A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections
Subhasish Baral, Rustom Antia, and Narendra M. Dixit
PNAS August 27, 2019 116 (35) 17393-17398; first published August 14, 2019 https://doi.org/10.1073/pnas.1902178116
Edited by Michael B. A. Oldstone, Scripps Research Institute, La Jolla, CA, and approved July 23, 2019 (received for review February 5, 2019)
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Viral infections have different outcomes in different individuals. They could be cleared spontaneously, turn chronic, or cause host death due to tissue damage. Identifying what determines these outcomes has been a longstanding challenge in immunology. Many factors, including viral inoculum size and host genetics, that influence the outcomes have been identified, suggesting that a complex interplay of numerous factors determines the outcomes. In striking contrast, we argue that the outcomes are determined by a dynamical motif comprising a few, essential interactions between viral antigens and CD8 T cells. The other factors influence the outcomes indirectly by modulating these essential interactions. The motif presents a conceptual understanding of the outcomes, explains several confounding experimental observations, and proposes interventions.
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.
包含抗原和CD8 T细胞之间相互作用的动力基序可能是病毒感染结果的基础
Subhasish Baral，Rustom Antia和Narendra M. Dixit
PNAS 2019年8月27日116（35）17393-17398;首次发布于2019年8月14日https://doi.org/10.1073/pnas.1902178116
由Michael B. A. Oldstone编辑，Scripps研究所，La Jolla，CA，并于2019年7月23日批准（收到2019年2月5日审查）