Natural killer cells act as rheostats modulating anti-viral T cells

Waggoner, Stephen N.; Cornberg, Markus; Selin, Liisa K.; Welsh, Raymond M.

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 infection(1–3), 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 humans(4–5), 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 cells(6–7). In contrast to MCMV, lymphocytic choromeningitis virus (LCMV) infection in mice seems resistant to any direct anti-viral effects of NK cells(5,8). 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.