Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation

Masuda, Ai; Nakamura, Akira; Maeda, Tsutomu; Sakamoto, Yuzuru; Takai, Toshiyuki

doi:10.1084/jem.20060631

Cited by 80 publications

(97 citation statements)

References 54 publications

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“…1B) and freshly isolated splenic B220 ϩ B cells (Fig. S1) also exhibited PIR-B binding to MHC-I on the same cell membrane, suggesting that the PIR-B-MHC-I interaction primarily takes place in cis on these antigen-presenting cells (APCs) as well as on cultured mast cells described previously (25).…”

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confidence: 64%

“…Principally, like LILRB1/B2, PIR-B is considered to play an indispensable role in immune regulation by recruiting SH2 domain-containing tyrosine phosphatase-1 to its cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on its constitutive binding to the ligand MHC-I, because PIR-B-deficient (Pirb Ϫ/Ϫ ) mice exhibit various augmented immune responses due to hyperactivated B cells and myeloid cells (20,24,25). Simultaneously, however, the above knowledge obtained on SPR analysis of the competition between LILRB1/B2 and CD8 in binding to a constant portion of MHC-I (16) predicts that a possible steric conflict between PIR-B and CD8 in binding to H-2 may also play a role in immune regulation such as modulation of CTL activity in mice.…”

mentioning

confidence: 99%

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Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells

Endo

Sakamoto

Kobayashi

et al. 2008

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

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confidence: 64%

mentioning

confidence: 99%

Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells

Endo

Sakamoto

Kobayashi

et al. 2008

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

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“…1 A). A cis interaction on the same membrane between LIR-1 and class I MHC molecules has been proposed (27) but is hard to rationalize when analytical ultracentrifugation data suggest an extended LIR-1 structure (18), because a cis interaction would require LIR-1 D3, D4, and the C-terminal residues before the transmembrane region to nearly reverse directions compared with D1-D2.…”

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.

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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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“…The mouse inhibitory receptor Ly49A has been shown to interact with its MHC-I ligand in cis, and this interaction directly reduces its accessibility to ligands in trans, thereby lowering the threshold for activation [23,24]. The murine orthologue of LIR-1, PIR-B, interacts with MHC-I in cis on the surface of mast cells and this interaction was suggested to influence cellular activation during allergic responses [25]. LIR-1 has also been shown to interact with MHC-I in cis on the surface of osteoclast precursors, with this binding suggested to contribute to the regulation of osteoclast development [26].…”

Section: Introductionmentioning

confidence: 99%

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Uchtenhagen

et al. 2013

Eur J Immunol

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IntroductionNK cells are cytotoxic lymphocytes of the immune system, which provide innate protection against viral infection and tumor transformation [1]. NK cells eliminate altered self-cells through the direct recognition and subsequent lysis of engaged targets. The effector functions of these immune cells are dynamically regulated through the coordinated signaling of cell surface receptors that either activate or inhibit responses [2]. The stimulatory Correspondence: Dr. Deborah N. Burshtyn e-mail: burshtyn@ualberta.ca NK-cell receptors signal through coupled adaptor proteins that encode cytoplasmic ITAMs [3]. Conversely, the inhibitory receptors dampen NK-cell responses via long cytoplasmic tails encoding ITIMs, which recruit SH2 domain-containing phosphatases such as SHP-1 following tyrosine phosphorylation [4]. The inhibitory receptors typically recognize MHC class I (MHC-I) molecules, and therefore healthy self-cells expressing a full complement of MHC-I are protected from NK-cell lysis. NK cells thus sense the density of ligands on engaged cells, and it is the balance of signals received through these functionally opposing receptors that ultimately determines both the response of the effector cell and the fate of the target cell.Inhibitory MHC-I receptors expressed on human NK cells include the killer cell Ig-like receptors (KIRs) and leukocyte Ig-like C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1042-1052 Molecular immunology 1043 receptor-1 (LIR-1), which are encoded on chromosome 19q13.4 within the leukocyte receptor complex [5]. The LIR family encodes receptors with either two or four Ig domains and includes both inhibitory and activating members. While the ligands for all LIR family members have not yet been identified, the inhibitory members LIR-1 and LIR-2 bind MHC-I at the relatively conserved α3 domain and β 2 -microglobulin, allowing for broad specificity and recognition of both classical and nonclassical molecules [6,7]. NK-cell expression of LIR-1 varies between individuals and mediates inhibition of NK cells in response to MHC-I, particularly 9]. LIR-1 is also targeted by a virally encoded MHC-I homologue known as UL18 [10], which shares approximately 25% amino acid sequence identity with MHC-I and associates with human β 2 -microglobulin [11,12]. UL18 binds to LIR-1 with more than 1000-fold greater affinity than MHC-I molecules [7,13,14] and has been shown to mediate suppression of LIR-1 + NK cells in vitro [15]. Studies of LIR-1 function to date have primarily focused on the interaction of the receptor with its ligand in trans, such as inhibition of NK or T cells through recognition of a ligand expressed on a target cell or APC [16][17][18][19][20][21]. However, there is mounting evidence that the interaction of these immune receptors with ligands on the same cell, or in cis, influence how they function [22]. In the murine system, the cis interaction of MHC-I specific NK-cell receptors plays a key role in regulating NK-cell responses. The ...

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Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation

Cited by 80 publications

References 54 publications

Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells

Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells

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

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

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