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Abstract
Dendritic cells play a key role in processing and presenting antigens to naïve T cells to prime adaptive immunity. Circadian rhythms are known to regulate many aspects of immunity; however, the role of circadian rhythms in dendritic cell function is still unclear. Here, we show greater T cell responses when mice are immunised in the middle of their rest versus their active phase. We find a circadian rhythm in antigen processing that correlates with rhythms in both mitochondrial morphology and metabolism, dependent on the molecular clock gene, Bmal1. Using Mdivi-1, a compound that promotes mitochondrial fusion, we are able to rescue the circadian deficit in antigen processing and mechanistically link mitochondrial morphology and antigen processing. Furthermore, we find that circadian changes in mitochondrial Ca2+ are central to the circadian regulation of antigen processing. Our results indicate that rhythmic changes in mitochondrial calcium, which are associated with changes in mitochondrial morphology, regulate antigen processing.
Circadian rhythms are known to impact a range of biological processes including in the immune system. Here the authors show how circadian rhythms modulate the T cell response to vaccination via regulation of dendritic cell metabolism.
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1 Royal College of Surgeons in Ireland RCSI, Curtis Clock Laboratory, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120)
2 Trinity College Dublin, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Dublin, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705); Jagiellonian University, Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Krakow, Poland (GRID:grid.5522.0) (ISNI:0000 0001 2162 9631)
3 Trinity College Dublin, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Dublin, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705)
4 Royal College of Surgeons in Ireland RCSI, Curtis Clock Laboratory, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120); Royal College of Surgeons in Ireland RCSI, Tissue Engineering Research Group (TERG), Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120)
5 Royal College of Surgeons in Ireland RCSI, Curtis Clock Laboratory, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120); Royal College of Surgeons in Ireland RCSI, Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120)
6 Royal College of Surgeons in Ireland RCSI, Curtis Clock Laboratory, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120); Soochow University, Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Suzhou, China (GRID:grid.263761.7) (ISNI:0000 0001 0198 0694)
7 Rensselaer Polytechnic Institute, Department of Biological Sciences & Center for Biotechnology and Interdisciplinary Sciences, Troy, USA (GRID:grid.33647.35) (ISNI:0000 0001 2160 9198)
8 Royal College of Surgeons in Ireland RCSI, Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120)
9 Instituto Politécnico Nacional, Immunoregulation Laboratory, Department of Immunology, Escuela Nacional de Ciencias Biológicas, México City, Mexico (GRID:grid.418275.d) (ISNI:0000 0001 2165 8782)
10 Royal College of Surgeons in Ireland RCSI, Curtis Clock Laboratory, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120); Trinity College Dublin, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Dublin, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705); Royal College of Surgeons in Ireland RCSI, Tissue Engineering Research Group (TERG), Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120); Royal College of Surgeons in Ireland RCSI, Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Dublin, Ireland (GRID:grid.4912.e) (ISNI:0000 0004 0488 7120)