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      Human Herpesviridae Methods of Natural Killer Cell Evasion

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          Abstract

          Human herpesviruses cause diseases of considerable morbidity and mortality, ranging from encephalitis to hematologic malignancies. As evidence emerges about the role of innate immunity and natural killer (NK) cells in the control of herpesvirus infection, evidence of viral methods of innate immune evasion grows as well. These methods include interference with the ligands on infected cell surfaces that bind NK cell activating or inhibitory receptors. This paper summarizes the most extensively studied NK cell receptor/ligand pairs and then describes the methods of NK cell evasion used by all eight herpesviruses through these receptors and ligands. Although great strides have been made in elucidating their mechanisms, there is still a disparity between viruses in the amount of knowledge regarding innate immune evasion. Further research of herpesvirus innate immune evasion can provide insight for circumventing viral mechanisms in future therapies.

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          Most cited references155

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          NK cell recognition.

          The integrated processing of signals transduced by activating and inhibitory cell surface receptors regulates NK cell effector functions. Here, I review the structure, function, and ligand specificity of the receptors responsible for NK cell recognition.
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            HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

            The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.
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              Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy.

              Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface. Aberrant cells which fail to express MHC products adequately can therefore avoid detection. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H-2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.

                Author and article information

                Journal
                Adv Virol
                Adv Virol
                AV
                Advances in Virology
                Hindawi Publishing Corporation
                1687-8639
                1687-8647
                2012
                8 July 2012
                : 2012
                : 359869
                Affiliations
                1School of Medicine, University of Alabama at Birmingham, 1600 6th Avenue South, CHB 118C, Birmingham, AL 35233-1701, USA
                2Division of Neurosurgery, Department of Surgery, University of Alabama at Birmingham, 1530 3rd Avenue South, FOT 1060, Birmingham, AL 35294-3410, USA
                3Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294-3410, USA
                4Division of Infectious Disease, Department of Pediatrics, University of Alabama at Birmingham, 600 7th Avenue South, CHB 118, Birmingham, AL 35233-1701, USA
                Author notes
                *Kevin A. Cassady: kcassady@ 123456uab.edu

                Academic Editor: John Frater

                Article
                10.1155/2012/359869
                3399383
                22829821
                7b672fb4-9f8b-479f-92d9-77eb7b14f09d
                Copyright © 2012 Carl I. Odom et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 March 2012
                : 24 April 2012
                Categories
                Review Article

                Microbiology & Virology
                Microbiology & Virology

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