How Does Cross-Reactive Stimulation Affect the Longevity of CD8+ T Cell Memory?

Immunological memory—the ability to “remember” previously encountered pathogens and respond faster upon re-exposure is a central feature of the immune response in vertebrates. The cross-reactive stimulation hypothesis for the maintenance of memory proposes that memory cells specific for a given pathogen are maintained by cross-reactive stimulation following infections with other (unrelated) pathogens. We use mathematical models to examine the cross-reactive stimulation hypothesis. We find that: (i) the direct boosting of cross-reactive lineages only provides a very small increase in the average longevity of immunological memory; (ii) the expansion of cross-reactive lineages can indirectly increase the longevity of memory by reducing the magnitude of expansion of new naive lineages which occupy space in the memory compartment and are responsible for the decline in memory; (iii) cross-reactive stimulation results in variation in the rates of decline of different lineages of memory cells and enrichment of memory cell population for cells that are cross-reactive for the pathogens to which the individual has been exposed.Synopsis: 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. Exposure to a pathogen results in the clonal expansion of a few relatively rare clones of immune cells which are specific for the pathogen to form a population large enough to control the pathogen. Immunological memory arises from the maintenance of an elevated numbers of these pathogen-specific immune cells. There has been much debate on the contribution of different processes such as the persistence of antigen, cross-reactive stimulation, and homeostasis to the maintenance of the elevated number of “memory” cells. Models have been useful in understanding the contributions of these various processes to the maintenance of memory. The models have shown that the decline rate of memory specific for previously encountered pathogens arises due to exposure to new pathogens—this causes the replacement of a fraction of “old” memory cells with memory cells specific for new pathogens. In this paper Ganusov, Antia, and colleagues use mathematical models to explore how the ability of cross-reactive memory cells to respond to the antigens on more than one pathogen can help in the maintenance of immunological memory.