Dynamics of killer T cell inflation in viral infections
Dominik Wodarz1, Sophie Sierro, Paul Klenerman
1Department of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697, USA. dwodarz@uci.edu
Insights
Cytotoxic T lymphocyte (CTL) memory inflation occurs when CTLs expand post-infection. This phenomenon is driven by competition with natural killer (NK) cells, which maintain a chronic viral load, promoting further CTL proliferation.
Area of Science:
- Immunology
- Virology
- Mathematical Biology
Background:
- Cytotoxic T lymphocyte (CTL) responses typically contract after viral infections.
- CTL memory inflation, an unusual expansion of antigen-specific CTLs post-resolution, has been observed in murine cytomegalovirus (MCMV) infections.
- The underlying mechanisms driving CTL memory inflation remain incompletely understood.
Purpose of the Study:
- To investigate the dynamics of CTL memory inflation using a mathematical model.
- To identify key factors influencing CTL memory inflation, particularly the interplay between innate and adaptive immune responses.
- To explore the role of natural killer (NK) cells in the CTL memory inflation phenomenon.
Main Methods:
- Development of a mathematical model to simulate immune responses during viral infections.
- Analysis of the model to assess the impact of varying NK cell and CTL efficiencies on viral load and CTL dynamics.
- Comparison of theoretical predictions with experimental data from MCMV-infected mice.
Main Results:
- The model indicates that competition between CTLs and NK cells is a significant contributor to CTL memory inflation.
- CTL inflation is most pronounced when NK cells are highly effective during acute infection but permit chronic viral persistence.
- Weaker NK cell-mediated protection correlates with more significant CTL inflation over time.
- Experimental data from MCMV-infected mice support the model's predictions.
Conclusions:
- The interplay between NK cell activity and CTL responses is crucial for understanding CTL memory inflation.
- The mathematical model provides a framework for explaining CTL memory inflation, particularly in the context of cytomegalovirus infections.
- This research offers insights into age-related changes in cytomegalovirus (CMV)-specific CD8+ T cells in humans.
Abstract:
Upon acute viral infection, a typical cytotoxic T lymphocyte (CTL) response is characterized by a phase of expansion and contraction after which it settles at a relatively stable memory level. Recently, experimental data from mice infected with murine cytomegalovirus (MCMV) showed different and unusual dynamics. After acute infection had resolved, some antigen specific CTL started to expand over time despite the fact that no replicative virus was detectable. This phenomenon has been termed as "CTL memory inflation". In order to examine the dynamics of this system further, we developed a mathematical model analysing the impact of innate and adaptive immune responses. According to this model, a potentially important contributor to CTL inflation is competition between the specific CTL response and an innate natural killer (NK) cell response. Inflation occurs most readily if the NK cell response is more efficient than the CTL at reducing virus load during acute infection, but thereafter maintains a chronic virus load which is sufficient to induce CTL proliferation. The model further suggests that weaker NK cell mediated protection can correlate with more pronounced CTL inflation dynamics over time. We present experimental data from mice infected with MCMV which are consistent with the theoretical predictions. This model provides valuable information and may help to explain the inflation of CMV specific CD8+T cells seen in humans as they age.
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