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Benefit of circadian clocks in adaptive immunity and vaccination responses

ABSTRACT: The adaptive immune response is under circadian control, yet, the benefit of this rhythmicity for the organism is unknown. Furthermore, it is not understood why adaptive immune reactions continue to exhibit circadian changes over long periods of time. Using a combination of experimental and mathematical modelling approaches, we show here that dendritic cells (DCs) migrate from the skin to the draining lymph node (LN) in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Greater numbers of infiltrating DCs induce rhythmic expression of TNF-α in the draining LN, which enhances ICAM-1 expression in high endothelial venules (HEVs), resulting in lymphocyte infiltration and LN expansion. Icam1 is controlled by binding of the core circadian clock transcription factor BMAL1 to its promoter region, and rhythmic Icam1 expression is lost in mice lacking endothelial cell BMAL1. LN cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which determines the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2, as evidenced by rhythmic T cell reactions, germinal center formation and antibody production. Our results provide the mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, demonstrating its dependency upon the timing of the initial challenge and the interactions of rhythmicity in multiple parameters. This provides a strategy for using time-of-day to optimize vaccination regimes.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lymphoid Cell

SUBMITTER: Mario Oroshi

LAB HEAD: Christoph Scheiermann

PROVIDER: PXD039050 | Pride | 2023-02-08

REPOSITORIES: Pride

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			Action	DRS
	20161008_QEp3_JeGe_SA_Tcell_ZT_1-1.raw	Raw
	20161008_QEp3_JeGe_SA_Tcell_ZT_1-2.raw	Raw
	20161008_QEp3_JeGe_SA_Tcell_ZT_1-3.raw	Raw
	20161008_QEp3_JeGe_SA_Tcell_ZT_1-4.raw	Raw
	20161008_QEp3_JeGe_SA_Tcell_ZT_1-5.raw	Raw

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Project description:Over the past decade, genome-wide assays have underscored the broad sweep of circadian gene expression. A substantial fraction of the transcriptome undergoes oscillations in many organisms and tissues, which governs the many biochemical, physiological and behavioral functions under circadian control. Based predominantly on the transcription feedback loops important for core circadian timekeeping, it is commonly assumed that this widespread mRNA cycling reflects circadian transcriptional cycling. To address this issue, we directly measured dynamic changes in mouse liver transcription using Nascent-Seq. Many genes are rhythmically transcribed over the 24h day, which include precursors of several non-coding RNAs as well as the expected set of core clock genes. Surprisingly however, nascent RNA rhythms overlap poorly with mRNA abundance rhythms assayed by RNA-seq. This is because most mouse liver genes with rhythmic mRNA expression manifest poor transcriptional rhythms, indicating a prominent role of post-transcriptional regulation in setting mRNA cycling amplitude. To gain further insight into circadian transcriptional regulation, we also characterized the rhythmic transcription of liver genes targeted by the transcription factors CLOCK and BMAL1; they directly target other core clock genes and sit at the top of the molecular circadian clock hierarchy in mammals. CLK:BMAL1 rhythmically bind at the same discrete phase of the circadian cycle to all target genes, which not surprisingly have a much higher percentage of rhythmic transcription than the genome as a whole. However, there is a surprisingly heterogeneous set of cycling transcription phases of direct target genes, which even include core clock genes. This indicates a disconnect between rhythmic DNA binding and the peak of transcription, which is likely due to other transcription factors that collaborate with CLK:BMAL1. In summary, the application of Nascent-Seq to a mammalian tissue provides surprising insights into the rhythmic control of gene expression and should have broad applications beyond the analysis of circadian rhythms. Mouse liver nascent RNA profile over 6 time points of the 24h light:dark cycle, in duplicate, sequenced using Ilumina GAII (Nascent-Seq); Mouse liver mRNA profile over 6 time points of the 24h light:dark cycle, in duplicate, sequenced using Ilumina HiSeq2000 (RNA-Seq); CLK and BMAL1 DNA binding profile in the mouse liver at ZT8, sequenced along an Input sample using GAII (ChIP-Seq); Mouse liver strand-specific nascent RNA profile over 6 time points of the 24h light:dark cycle, in duplicate, sequenced using Ilumina HiSeq2000 (Strand-specific Nascent-Seq);

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Benefit of circadian clocks in adaptive immunity and vaccination responses

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