Quantitative analysis of long-term virus-specific CD8 ⁺ -T-cell memory in mice challenged with unrelated pathogens

The consequences for the long-term maintenance of virus-specific CD8 ⁺ -T-cell memory have been analyzed experimentally for sequential respiratory infections with readily eliminated (influenza virus) and persistent (gammaherpesvirus 68 [γHV681]) pathogens. Sampling a broad range of tissue sites established that the numbers of CD8 ⁺ T cells specific for the prominent influenza virus D ^b NP ₃₆₆ epitope were reduced by about half in mice that had been challenged 100 days previously with γHV68, though the prior presence of a large CD8 ⁺ D ^b NP ₃₆₆ ⁺ population caused no selective defect in the γHV68-specific CD8 ⁺ K ^b p79 ⁺ response. Conversely, mice that had been primed and boosted to generate substantial γHV68-specific CD8 ⁺ D ^b p56 ⁺ populations did not show any decrease in prevalence for this set of CD8 ⁺ memory cytotoxic T lymphocytes (CTL) at 200 days after respiratory exposure to an influenza A virus. However, in both experiments, the total magnitude of the CD8 ⁺ -T-cell pool was significantly diminished in those that had been infected with γHV68 and the influenza A virus. The broader implications of these findings, especially under conditions of repeated exposure to unrelated pathogens, are explored with a mathematical model which emphasizes that the immune effector and memory "phenome" is a function of the overall infection experience of the individual.