The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways

Abstract

Circadian variations of various aspects of the immune system have been described. However, the circadian control of T cells has been relatively unexplored. Here, we investigated the role of circadian clocks in regulating CD8 T cell response to antigen presentation by dendritic cells (DCs). The in vivo CD8 T cell response following vaccination with DCs loaded with the OVA 257-264 peptide antigen (DC-OVA) leads to a higher expansion of OVA-specific T cells in response to vaccination done in the middle of the day, compared to other time points. This rhythm was dampened when DCs deficient for the essential clock gene Bmal1 were used and abolished in mice with a CD8 T cell-specific Bmal1 deletion. Thus, we assessed the circadian transcriptome of CD8 T cells and found an enrichment in the daytime of genes and pathways involved in T cell activation. Based on this, we investigated early T cell activation events. Three days postvaccination, we found higher T cell activation markers and related signaling pathways (including IRF4, mTOR, and AKT) after a vaccination done during the middle of the day compared to the middle of the night. Finally, the functional impact of the stronger daytime response was shown by a more efficient response to a bacterial challenge at this time of day. Altogether, these results suggest that the clock of CD8 T cells modulates the response to vaccination by shaping the transcriptional program of these cells and making them more prone to strong and efficient activation and proliferation according to the time of day.

Regulatory T cells confer a circadian signature on inflammatory arthritis

“…Our observations that Tregs show phenotypic changes over 24 h, indicates that their function as immune regulators is under circadian control. Whilst CD8 + T cells are established to exhibit robust low amplitude circadian rhythms 40 . Previous reports regarding whether CD4 + T cells have an intrinsic clock are conflicting 23,24 .…”

Circadian Regulation of Immunity Through Epigenetic Mechanisms

“…Accordingly, CD8+ and CD4+ T cells show circadian fluctuation in proliferation, which is dampened in Clock mutant mice (Fortier et al, 2011;Druzd et al, 2017). Moreover, a circadian transcriptional program is apparent in CD8+ T cells, which allows them to respond more efficiently to antigen presentation during daytime, by rhythmically modulating downstream effectors of the T cell receptor, such as IRF4, AKT, and mTOR pathways (Nobis et al, 2019). At tissue level, lymphocytes including T cells CD8+, CD4+, and B cells show circadian oscillation in the entry/egress from the lymph nodes, and BMAL1 is necessary for this function by directing the circadian expression of key regulators of lymphocyte trafficking such as Ccr7 and S1pr1 (Druzd et al, 2017).…”

Personalized medicine and circadian rhythms: Opportunities for modern society

“…gov/ct2/show/NCT02781792). Also, vaccinations show time-of-day-dependent variations both in mice and humans (Long et al, 2016;Nobis et al, 2019). Thus, the time has come to start exploiting the growing amount of transcriptomic data now available and translate it to medical practice.…”