Summary: CD8 T cells behave differently depending on the time of day. New research reveals how the internal biological clock shapes immune responses and suggests timing could affect vaccination and immunotherapy outcomes.
Source: McGill University
A recent study published in Proceedings of the National Academy of Sciences demonstrates that the body’s internal clock influences the effectiveness of immune responses. CD8 T cells — immune cells critical for controlling infections and cancer — show markedly different activity depending on the time of day. The research was led by Nicolas Cermakian, PhD, at the Douglas Research Centre, and Nathalie Labrecque, PhD, at the Maisonneuve-Rosemont Hospital Research Centre.
Circadian rhythms arise from so-called “clock genes” that coordinate daily cycles across tissues and cell types, including components of the immune system. These rhythms regulate many physiological processes such as sleep-wake cycles, feeding behavior, hormone secretion, and body temperature. By synchronizing internal processes with predictable environmental changes like day and night or seasonal shifts, circadian clocks help the body optimize its functions and responses.
Previous work by this team showed that T cell reactions to foreign antigens can vary with the time of day. The new study probes the underlying mechanisms and identifies how the clock within CD8 T cells influences the timing and magnitude of their response. Using a mouse vaccination model, the researchers demonstrated that CD8 T cell expansion in response to vaccination was stronger when the vaccine was administered during the middle of the day compared with other times. When the essential clock gene Bmal1 was removed specifically from CD8 T cells, this daily variation disappeared and daytime responses were reduced. Similarly, removing Bmal1 from dendritic cells, which present antigen to T cells, blunted the rhythm, indicating that clocks in both cell types contribute to the time-dependent response.
To understand how the clock alters CD8 T cell readiness, the investigators examined the circadian transcriptome of these cells. They found that genes and signaling pathways linked to T cell activation were enriched during the daytime. Focusing on early activation events after vaccination, the team observed that, three days post-vaccination, markers of T cell activation and related signaling cascades — including IRF4, mTOR, and AKT pathways — were elevated following daytime vaccination versus night-time vaccination. Functionally, this translated into a more effective immune defense: mice vaccinated during the day displayed a stronger capacity to clear a subsequent bacterial challenge than mice vaccinated at night.
These results indicate that the intrinsic circadian clock of CD8 T cells helps to prime a transcriptional program that makes them more responsive to activation and proliferation at particular times of day. The study therefore provides evidence that timing affects not only hormone and metabolic responses but also cell-intrinsic immune readiness. By shaping both gene expression and downstream signaling, the CD8 T cell clock contributes to the rhythmicity of adaptive immune responses.
Implications of this work include potential opportunities to optimize vaccination schedules and improve immunotherapy strategies for infectious disease and cancer. If similar time-of-day effects occur in humans, scheduling vaccinations or immune-based treatments to coincide with periods of heightened T cell responsiveness could enhance efficacy. The authors emphasize that further research will be needed to translate these findings into clinical practice and to determine optimal timing across different vaccines, pathogens, and patient populations.
Funding: This research received support from the Canadian Institutes of Health Research (CIHR).
Source:
McGill University
Media Contacts:
Cynthia Lee – McGill University
Image Source:
The image is in the public domain.
Original Research: Open access. Title: “The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways”. Authors: Chloé C. Nobis, Geneviève Dubeau Laramée, Laura Kervezee, Dave Maurice De Sousa, Nathalie Labrecque, and Nicolas Cermakian. Journal: PNAS. DOI: 10.1073/pnas.1904931116
Abstract Summary
The study examined how circadian clocks control CD8 T cell responses to antigen presentation by dendritic cells using a DC-OVA vaccination model. Vaccination performed in the middle of the day produced greater expansion of antigen-specific CD8 T cells compared with other times. The rhythm was dampened when dendritic cells lacked the clock gene Bmal1 and abolished when Bmal1 was deleted specifically in CD8 T cells. Transcriptomic analysis revealed daytime enrichment of genes and pathways tied to T cell activation, and early activation markers and signaling (including IRF4, mTOR, and AKT) were higher after daytime vaccination. A stronger daytime response also corresponded to improved defense against bacterial challenge. These observations suggest that the CD8 T cell clock shapes their transcriptional and signaling programs to modulate the timing and strength of vaccination-induced immune responses.