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

Vitaly V Ganusov,Sergei S Pilyugin,Rafi Ahmed,Rustom Antia,Sebastion Bonhoeffer

doi:10.1371/journal.pcbi.0020055

Vitaly V Ganusov, Sergei S Pilyugin + Show 3 more

Open Access

https://doi.org/10.1371/journal.pcbi.0020055

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Abstract

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.

Highlights

Immunological memory—the ability to ‘‘remember’’ previously encountered pathogens and respond faster upon reexposure—is a central feature of the immune response of vertebrates
Stimulated naive cells expand in numbers, some die, and others differentiate into memory cells
We have used mathematical models to investigate the relative contribution of multiple processes, including crossreactive stimulation and homeostasis, on the longevity of immunological memory

Summary

Introduction

Immunological memory—the ability to ‘‘remember’’ previously encountered pathogens and respond faster upon reexposure—is a central feature of the immune response of vertebrates. This more rapid response arises, in large part, from an increase in the number of B and T cells specific to the pathogen, and usually (but not always, see [1]) results in protection from disease upon re-exposure. One possibility is that memory resulted in the generation of a population of non-dividing ‘‘memory’’ cells with a long lifespan This hypothesis was rejected by the elegant experiments that demonstrated that memory T cells incorporate BrdU, indicating that this population is undergoing division [5,6]. This result implies that the rate of division of immune cells and the death rate must be in balance for the population of memory cells to be long-lived

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