Abstract
Infection by Cytomegalovirus (CMV) is characterized by the massive expansion and continued maintenance of CMV-specific CD8+ T cells for certain CMV-derived peptides. This phenomenon called “memory inflation" has made CMV a primary target for the generation of T cell based vaccine vectors against various diseases. However, many aspects concerning the generation and maintenance of the inflationary CD8+ T cell response still remain to be resolved. In this study, we combined experimental data and mathematical models to analyze the dynamics of circulatory inflationary CD8+ T cells within individual mice infected by MCMV. Obtaining frequent measurements on the number and frequency of CMV-specific CD8+ T cells up to 70 days post infection, we find that mathematical models assuming differing viral stimuli during acute infection and the inflationary phase provide a better description for the observed dynamics than models relying on similar viral stimuli during both phases. In addition, our analysis allowed a detailed quantification of the different phases of memory inflation within individual mice (1st-expansion - contraction - 2nd expansion/maintenance) indicating remarkable consistency of the timing of these phases across mice, but considerable variation in the size of the individual responses between mice. Our analysis provides a first step toward generating a mechanistic framework for analyzing the generation and maintenance of inflationary CD8+ T cells while accounting for individual heterogeneity. Extending these analyses by incorporating measurements from additional compartments and more prolonged sampling will help to obtain a systematic and quantitative understanding of the factors regulating the process of memory inflation.
Highlights
Cytomegaloviruses (CMVs) are a group of doubled-stranded DNA viruses that are known to cause life-long persistent infections in different mammalian species, including mice (MCMV), rhesus monkeys (RhCMV) and humans (HCMV) [1,2,3]
Constant Influx Model (CI) As non-inflationary CD8+ T cells are generally observed to decline in numbers after reaching a peak around day 7–8 p.i. [28, 29], we considered a simplified model that accounted for a constant influx of cells into the circulating T cell pool, which neglected the consideration of additional viral activation compartments
To examine the individual dynamics of inflationary and noninflationary CD8+ T cells in the blood, we infected C57L/B6 mice with MCMV- and took repeated blood samples in a time period from 7 to 70 days p.i. that were analyzed for the number of M38- and M45- specific CD8+ T cells
Summary
Cytomegaloviruses (CMVs) are a group of doubled-stranded DNA viruses that are known to cause life-long persistent infections in different mammalian species, including mice (MCMV), rhesus monkeys (RhCMV) and humans (HCMV) [1,2,3]. An important hallmark of the immune response against CMV is the expansion and continued maintenance of large numbers of CMV-specific memory CD8+ T cells, a phenomenon called “memory inflation" [12,13,14,15] Due to these elevated, effector-memory type T cell levels, in combination with the ubiquity and general harmlessness of the virus, CMV is intensively investigated as a potential T-cell based vaccine vector for different diseases, e.g., including HIV and SIV infection [16,17,18,19]. Many questions regarding the generation, dynamics and maintenance of the inflationary CD8+ T cell response still need to be resolved
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