As mentioned in a couple of recent posts, evidence is emerging that natural killer (NK) cells can sometimes specifically recognize pathogens and retain memory of prior encounters (a property once thought to be restricted to T cells and B cells). A new paper in Nature Immunology adds to this evidence, showing that NK cells can specifically respond to antigens from several different pathogens including influenza, vesicular stomatitis virus and HIV-1. Importantly, these NK cell responses were more robust upon second encounter, indicating the development of antigen-specific memory (also sometimes described as “recall”). The researchers report that the capacity for developing memory appears to be linked to NK cell expression of a chemokine receptor named CXCR6.
In discussing the implications of their results, the study authors echo prior papers on this subject by stating that NK cell memory should be explored in the context of vaccine research. They also suggest that the observed linkage between NK cell memory and CXCR6 may be relevant to a recently published study (abstract appended below) that identified an association between a genetic polymorphism in the CXCR6 gene and long-term non-progression of HIV infection; i.e. the impact of this gene variant on disease progression could be due to enhanced HIV-specific NK cell responses.
Nat Immunol. 2010 Oct 24. [Epub ahead of print]
Paust S, Gill HS, Wang BZ, Flynn MP, Moseman EA, Senman B, Szczepanik M, Telenti A, Askenase PW, Compans RW, von Andrian UH.
[1] Harvard Medical School, Department of Pathology, Boston, Massachusetts, USA. [2] The Ragon Institute of MIT, MGH and Harvard, Charlestown, Massachusetts, USA.
Abstract
Hepatic natural killer (NK) cells mediate antigen-specific contact hypersensitivity (CHS) in mice deficient in T cells and B cells. We report here that hepatic NK cells, but not splenic or naive NK cells, also developed specific memory of vaccines containing antigens from influenza, vesicular stomatitis virus (VSV) or human immunodeficiency virus type 1 (HIV-1). Adoptive transfer of virus-sensitized NK cells into naive recipient mice enhanced the survival of the mice after lethal challenge with the sensitizing virus but not after lethal challenge with a different virus. NK cell memory of haptens and viruses depended on CXCR6, a chemokine receptor on hepatic NK cells that was required for the persistence of memory NK cells but not for antigen recognition. Thus, hepatic NK cells can develop adaptive immunity to structurally diverse antigens, an activity that requires NK cell-expressed CXCR6.
J Infect Dis. 2010 Sep 15;202(6):908-15.
Limou S, Coulonges C, Herbeck JT, van Manen D, An P, Le Clerc S, Delaneau O, Diop G, Taing L, Montes M, van't Wout AB, Gottlieb GS, Therwath A, Rouzioux C, Delfraissy JF, Lelièvre JD, Lévy Y, Hercberg S, Dina C, Phair J, Donfield S, Goedert JJ, Buchbinder S, Estaquier J, Schächter F, Gut I, Froguel P, Mullins JI, Schuitemaker H, Winkler C, Zagury JF.
Chaire de Bioinformatique, Conservatoire National des Arts et Métiers.
Abstract
BACKGROUND: The compilation of previous genomewide association studies of AIDS shows a major polymorphism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS.
METHODS: To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding "elite controller" patients, who were controlling the viral load at very low levels (<100 copies/mL).
RESULTS: The rs2234358 polymorphism in the CXCR6 gene was the strongest signal (P=2.5 x 10(-7); odds ratio, 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of P(combined)=9.7 x 10(-10). This association with LTNP is independent of the CCR2-CCR5 locus and the HCP5 polymorphisms.
CONCLUSIONS: The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation.
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