The Natural Selection of Herpesviruses and Virus-Specific NK Cell Receptors

Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, CA 94143, USA.
Viruses (Impact Factor: 3.35). 12/2009; 1(3):362. DOI: 10.3390/v1030362
Source: PubMed


During the co-evolution of cytomegalovirus (CMV) and natural killer (NK) cells, each has evolved specific tactics in an attempt to prevail. CMV has evolved multiple immune evasion mechanisms to avoid detection by NK cells and other immune cells, leading to chronic infection. Meanwhile, the host has evolved virus-specific receptors to counter these evasion strategies. The natural selection of viral genes and host receptors allows us to observe a unique molecular example of "survival of the fittest", as virus and immune cells try to out-maneuver one another or for the virus to achieve détente for optimal dissemination in the population.

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    • "Importantly, scientific findings from models investigating viral evasion and immunity are inherently based on a fixed point in evolution. Although viruses rapidly evolve to evade NK-cell detection, the immune system of a population is also constantly evolving to overcome these hurdles (110). "
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    ABSTRACT: Natural killer (NK) cells provide essential protection against viral infections. One of the defining features of this lymphocyte population is the expression of a wide array of variable cell surface stimulatory and inhibitory NK receptors (sNKR and iNKR, respectively). The iNKR are particularly important in terms of NK-cell education. As receptors specific for MHC class I (MHC I) molecules, they are responsible for self-tolerance and adjusting NK-cell reactivity based on the expression level of self-MHC I. The end result of this education is twofold: (1) inhibitory signaling tunes the functional capacity of the NK cell, endowing greater potency with greater education, and (2) education on self allows the NK cell to detect aberrations in MHC I expression, a common occurrence during many viral infections. Many studies have indicated an important role for iNKR and MHC I in disease, making these receptors attractive targets for manipulating NK-cell reactivity in the clinic. A greater understanding of iNKR and their ability to regulate NK cells will provide a basis for future attempts at translating their potential utility into benefits for human health.
    Full-text · Article · Apr 2014 · Frontiers in Immunology
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    • "Wikby, Pawelec and others in the Swedish NONA study have shown evidence linking long-lasting T CD8 cell clonopathies, with carriage of cytomegalovirus (CMV) infection and higher mortality [38-41] and this has been replicated more recently for carriers with high CMV seropositivity [42]. Increased mortality is associated with other chronic viraemias [43] and a recent paper associates all cause and cardiovascular mortality with levels of CMV seropositivity [44]. Pawelec and other researchers also reported that an inverted CD4/CD8 ratio was associated with chronic T cell clonopathies and poor outcome [38,40], though others including the BELFAST study authors [45] have found this to be either reversible or a non-consistent outcome in those followed up to the age of 100 years [39]. "
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    ABSTRACT: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well. In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 (high or low) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99--1.09; p=0.027) and 14% higher levels for TGF-beta (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99--1.09; p=0.002). In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood.
    Full-text · Article · Aug 2013 · Immunity & Ageing
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    ABSTRACT: The immune system has to recognize and destroy abnormal or infected cells to maintain homeostasis. Natural killer (NK) cells directly recognize and kill transformed or virus-infected cells without prior sensitization. We have studied both virus-infected and tumor cells in order to identify the target structures involved in triggering NK activity. Mouse/human cell hybrids containing various human chromosomes were used as targets. The human chromosome responsible for activating NK cell killing was identified to chromosome number 6. The results suggest that activated NK cells recognize ligands that are encoded on human chromosome 6. We showed that the ligand on the target cell side was intercellular adhesion molecule 2 (ICAM-2). There was no difference in the level of expression of ICAM-2, however, but a drastic difference was seen in the distribution of the molecule: ICAM-2 was evenly distributed on the surface of the NK-resistant cells, but almost totally redistributed to the tip of uropods, bud-like extensions, which were absent from the parental cells. Interestingly, the gene coding for cytoskeletal linker protein ezrin has been localized to human chromosome 6, and there was a colocalization of ezrin and ICAM-2 in the uropods. Furthermore, the transfected human ezrin into NK cell-resistant cells induced uropod formation, ICAM-2 and ezrin redistribution to newly formed uropods, and sensitized target cells to NK cell killing. These data reveal a novel form of NK cell recognition: target structures are already present on normal cells; they become detectable only after abnormal redistribution into hot spots on the target cell membrane. NK cells are central players in the defence against virus infections. They inhibit the spread of infection, allowing time for specific immune responses to develop. The virus-proteins that directly activate human NK cell killing are largely unknown. We studied the sensitivity of virus-specific early proteins of Semliki Forest virus (SFV) to NK killing. The viral non-structural proteins (nsP1-4) translated early in the virus cycle were transfected in NK-resistant cells. Viral early gene nsP1 alone efficiently sensitized target cells to NK activity, and the tight membrane association of nsP1 seems to be critical in the triggering of NK killing. NsP1 protein colocalized with (redistributed) ezrin in filopodia-like structures to which the NK cells were bound. The results suggest that also in viral infections NK cells react to rapid changes in membrane topography. Based on the results of this thesis, a new model of target cell recognition of NK cells can be suggested: reorganization of the cytoskeleton induces alterations in cell surface topography, and this new pattern of surface molecules is recognized as "altered-self". Väitöskirjatyössäni olen tutkinut, miten luonnolliset tappajasolut, NK-solut, erottavat terveet solut virus-infektoituneista tai pahanlaatuisista soluista. Luonnolliset tappajasolut (Natural Killer cells, NK-solut) ovat veren valkosoluja, jotka tuhoavat syöpäsoluja ja virusten infektoimia soluja ilman aikaisempaa immunisaatiota. Tapa, jolla NK-solut tunnistavat kohteensa, on eräs immunologian keskeisistä ongelmista. Yleisesti on ajateltu, että myös NK-solut tunnistaisivat jotakin vierasta T- ja B-solujen tapaan. Elimistölle vieraita NK-solujen kohderakenteita ei kuitenkaan ole löytynyt. Väitöskirjatyössäni olen paljastanut ensimmäisen mekanismin, jolla normaali rakenne muuttuu NK-solujen kohteeksi. Kohdesoluna käytimme soluhybridiä, jossa oli sekä hiiren että ihmisen kromosomeja. NK-solut tuhosivat tehokkaasti kohdesoluja, jotka sisälsivät ihmisen kromosomin 6. Sellaisia hybridisoluja, joista kromosomi 6 puuttui ei tapettu juuri lainkaan. Tulos osoitti, että kromosomissa 6 sijaitsee joko kohderakennetta koodaava tai sitä säätelevä geeni (tai geenejä), joka laukaisee NK-solutapon. Jatkotuloksemme osoittivat, että yksi normaalirakenne, solujen välistä tarttumista välittävä molekyyli, ICAM-2, muuttuu NK-solujen kohderakenteeksi. Havaitsimme, että ICAM-2 uudelleenjärjestäytyy herkissä kohdesoluissa solu-ulokkeiden päähän tihentymiksi, "kuumiksi pisteiksi", joissa sen määrä riittää NK-solutunnistukseen. Osoitimme myös, että solun tukirangan aktiiniin sitoutuva proteiini, ezrin (sijaitsee ihmisen kromosomissa 6), säätelee solu-ulokkeiden muodostusta ja ICAM-2:n uudelleenjärjestäytymistä. NK-solut toimivat ensilinjan puolustuksessa eritoten virusten infektoimia soluja vastaan. Keskeinen kysymys viruksen herkistäessä solun tappajasoluille on, mikä viruksen geeni tai geenit aiheuttaa NK-solutapon. Olemme tutkineet erilaisia Semliki Forest Viruksen (SFV) kandidaattigeenejä, jotka ekspressoituvat infektion alussa. Olemme osoittaneet, että infektion varhaisessa vaiheessa ekspressoituva viruksen tuottama säätelyproteiini, nsP1, herkistää kohdesolut NK-tapolle. NsP1 aiheuttaa solu-ulokkeiden muodostusta, joihin ezrin uudelleenjärjestäytyy, ja joihin NK-solut yleensä tarttuvat. NsP1 on ainakin yksi NK-solujen tapon laukaiseva virusproteiini, ja se yksinään herkisti NK-solutapon yhtä vahvasti kuin koko virus (SFV). Tulostemme perusteella esitän uuden mallin, jolla NK-solut erottavat muuntuneet solut terveistä: NK-solut eivät tunnistakaan mitään vierasta kohdesolun pinnalla vaan solun normaali pintaproteiini uudelleenjärjestäytyy solukalvolla tihentymiksi muuntuneissa soluissa (esim. virusinfektiossa), jolloin pintaproteiinien suhteellinen osuus kasvaa, ja tämä riittää aktivoimaan NK-solutapon. Kohdesolun pintaproteiinin uudelleenjärjestäytyminen on solun tukirangan säätelemää, joten voidaan sanoa, että NK-solut tunnistavat myös muuntuneen (sairaan) solun tukirangan.
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