CD94 Is Essential for NK Cell-Mediated Resistance to a Lethal Viral Disease

Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Immunity (Impact Factor: 21.56). 03/2011; 34(4):579-89. DOI: 10.1016/j.immuni.2011.02.015
Source: PubMed


It is well established that natural killer (NK) cells confer resistance to many viral diseases, but in only a few instances the molecular mechanisms whereby NK cells recognize virus-infected cells are known. Here we show that CD94, a molecule preferentially expressed by NK cells, is essential for the resistance of C57BL/6 mice to mousepox, a disease caused by the Orthopoxvirus ectromelia virus. Ectromelia virus-infected cells expressing the major histocompatibility complex (MHC) class Ib molecule Qa-1(b) are specifically recognized by the activating receptor formed by CD94 and NKG2E. Because CD94-NKG2 receptors and their ligands are highly conserved in rodents and humans, a similar mechanism may exist during human infections with the smallpox and monkeypox viruses, which are highly homologous to ectromelia virus.

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    • "In summary, D2 substrains differ greatly in Klrd1 gene structure and expression (Fig. 1). The differences between substrains from JAX (D2J) and Janvier (D2Rj) and the difference in CD94 expression represent a valuable resource for functional studies of CD94. Whereas CD94 is essential for NK cell-mediated resistance to mousepox (FANG et al. 2011) we did not detect a significant QTL at the Klrd1 locus after influenza A infection with the mouse-adapted H1N1 virus PR8 (A/PuertoRico/8/34) (NEDELKO et al. 2012). Similarly, no significant phenotypic differences were found between D2J and D2Rj after infection with PR8."
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    ABSTRACT: Current model DBA/2J (D2J) mice lack CD94 expression due to a deletion spanning the last coding exon of the Klrd1 gene that occurred in the mid to late-1980s. In contrast, DBA/2JRj (D2Rj) mice, crosses derived from DBA/2J prior to 1984, and C57BL/6J (B6) mice lack the deletion and have normal CD94 expression. For example, BXD lines (BXD1-32) generated in the 1970s by crossing B6 and D2J do not segregate for the exonic deletion and have high expression whereas BXD lines 33 and higher were generated after 1990 are segregating for the deletion and have highly variable Klrd1 expression. We performed quantitative trait locus (QTL) analysis of Klrd1 expression using BXD lines with different generation times and found that the expression difference in Klrd1 in the later BXD set is driven by a strong cis eQTL. Although the Klrd1/CD94 locus is essential for mousepox resistance, the genetic variation among D2 substrains and the later set of BXD strains is not associated with susceptibility to the Influenza A virus PR8 strain. Substrains with nearly identical genetic backgrounds that are segregating functional variants such as the Klrd1 deletion are useful genetic tools to investigate biological function. Copyright © 2014 Author et al.
    Full-text · Article · Dec 2014 · G3-Genes Genomes Genetics
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    • "The ablation of cytokine expression by MPXV infection could have serious consequences. First, compromised IFN-γ production may directly reduce the capacity of NK cells to clear MPXV-infected cells as both IFN-γ and perforin are required to clear ECTV [22]. Secondly, full battle of the immune system against virus infection requires the collaboration of different arms of immunity such as T cell responses and virus-specific Abs to handle large virus loads. "
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    ABSTRACT: Natural killer (NK) cells play critical roles in innate immunity and in bridging innate and adaptive immune responses against viral infection. However, the response of NK cells to monkeypox virus (MPXV) infection is not well characterized. In this intravenous challenge study of MPXV infection in rhesus macaques (Macaca mulatta), we analyzed blood and lymph node NK cell changes in absolute cell numbers, cell proliferation, chemokine receptor expression, and cellular functions. Our results showed that the absolute number of total NK cells in the blood increased in response to MPXV infection at a magnitude of 23-fold, manifested by increases in CD56+, CD16+, CD16-CD56- double negative, and CD16+CD56+ double positive NK cell subsets. Similarly, the frequency and NK cell numbers in the lymph nodes also largely increased with the total NK cell number increasing 46.1-fold. NK cells both in the blood and lymph nodes massively proliferated in response to MPXV infection as measured by Ki67 expression. Chemokine receptor analysis revealed reduced expression of CXCR3, CCR7, and CCR6 on NK cells at early time points (days 2 and 4 after virus inoculation), followed by an increased expression of CXCR3 and CCR5 at later time points (days 7-8) of infection. In addition, MPXV infection impaired NK cell degranulation and ablated secretion of interferon-γ and tumor necrosis factor-α. Our data suggest a dynamic model by which NK cells respond to MPXV infection of rhesus macaques. Upon virus infection, NK cells proliferated robustly, resulting in massive increases in NK cell numbers. However, the migrating capacity of NK cells to tissues at early time points might be reduced, and the functions of cytotoxicity and cytokine secretion were largely compromised. Collectively, the data may explain, at least partially, the pathogenesis of MPXV infection in rhesus macaques.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "Subsequent crosses of DBA2/J and C57BL/6 did reveal one of the four resistance markers, rmp3, to be on chromosome 17 near the H-2 locus but not H-2D b itself (Brownstein et al., 1992). It is quite possible that the rmp3 locus is Qa-1 itself, although deletion of Qa-1 in CD57BL/6 does not completely recapitulate the loss of CD94 and produces an intermediate phenotype (Fang et al., 2011). On the other hand, for C57BL/6 mice, the presence of Ly49H is somewhat detrimental to the response to ectromelia virus (Fodil-Cornu et al., 2008). "
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    ABSTRACT: In recent years, our understanding of the role of natural killer (NK) cells in the response to viral infection has grown rapidly. Not only do we realize viruses have many immune-evasion strategies to escape NK cell responses, but that stimulation of NK cell subsets during an antiviral response occurs through receptors seemingly geared directly at viral products and that NK cells can provide a memory response to viral pathogens. Tremendous knowledge has been gained in this area through the study of herpes viruses, but appreciation for the significance of NK cells in the response to other types of viral infections is growing. The function of NK cells in defense against poxviruses has emerged over several decades beginning with the early seminal studies showing the role of NK cells and the NK gene complex in susceptibility of mouse strains to ectromelia, a poxvirus pathogen of mice. More recently, greater understanding has emerged of the molecular details of the response. Given that human diseases caused by poxviruses can be as lethal as smallpox or as benign as Molluscum contagiosum, and that vaccinia virus, the prototypic member of the pox family, persists as a mainstay of vaccine design and has potential as an oncolytic virus for tumor therapy, further research in this area remains important. This review focuses on recent advances in understanding the role of NK cells in the immune response to poxviruses, the receptors involved in activation of NK cells during poxvirus infection, and the viral evasion strategies poxviruses employ to avoid the NK response.
    Full-text · Article · Jan 2013 · Frontiers in Immunology
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