Predicting the dynamics of antiviral cytotoxic T-cell memory in response to different stimuli: Cell population structure and protective function

This paper examines the numerical and functional consequences of various st imuli on antiviral CD8(+) T-cell memory using a mathematical model. The mod el is based upon biological evidence from the murine model of infection wit h lymphocytic choriomeningitis virus (LCMV) that the phenotype of immunolog ical memory represents low-level responses driven by various stimuli, and t he memory CTL population is partitioned between resting, cycling and effect or cells. These subpopulations differ in their lifespan, their potential to mediate antiviral protection and in the stimuli needed for their maintenan ce. Three types of maintenance stimuli are examined: non-antigen-specific ( bystander) stimulation, persisting antigen stimulation and reinfection-medi ated stimulation. The modelling predicts that: (i) stable persistence of CT L memory requires the presence of either bystander or antigen-specific stim ulation above a certain threshold depending on the sensitivity of memory CT L to stimulation and their life-span; (ii) a relatively low level of stimul i (approximately 10(4) fold less on a per CTL basis compared to acute infec tion) is needed to stabilize the expanded memory CTL population; (iii) the presence of CTL subsets in the memory pool of different activation states a nd lifespans ensures the robustness of memory persistence in the face of te mporal variation in the low-level stimuli and; (iv) an 'optimal' population structure of the memory CTL pool, in terms of immediate protection, requir es the presence of both activated cycling and effector CTL. For this, persi sting antigen alone or synergistically with bystander signals provide the a ppropriate stimulation, so that the stimuli equivalent to approximately 30 p.f.u. of LCMV in the spleen are sufficient to maintain approximately 10(5) -10(6) specific CTL in the memory pool. These observations are relevant bot h to our understanding of natural protective immunity and to vaccine design .