Article

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: 3.28). 12/2009; 1(3):362. DOI: 10.3390/v1030362
Source: PubMed

ABSTRACT 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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    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. 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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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    ABSTRACT: Cytomegalovirus infection is very common and leads to the generation of a very strong humoral and cellular immune response that is maintained for life and appears necessary to control viral replication. This leads to marked alterations in the composition of the immune cell repertoire and epidemiological evidence shows that this can be associated with increased levels of morbidity and mortality in the elderly. The immune response appears to be triggered by frequent episodes of subclinical viral reactivation and the predominant effect is of the accumulation of large numbers of cytotoxic cells. These observations suggest that mechanisms that could serve to control the expansion of this immune response could have significant potential in improving the health of elderly donors.
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