A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections.

ABSTRACT

Some viral infections culminate in very different outcomes in different individuals. They can be rapidly cleared in some, cause persistent infection in others, and cause mortality from immunopathology in yet others. The conventional view is that the different outcomes arise as a consequence of the complex interactions between a large number of different factors (virus, different immune cells, and cytokines). Here, we identify a simple dynamical motif comprising the essential interactions between antigens and CD8 T cells and posit it as predominantly determining the outcomes. Viral antigen can activate CD8 T cells, which in turn, can kill infected cells. Sustained antigen stimulation, however, can cause CD8 T-cell exhaustion, compromising effector function. Using mathematical modeling, we show that the motif comprising these interactions recapitulates all of the outcomes observed. The motif presents a conceptual framework to understand the variable outcomes of infection. It also explains a number of confounding experimental observations, including the variation in outcomes with the viral inoculum size, the evolutionary advantage of exhaustion in preventing lethal pathology, the ability of natural killer (NK) cells to act as rheostats tuning outcomes, and the role of the innate immune response in the spontaneous clearance of hepatitis C. Interventions that modulate the interactions in the motif may present routes to clear persistent infections or limit immunopathology.