Abstract
It has been difficult to correlate the quality of CD8 T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8 effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8 T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8 T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8 T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8 T cell response.
Highlights
Vaccination is one of the most successful medical achievements of the last century
Using information on the rate of virus replication and the per cell killing efficacy of virusspecific CD8z T cells one can calculate the critical number of memory CD8z T cells required to control viral growth [23]. If these results can be generalized to other lymphoid and nonlymphoid organs and to other acute viral infections our results suggest that memory CD8z T cells are able to provide sterilizing immunity, if they are to be present at the right place and at high enough frequencies [24,25]
The death rate of targets was highly correlated with the magnitude of the epitope-specific CD8z T cell response [22]
Summary
Vaccination is one of the most successful medical achievements of the last century. Due to our limited understanding of the correlates of protection, most vaccines have been developed by a trial and error approach, and we have yet failed to deliver vaccines for important diseases like AIDS or malaria. It is generally believed that most of the currently used vaccines provide protection by inducing high titers of pathogen-neutralizing antibodies [1]. The new vaccines that are currently being developed for devastating chronic infections, such as HIV and malaria, are designed to stimulate cellular CD4z and CD8z T cell responses. Such vaccines elicit memory T cells, but at present it remains unclear whether or not this T cell memory can provide protection to infection, and which parameters of these T cells would correlate with protection [1]. Evidence from HIV infected patients suggests that memory T cells loose functionality when viral loads are high [6,7], arguing that the frequency of polyfunctional memory T cells is a consequence of the level of protection rather than its cause
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