Immune inhibitory receptors: Essential regulators of phagocyte function

Steevels, Tessa A. M.; Meyaard, Linde

doi:10.1002/eji.201041179

Cited by 71 publications

(64 citation statements)

References 131 publications

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“…As activating FcγR signals through immunoreceptor tyrosine-based activation motif (ITAM), we postulated that DENV coligates an immunoreceptor tyrosine-based inhibition motif (ITIM)-bearing receptor to inhibit Syk activation (14) in THP-1.2S. Examination of the gene expression data identified two such possible receptors.…”

Section: Early Isg Expression During Ade Is Independent Of Rig-i/mda5mentioning

confidence: 99%

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Chan

Ong

Tan

et al. 2014

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

104

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Viruses must evade the host innate defenses for replication and dengue is no exception. During secondary infection with a heterologous dengue virus (DENV) serotype, DENV is opsonized with sub-or nonneutralizing antibodies that enhance infection of monocytes, macrophages, and dendritic cells via the Fc-gamma receptor (FcγR), a process termed antibody-dependent enhancement of DENV infection. However, this enhancement of DENV infection is curious as cross-linking of activating FcγRs signals an early antiviral response by inducing the type-I IFN-stimulated genes (ISGs). Entry through activating FcγR would thus place DENV in an intracellular environment unfavorable for enhanced replication. Here we demonstrate that, to escape this antiviral response, antibody-opsonized DENV coligates leukocyte Ig-like receptor-B1 (LILRB1) to inhibit FcγR signaling for ISG expression. This immunoreceptor tyrosine-based inhibition motif-bearing receptor recruits Src homology phosphatase-1 to dephosphorylate spleen tyrosine kinase (Syk). As Syk is a key intermediate of FcγR signaling, LILRB1 coligation resulted in reduced ISG expression for enhanced DENV replication. Our findings suggest a unique mechanism for DENV to evade an early antiviral response for enhanced infection.early innate immune response | innate immune signaling | immune evasion D espite long-lived serotype-specific immunity upon initial infection, predicted global prevalence of dengue now surpasses World Health Organization estimates by more than threefold with 390 million cases annually (1). Furthermore, the risk of severe disease is augmented by cross-reactive or subneutralizing levels of antibody (2, 3), which opsonize dengue virus (DENV) to ligate Fc-gamma receptor (FcγR) for entry into monocytes, macrophages, and dendritic cells, a phenomenon known as antibody-dependent enhancement (ADE) of DENV infection (4, 5). The resultant greater viral burden leads to increased systemic inflammation that precipitates plasma leakage, a hallmark of dengue hemorrhagic fever (6). However, ligation of the activating FcγRs by immune complexes has been shown to induce type-I IFN stimulated genes (ISGs), independent of autocrine or paracrine IFN activity, unless the inhibitory FcγRIIB is coligated (7). We and others reported recently that coligation of FcγRIIB by DENV immune complexes requires high antibody concentration, and such coligation inhibited the entry of DENV immune complexes into monocytes (8, 9). At low antibody concentrations where ADE occurs, the inhibitory FcγRIIB is not coligated (9). Ligation of the activating FcγRs by DENV opsonized with subneutralizing levels of antibody would thus induce the expression of ISGs and hinder DENV replication (10). Here, we demonstrate that DENV employs a unique evasive mechanism by coligating LILRB1 to down-regulate the early antiviral responses triggered by activating FcγRs for ADE.Results ADE Differs in THP-1 Subclones. Our work was enabled by the isolation of subclones of THP-1 cells with different phenotypes to ADE. The low rate of...

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Section: Early Isg Expression During Ade Is Independent Of Rig-i/mda5mentioning

confidence: 99%

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Chan

Ong

Tan

et al. 2014

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

104

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“…Even though this process has been considered as the main regulator of their activity, growing evidence indicates that inhibitory receptors are also involved in the control of neutrophil function preventing exacerbated responses and tissue damages (6). In this regard, we focused on the Ig-like transcript 4 (ILT4/LILRB2/CD85d) inhibitory receptor, which is composed of four extracellular Ig-like domains and three immuno-receptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic part (7).…”

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confidence: 99%

Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions

Baudhuin

Migraine

Faivre

et al. 2013

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

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Neutrophils play a major role in inflammatory responses and immune defense against pathogens. Even though expression of inhibitory receptors has been reported on neutrophils, their role remains poorly defined. Here we show that primary human neutrophils expressed immunoglobulin-like transcript 4 (ILT4) inhibitory receptor and that this expression was induced during differentiation of the myelomonoblast PLB-985 cell line into "neutrophil-like" cells. Functional assays indicated that human leukocyte antigen G, the preferred ligand of ILT4, inhibited the phagocytic function of neutrophils. ILT4 engagement also impaired reactive oxygen species production induced through CD32a and both receptors were found colocalized into neutrophil lipid rafts. Moreover, neutrophil degranulation induced through inflammatory stimuli increased ILT4 expression as a result of the rapid translocation of an intracellular pool to the cell surface. Consequently to this ILT4 upregulation, the human leukocyte antigen G-mediated inhibition of neutrophil phagocytic function was enhanced. Finally, we found that ILT4 up-regulation induced on healthy donor neutrophils following stimulation was impaired in presence of plasma from patients with sepsis. Similarly, ILT4 up-regulation was inhibited in neutrophils from septic patients. Altogether, our results reveal a unique mechanism of regulation of neutrophil functions through ILT4 and its exocytosis that may have implications in inflammatory disorders.granulocytes |

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“…4A; supplemental Table S4). Notably, all of the ITIM peptides, except for pY796, interacted with the tyrosine phosphatases SHP-1 (PTPN6) and SHP-2 (PTPN11), suggesting that the corresponding pTyr sites mediate inhibitory signaling (6). The pY796 peptide, in contrast, bound to the tyrosine kinases ABL2 and SYK, which are associated with activating signaling in B-cells (27), and to CSK, which inactivates SRC by phosphorylating a C-terminal Tyr residue in the kinase (28).…”

Section: Identification Of Authentic Interactions By Integrating Peptmentioning

confidence: 99%

“…Nevertheless, these distinctions are only relative and both motifs may be involved in either positive or negative immune functions. For example, ITIM-containing inhibitory receptors found on phagocytes can suppress or enhance inflammatory cytokine production depending on the downstream proteins that they recruit (6). Similarly, ITAM sequences have been found to mediate inhibitory signaling (8).…”

mentioning

confidence: 99%

A Comprehensive Immunoreceptor Phosphotyrosine-based Signaling Network Revealed by Reciprocal Protein–Peptide Array Screening

Liu

Voss

et al. 2015

Molecular & Cellular Proteomics

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Immune receptor signaling, critical for proper immune response, involves signaling pathways mediated by specific tyrosine residues that are phosphorylated upon receptor activation (1). These tyrosine phosphorylation sites are frequently found in one of the three types of immunoreceptor tyrosine-based regulatory motifs (ITRMs)1 . The immunoreceptor tyrosine-based activation motifs (ITAMs) with the consensus sequence YxxI/Lx(6 -12)YxxI/L, where x represents any amino acid, are typically associated with positive or activating immune response (2). In contrast, the immune system elicits negative or inhibitory response through receptors bearing the immunoreceptor tyrosine-based inhibition motifs (ITIMs) with the degenerated sequence S/I/V/LxYxxI/V/L (3). Interestingly, SLAM/CD150 and related receptors of the CD2 subfamily contain a third type of signaling motif called Immunoreceptor Tyrosine-based Switch Motif (ITSM) with the consensus sequence TxYxx(V/I) (4). An ITSM can convey either an activating or inhibitory signal, depending on the type of immune cell, the receptor and the bound protein (5).In general, phosphorylated ITIMs recruit the SH2 domaincontaining tyrosine phosphatase SHP-1 or SHP-2 (6), and phosphorylated ITAMs are recognized by protein tyrosine kinases such as ZAP70 in T cells and SYK in B cells (7). Nevertheless, these distinctions are only relative and both motifs may be involved in either positive or negative immune functions. For example, ITIM-containing inhibitory receptors found on phagocytes can suppress or enhance inflammatory cytokine production depending on the downstream proteins that they recruit (6). Similarly, ITAM sequences have been found to mediate inhibitory signaling (8). Indeed, even within the same cell type, an ITAM-containing receptor may mediate From the ‡Department of Biochemistry and the Siebens-Drake

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Immune inhibitory receptors: Essential regulators of phagocyte function

Cited by 71 publications

References 131 publications

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue

Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions

A Comprehensive Immunoreceptor Phosphotyrosine-based Signaling Network Revealed by Reciprocal Protein–Peptide Array Screening

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