Mathematical models of memory T-cell compartment size and repertoire dynamics.

摘要

Immunity to infections is conferred by the immune system via memory cells, which are created when a host first encounters a virus and serve as sentinels that activate quickly to eliminate any reinfections that occur. Some memory cells secrete antibodies against extracellular invaders, others act as coordinators of the immune response, and some—the memory CD8+ T-cells—eradicate intracellular pathogens by killing infected host cells. These latter cells are each equipped with T-cell receptors that recognize and become activated only in response to a particular virus; thus, a host must possess a broad repertoire of memory CD8+ T-cells with a range of specificities to effectively protect against viral invasions. The breadth of the memory repertoire is constrained, however, by the fact that the number of memory CD8+ T-cells is remarkably constant between infections. Therefore, some attrition of existing memory cells is necessary following infections to make room for new memory cells. Furthermore, some viruses induce memory attrition early in infections creating an underfilled memory compartment; cells must then proliferate to restore the memory compartment to its homeostatic size.;In this thesis, we use deterministic mathematical models to investigate possible mechanisms that maintain memory compartment size. In particular, we examine whether resource competition for survival signals is sufficient to regulate the number of memory cells, even with repeated or persistent cellular influx. To examine how viral infections impact the composition of the memory CD8+ T-cell repertoire, we use stochastic approaches to develop probabilistic models of cellular attrition and proliferation events. We apply these models to acute viruses that stimulate T-cell responses as well as to viruses that cause a drastic early T-cell attrition in order to find probability distributions for the post-infection size of every memory T-cell lineage (as defined by T-cell receptor specificities) in the repertoire. This allows us to determine and compare the effects of such viruses on overall memory compartment diversity, individual T-cell lineage representation, lineage extinction times and probabilities, and other compartment dynamics. Using this information, we draw conclusions about how immunity to past diseases changes or is lost as a result of new infections.