Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations

Hirayasu, Kouyuki; Arase, Hisashi

doi:10.1038/jhg.2015.64

Cited by 98 publications

(89 citation statements)

References 81 publications

(89 reference statements)

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“…1E, the Zika virus-induced upregulation of MHC class I expression resulted in increased binding of KIR2DL2 Ig, which binds HLA-C proteins carrying asparagine at position 80 (49), and LILRB1 Ig, which interacts with HLA-A, -B, and -C proteins (50).…”

Section: Resultsmentioning

confidence: 99%

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

Glasner

Oiknine‐Djian

Weisblum

et al. 2017

J Virol

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NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-␤). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus.IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus infection is largely unknown. Here we demonstrate that Zika virus infection is almost undetected by NK cells, as evidenced by the fact that the expression of activating ligands for NK cells is not induced following Zika infection. We identified a mechanism whereby Zika virus sensing via the RIGI-IRF3 pathway resulted in IFN-␤-mediated upregulation of MHC-I molecules and inhibition of NK cell activity. Countering MHC class I upregulation and boosting NK cell activity may be employed as prophylactic measures to combat Zika virus infection.KEYWORDS Zika virus, MHC class I, NK cells, NK escape mechanisms N K cells are lymphocytes belonging to the innate immune system. NK cells participate in many immunological activities, from killing cancerous cells (1-7) and fighting bacteria (8-10) and fungi (11) to playing roles in allergy (12) and graft-versushost disease (13). NK cells also play roles in autoimmunity (14-18) and pregnancy (19).

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Section: Resultsmentioning

confidence: 99%

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

Glasner

Oiknine‐Djian

Weisblum

et al. 2017

J Virol

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“…Although LILR interactions with classical class I has been extensively examined in terms of class I variation, the reciprocal examining diversity of LILRs binding to MHC-I has only been tested in one case in which a link between polymorphism in LILRB1 and rheumatoid arthritis showed that alterations in expression levels and not binding were involved (25). However, LILR genetic diversity and/or altered expression is quite possibly involved with autoimmune disease or changes in the response to infection, and this has been reviewed elsewhere recently (33).…”

Section: Nonconventional Mhc-i Ligandsmentioning

confidence: 99%

The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors

Burshtyn

Morcos

2016

The Journal of Immunology

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The human leukocyte Ig-like receptor family is part of the paired receptor system. The receptors are widely expressed by various immune cells, and new functions continue to emerge. Understanding the range of functions of the receptors is of general interest because several types of pathogens exploit the receptors and genetic diversity of the receptors has been linked to various autoimmune diseases. Class I major histocompatibility molecules were the first ligands appreciated for these receptors, but the types of ligands identified over the last several years are quite diverse, including intact pathogens, immune-modulatory proteins, and molecules normally found within the CNS. This review focuses on the types of ligands described to date, how the individual receptors bind to several distinct types of ligands, and the known functional consequences of those interactions.

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“…Although counterintuitive, the direct tumor-supportive roles of LILRBs are consistent with the generally immune-suppressive and thus tumor-promoting functions of the inhibitory receptors in the immune system [45]. The roles of LILRBs in immune and neuronal diseases have been recently reviewed [2,4,46,47]. Here we will focus on the ligands, expression pattern, signaling, and the immune-modulatory and direct tumor-supportive roles of LILRBs in cancer development.…”

Section: Introduction To Itim-containing Receptors and Lilrbsmentioning

confidence: 99%

Inhibitory leukocyte immunoglobulin-like receptors in cancer development

Zhang

Zheng

Kang

et al. 2015

Sci. China Life Sci.

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Inhibitory leukocyte immunoglobulin-like receptors (LILRB1-5) signal through immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their intracellular domains and recruit phosphatases protein tyrosine phosphatase, non-receptor type 6 (PTPN6, SHP-1), protein tyrosine phosphatase, non-receptor type 6 (PTPN6, SHP-2), or Src homology 2 domain containing inositol phosphatase (SHIP) to negatively regulate immune cell activation. These receptors are known to play important regulatory roles in immune and neuronal functions. Recent studies demonstrated that several of these receptors are expressed by cancer cells. Importantly, they may directly regulate development, drug resistance, and relapse of cancer, and the activity of cancer stem cells. Although counterintuitive, these findings are consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system. This review focuses on the ligands, expression pattern, signaling, and function of LILRB family in the context of cancer development. Because inhibition of the signaling of certain LILRBs directly blocks cancer growth and stimulates immunity that may suppress tumorigenesis, but does not disturb normal development, LILRB signaling pathways may represent ideal targets for treating hematological malignancies and perhaps other tumors.

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Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations

Cited by 98 publications

References 81 publications

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules

The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors

Inhibitory leukocyte immunoglobulin-like receptors in cancer development

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