The influence of circadian rhythms on CD8+ T cell proliferation upon vaccination: a mathematical modeling perspective

Abstract

Circadian rhythms have been implicated in the modulation of many physiological processes, including those associated with the immune system. For example, these rhythms influence CD8+ T cell responses within the adaptive immune system. The mechanism underlying this immune-circadian interaction, however, remains unclear, particularly in the context of vaccination. Here, we devise a molecularly-explicit gene regulatory network model of early signaling in the nave CD8+ T cell activation pathway, comprised of three axes (or subsystems) labeled ZAP70, LAT and CD28, to elucidate the molecular details of this immune-circadian mechanism and its relation to vaccination. This is done by coupling the model to a periodic forcing function to identify the molecular players targeted by circadian rhythms, and analyzing how these rhythms subsequently affect CD8+ T cell activation under differing levels of T cell receptor (TCR) phosphorylation, which we designate as vaccine load. By performing both bifurcation and parameter sensitivity analyses on the model at the single cell and population levels, we find that applying periodic forcing on molecular targets within the ZAP70 axis is sufficient to create a day-night discrepancy in CD8+ T cell activation in a manner that is dependent on the bistable switch inherent in CD8+ T cell early signaling. We also demonstrate that the resulting CD8+ T cell activation is dependent on the strength of the periodic coupling as well as on the level of TCR phosphorylation. Our results show that this day-night discrepancy is not transmitted to certain downstream molecules within the LAT subsystem, such as mTORC1, suggesting a secondary, independent circadian regulation on that protein complex. We also corroborate experimental results by showing that the circadian regulation of CD8+ T cell primarily acts at a baseline, pre-vaccination state, playing a facilitating role in priming CD8+ T cells to vaccine inputs according to time of day. By applying a population level analysis using bifurcation theory and by including several hypothesized molecular targets of this circadian rhythm, we further demonstrate an increased variability between CD8+ T cells (due to heterogeneity) induced by its circadian regulation, which may allow a population of CD8+ T cells to activate at a lower vaccine load, improving its sensitivity. This modeling study thus provides insights into the immune targets of the circadian clock, and proposes an interaction between vaccine load and the influence of circadian rhythms on CD8+ T cell activation. HighlightsO_LIPotential targets of circadian rhythms within the ZAP70 signaling pathway were identified. C_LIO_LIThe level of vaccine load to a CD8+ T cell was shown to be crucial in dictating a circadian rhythms influence on its signaling response. C_LIO_LIThe priming effect of a circadian rhythm on CD8+ T cell activation upon vaccination was demonstrated. C_LIO_LImTORC1 and its immediate upstream signaling molecules were shown to be regulated by circadian rhythms through independent mechanisms. C_LIO_LIA heterogeneity in CD8+ T cells, induced by its circadian regulation, may influence their sensitivity to vaccination. C_LI