From quiet to quick recall response: a key role for quiescent CD8+ T cells?

Abstract

Although the overall CD8+ T cell immune response is reproducible, individual naïve CD8+ T cells vary significantly in their contributions. A single naïve CD8+ T cell and all its descendants constitute a “family”. Interestingly, while the size of a family in the primary response shows little correlations with its size in the secondary response, there is a strong correlation between family sizes across recall responses. Recent findings using the DivisionRecorder system have revealed that recall responses are primarily driven by lowly divided memory T cells with stem-cell like properties. Understanding how cells responsible for immunological memory are generated and maintained is crucial for improving immune protection post-vaccination. In this report, we develop a model, informed by recent literature, in which activated CD8+ T cells initially undergo a few rapid, highly synchronized burst divisions. After a burst, the resulting daughter cells have diversified in branches. Some branches continue to divide and combat the current infection, while others return to quiescence and provide future protection by generating recall responses upon re-infection. The inclusion of these quiescent cells in the model accounts for the observed improved correlation between family sizes across recall responses. This is because the number of quiescent cells formed during the primary response is stochastic but correlated with the number formed during the subsequent response. In conclusion, a growing body of research highlights the crucial role of lowly divided memory T cells in long-term protection against pathogens.