Waggoner, S.N., Taniguchi, R.T., Mathew, P.A., Kumar, V. & Welsh, R.M. Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J. Clin. Invest. 120, 1925-1938

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 06/2010; 120(6):1925-38. DOI: 10.1172/JCI41264
Source: PubMed


Persistent viral infections are often associated with inefficient T cell responses and sustained high-level expression of inhibitory receptors, such as the NK cell receptor 2B4 (also known as CD244), on virus-specific T cells. However, the role of 2B4 in T cell dysfunction is undefined, and it is unknown whether NK cells contribute to regulation of these processes. We show here that persistent lymphocytic choriomeningitis virus (LCMV) infection of mice lacking 2B4 resulted in diminished LCMV-specific CD8+ T cell responses, prolonged viral persistence, and spleen and thymic pathologies that differed from those observed in infected wild-type mice. Surprisingly, these altered phenotypes were not caused by 2B4 deficiency in T cells. Rather, the entire and long-lasting pathology and viral persistence were regulated by 2B4-deficient NK cells acting early in infection. In the absence of 2B4, NK cells lysed activated (defined as CD44hi) but not naive (defined as CD44lo) CD8+ T cells in a perforin-dependent manner in vitro and in vivo. These results illustrate the importance of NK cell self-tolerance to activated CD8+ T cells and demonstrate how an apparent T cell-associated persistent infection can actually be regulated by NK cells.

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Available from: Stephen N Waggoner, Oct 06, 2015
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    • "NK cells have the capacity to exert antiviral activity in HBV infection through direct effects or indirectly, by modulating T cell responses. Whilst NK cells can promote T cell responses through their production of cytokines like IFN-γ, emerging data are highlighting their capacity to conversely limit antiviral responses by deletion or inhibition of T cells (Waggoner et al., 2010, 2012; Lang et al., 2012). Direct NK cell effects could involve lysis of infected hepatocytes through granzyme/perforin or death receptor pathways. "
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    ABSTRACT: There is natural enrichment of NK cells in the human liver and this intrahepatic predominance underscores their potential importance in the control of infections with hepatotropic viruses such as hepatitis B virus (HBV). The contribution of innate components during chronic HBV infection has been a relatively under-investigated area. However, recent data have highlighted that NK cells are capable of exerting antiviral and immunoregulatory functions whilst also contributing to the pathogenesis of liver injury via death receptor pathways. We will present an overview of current knowledge regarding the complex biology of NK cells in the context of their antiviral versus pathogenic role in chronic hepatitis B as a clinically relevant avenue for further investigation.
    Frontiers in Immunology 03/2013; 4:57. DOI:10.3389/fimmu.2013.00057
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    • "FasL and GzmB are also associated with T cell death induced by other cytotoxic T cells (CTL) changing the balance of T cell subsets {e.g. CD8 T cells, CD4 T helper cells (TH1, TH2, TH17), and CTL} and altering immune responses [28]–[30]. T cell apoptosis may thus contribute toward plaque progression [12], [13], [16], [17], [19]–[22], [26], [27] but the precise role and effects on the balance of different T cell subsets remains only partially defined. "
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    PLoS ONE 09/2012; 7(9):e44694. DOI:10.1371/journal.pone.0044694 · 3.23 Impact Factor
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    ABSTRACT: Programmed T cell differentiation is critically influenced by the complement of costimulatory and coinhibitory signals transmitted during initial antigen encounter. We previously showed that selective CD28 blockade with novel domain antibodies that leave CTLA-4-mediated coinhibitory signaling intact resulted in more profound attenuation of donor-reactive T cell responses and improved graft survival in a murine transplant model. Selective CD28 blockade was also associated with decreased ICOS expression on donor-reactive CD8+ T cell responses as compared to CTLA-4 Ig, but the functional importance of this reduced ICOS expression was not known. In this study, we created retrogenic donor-reactive CD8+ T cells that overexpress ICOS in order to determine whether reduced ICOS expression mechanistically underlies the increased efficacy of selective CD28 blockade in controlling graft-specific T cell responses as compared to conventional costimulation blockade with CTLA-4 Ig. Results indicated that the ability of selective CD28 blockade to blunt donor-reactive CD8+ T cell expansion following transplantation was independent of its ability to inhibit ICOS expression. Furthermore, we have previously published that 2B4 coinhibitory signals are functionally important for controlling graft-specific CD8+ T cell responses in mice treated with CD28 blockade. Here we used a co-adoptive transfer approach to determine that 2B4 coinhibitory signals on antigen-specific CD8+ T cells function in a cell-intrinsic manner to limit ICOS expression in the setting of selective CD28 blockade.
    PLoS ONE 06/2015; 10(6):e0130490. DOI:10.1371/journal.pone.0130490 · 3.23 Impact Factor
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