, the Ig-like loop of the ␣2 domain is 10 amino acids longer than the corresponding MHC class I loop, and the CD loop of the Ig-like ␣3 domain contains three additional cysteines. As opposed to MHC class I molecules, which have only one to three N-glycosylation sites, the UL18 molecule bears 13 potential glycosylation sites (1), resulting in the expression of highly glycosylated forms (6). The only molecule known so far to bind UL18 is the transmembrane protein CD85j (previously reported as ILT2 or LIR-1) (7).CD85j is a transmembrane receptor expressed on the surface of subsets of NK and T cells and of all B cells and monocytes (7,8). It is formed by four I...

show abstract

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

Cited by 35 publications

References 46 publications

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

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

Murine cytomegalovirus regulation of NKG2D ligands

Dissecting the Structural Determinants of the Interaction between the Human Cytomegalovirus UL18 Protein and the CD85j Immune Receptor

Contact Info

Product

Resources

About