Natural killer cells act as rheostats modulating antiviral T cells

Abstract

Anti-viral T cells are thought to regulate whether hepatitis C virus (HCV) and HIV infections result in viral control, asymptomatic persistence, or severe disease, though the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK) cell receptors and progression of both HIV and HCV infection1–3, implying that NK cells are playing a role in these T cell-associated diseases. While direct NK cell-mediated lysis of virus-infected cells may contribute to anti-viral defense during some virus infections, especially murine cytomegalovirus (MCMV) infections in mice and perhaps HIV in humans4–5, NK cells have also been suspected as having immunoregulatory functions. For instance, NK cells may indirectly regulate T cell responses by lysing MCMV-infected antigen-presenting cells6–7. In contrast to MCMV, lymphocytic choromeningitis virus (LCMV) infection in mice seems resistant to any direct anti-viral effects of NK cells5,8. Here the roles of NK cells in regulating T cell-dependent viral persistence and immunopathology were examined in mice infected with LCMV, an established model for HIV and HCV infections in humans. We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion. At high virus dose NK cells prevented fatal pathology while enabling T-cell exhaustion and viral persistence, but at a medium dose NK cells paradoxically facilitated lethal T cell-mediated pathology. Thus, NK cells can act as rheostats, regulating CD4 T cell-mediated support for the anti-viral CD8 T cells that control viral pathogenesis and persistence.

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…Such an adjustment in combination with persisting expression of PD-1 could be of vital importance in chronic infections 64,65 . In strong support of this concept, it was recently shown that a high dose virus infection, which induced a strong "exhausted" phenotype, protected mice from immunopathology while a lower dose, which failed to induce an "exhausted" phenotype, resulted in substantial pathology 74,77 . Similarly, disrupting the von Hippel-Lindau tumor suppressor (VHL) gene causes overwhelming immunopathology by enforcing cytotoxic activity of T-cells in persisting infections 78 .…”

“…Accordingly, the deterioration in the T-cell response following CD4 depletion in chronic infection might be a consequence of losing these memory-like T-cells. Interestingly, a recent publication indicated that the impact of CD4 T-cells on CD8 T-cells in chronic infection could also be controlled by NK cells, which reduce the number of CD4 T-cells and concomitantly the number of CD8 T-cells 74 .…”

Natural killer cell memory in infection, inflammation and cancer

“…Whether memory NK cells limit T cell responses by directly killing activated T cells has not been assessed but should be considered 71 . It is tempting to speculate that, in situations in which T cell memory is impaired, memory NK cells might in part provide protection against disease.…”

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

“…It has been reported that NK cells regulate T cell responses through multiple direct and indirect mechanisms, including NK cell-mediated killing of activated CD8 + T cells (14,15,(18)(19)(20)(21), CD4 + T cells (18,19,22,23), and also of dendritic cells (DCs) (12,24,25). However, little is known about a possible NK cell-mediated inhibitory/regulatory role during antitumor immune responses.…”