Circadian Variation of the Response of T Cells to Antigen

Abstract

Circadian clocks regulate many important aspects of physiology, and their disturbance leads to various medical conditions. Circadian variations have been found in immune system variables, including daily rhythms in circulating WBC numbers and serum concentration of cytokines. However, control of immune functional responses by the circadian clock has remained relatively unexplored. In this study, we show that mouse lymph nodes exhibit rhythmic clock gene expression. T cells from lymph nodes collected over 24 h show a circadian variation in proliferation after stimulation via the TCR, which is blunted in Clock gene mutant mice. The tyrosine kinase ZAP70, which is just downstream of the TCR in the T cell activation pathway and crucial for T cell function, exhibits rhythmic protein expression. Lastly, mice immunized with OVA peptide-loaded dendritic cells in the day show a stronger specific T cell response than mice immunized at night. These data reveal circadian control of the Ag-specific immune response and a novel regulatory mode of T cell proliferation, and may provide clues for more efficient vaccination strategies.

Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

“…Consistent with the possible importance of this regulation, clock protein misexpression and/or a lack of circadian control has been documented in multiple tumor types (Hwang-Verslues et al, 2013; Luo et al, 2012;Zhao et al, 2013) and immortalized cell lines (Yeom et al, 2010). In normal physiology, circadian cell division has been documented in adult hippocampal neurogenesis (BouchardCannon et al, 2013), in intestinal and skin epithelial cell division (Geyfman et al, 2012;Janich et al, 2013;Karpowicz et al, 2013), and in multiple immune cell populations (Fortier et al, 2011;Keller et al, 2009) -essentially anywhere that cell division occurs in adult animals.…”

“…Bmal1 deficiency is also linked to reduced osteoblast proliferation in adult mice, although a circadian role here has not been proven . Furthermore, in the complex differentiation processes leading to the development of the immune system, T h 17 T helper cell development is regulated by the circadian factors REV-ERBα and RORγ (RORC -Mouse Genome Informatics) , and circadian cytokine release in vivo and in vitro is likely to influence other immune cell subpopulations (Fortier et al, 2011;Keller et al, 2009;Wang et al, 2011). Finally, in addition to regulating metabolism, multiple circadian clock genes directly regulate the size and differentiation of pancreatic islets (Marcheva et al, 2010).…”

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

“…Among them, the innate and adaptive immune systems were shown to display daily rhythms in rodents and humans (14). This includes rhythms in cell counts in the blood (15)(16)(17)(18) and peripheral lymphoid organs (19), lymphocyte proliferation (20), cytokine levels in the blood (21)(22)(23)(24), and following ex vivo stimulation with various stimuli (16,19,(25)(26)(27)(28).…”

“…In central and peripheral clocks, rhythms with a period of ∼ 24 h are generated by autoregulatory feedback loops involving clock genes (e.g., CLOCK, BMAL1, Period or PER1-3, Cryptochrome or CRY1-2) (32). Hence, immune cells (e.g., monocytes/macrophages, lymphocytes) have the molecular clock machinery and display circadian gene expression (19,20,25,(33)(34)(35).…”

The Genetics of Circadian Rhythms

“…Furthermore mice display time-of-day dependent responses to bacterial endotoxins and exotoxins, and pro-inflammatory cytokines (83,84). Clock disruption studies have shown that T-cell antigen response is partially mediated by clock (84).…”