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THE ROLE OF MODELS IN UNDERSTANDING CD8+ T-CELL MEMORY
Rustom Antia*, Vitaly V. Ganusov* and Rafi Ahmed
Abstract | Immunological memory the ability to remember previously encountered pathogens and respond faster on re-exposure is a central feature of the immune response of vertebrates. We outline how mathematical models have contributed to our understanding of CD8+ T-cell memory. Together with experimental data, models have helped to quantitatively describe and to further our understanding of both the generation of memory after infection with a pathogen and the maintenance of this memory throughout the life of an individual.
Immunological memory protects hosts on re-infection1,2.
The practical importance of this phenomenon was noted by the Greek historian Thucydides, who wrote that, during an outbreak of plague in Athens, those who had recovered from the disease were best able to help the sick because they had now no fear for themselves; for the same man was never attacked twice never at least fatally3.The most important application of immuno-logical memory is vaccination. The discovery of vaccines based on attenuated4 or killed5,6 pathogens has formed the basis of the development of most of the vaccines that are currently in use79.For the most part, these developments did not require an understanding of the biological basis of immunity or immunological memory indeed, many vaccines, including the smallpox vaccine, were in widespread use before BURNETS THEORY OF CLONAL SELECTION10.
These largely empirical methods for the generation of vaccines work best for pathogens that naturally cause acute infections, because recovery from acute infections is typically characterized by clearance of the pathogen and generation of long-lasting immunity. The generation of vaccines against persistent infections that do not elicit natural long-term immunity, such as infection with malaria-causing Plasmodium spp. or HIV, has proven to be problematic and might require advances in our current understanding of virology and immunology1113.
In this review, we describe some of the contributions that mathematical models have made to our
understanding of various aspects of immunological memory, focusing on CD8+ T-cell responses to intracellular pathogens after acute infections. CD8+ T-cell memory to a specific pathogen (usually a virus or intracellular bacterium) can be divided into phases with different time-scales (FIG. 1).The first phase involves the primary response after exposure to the pathogen...