by RCSI
Circadian variation in mitochondrial calcium and antigen processing is directed via control of the mitochondrial calcium uniporter. a Spleens were isolated from WT mice at ZT 1, 7, 13 and 19. CD11c+ cells were isolated and mRNA analyszd by qPCR. Circadian analysis was performed using Metacycle and cycMethod set to “JTK”. P value for each gene is specified on the graph. (n = 3 mice) (b, c) Bmal1+/+ and Bmal1−/− BMDCs were synchronized by serum shock. DQ-OVA and mitochondrial calcium uptake was quantified at 12 h post synchronization in the presence and absence of ruthenium red (5 µM) (n = 3 biologically independent samples). d CD11c+ cells were isolated from WT spleen at ZT4 and treated with ruthenium red (10 µM) for 3 h. OVA protein (25 µg/mL) was then added for 2 h. Supernatants were removed and indicated number of OTII CD4+ T-cells were added to CD11c+ cells. Cells were incubated for 3 days before IFNγ were analyzed by ELISA (n = 3 biologically independent samples) p = 0.02. e Schematic showing proposed mechanisms by which the circadian clock in DCs controls antigen processing as inferred from the present study. Data shown are means with error bars representing ± SEM. Data were analyzed by Ordinary one-way ANOVA with Tukey’s post-hoc test for multiple comparisons (b, c) or by a two-tailed t-test (d). **p < 0.01 and ****p < 0.0001. Credit: Nature Communications (2022). DOI: 10.1038/s41467-022-34897-z
Research by RCSI University of Medicine and Health Sciences has provided new insights into the mechanism behind how our circadian 24-hour body clock influences our immune response to vaccines, depending on the time of day.
The paper published in Nature Communications examined the changes taking place in the mitochondria of a key immune cell involved in the vaccine response and could help improve the design and timing of administration of future vaccines to maximize effectiveness.
It had been previously found that humans mount a greater response to certain vaccines depending on the time of day at which the vaccine is administered, however the reason behind this wasn’t clearly understood. This research has uncovered that our circadian clock is changing the shape of mitochondria within dendritic cells. The variations in the structure of mitochondria influence how well dendritic cells function throughout the day.
Research author Professor Annie Curtis, School of Pharmacy and Biomolecular Sciences at RCSI said, “Our discovery has shed light on a crucial aspect of our body’s response to vaccination and highlights the importance of circadian rhythms in immunity. We can apply this understanding in vaccine development to ensure we receive the maximum benefits from vaccination.”
The circadian clock within dendritic cells is controlling whether mitochondria form one of two shapes either long strings, “networked,” or broken into small punctate pieces. It is within the networked formation that vaccination is most effective as dendritic cells have a better ability break up the vaccine into small pieces for interaction with our immune cells (T cells). Within the study, researchers used an approach to induce the networked phase which could have implications in vaccine design allowing us to optimize our immune response, irrespective of time of day.
Dr. Mariana Cervantes-Silva and Dr. Richard Carroll, lead authors on the paper, said, “The importance of mitochondria beyond their common label as the ‘powerhouse of the cell’ has become increasingly clear in recent years especially within cells of the immune system. We are excited to uncover this new link to our immune system and vaccine responses.”
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