Summary: CD8 T cells function differently, according to the time of day. Study shows how the biological clock influences immune response.
Source: McGill University
According to a recent study published in Proceedings of the National Academy of Sciences of the United States of America, the biological clock influences immune response efficacy. Indeed, CD8 T cells, which are essential to fight infections and cancers, function very differently according to the time of day. The study was carried out by a team of researchers led by Nicolas Cermakian, PhD, of the Douglas Research Centre, and Nathalie Labrecque, PhD, of the Maisonneuve-Rosemont Hospital Research Centre.
We know that circadian rhythms are generated by “clock genes”, which influence most organs and cells–including those of the immune system, whose function varies according to the time of day. Accordingly, circadian rhythms are found for various aspects of physiology, including sleep, nutrition, hormonal activity, and body temperature. These daily rhythms help the body adapt to cyclical changes in the environment, such as seasons and the day and night cycle.
In earlier research, the team had demonstrated that T cells react more or less strongly to a foreign body according to the time of day, but the role of the biological clock in this phenomenon remained unknown. “Using a mouse vaccine model, we observed that after vaccination, the strength of the CD8 T cell response varied according to the time of day. Conversely, in mice whose CD8 T cells were deficient for the clock gene, this circadian rhythm was abolished, and response to the vaccine was diminished in the daytime,” explains Dr. Cermakian, who is also Professor at the McGill University Department of Psychiatry.
“Our study shows that T cells are more prone to be activated at certain times of the day. Identifying the mechanisms through which the biological clock modulates the T cell response will help us better understand the processes that regulate optimal T cell responses. This knowledge will contribute to improving vaccination strategies and cancer immune therapies,” states Nathalie Labrecque, Professor at the Departments of Medicine and Microbiology, Infectious Diseases and Immunology at Université de Montréal.
Funding: This research was supported by grants from the Canadian Institutes of Health Research (CIHR).
About this neuroscience research article
Source: McGill University Media Contacts: Cynthia Lee – McGill University Image Source: The image is in the public domain.
The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways
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 OVA257–264 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.