Sleep and immune function

Abstract

Sleep and the circadian system exert a strong regulatory influence on immune functions. Investigations of the normal sleep-wake cycle showed that immune parameters like numbers of undifferentiated naïve T cells and the production of pro-inflammatory cytokines exhibit peaks during early nocturnal sleep whereas circulating numbers of immune cells with immediate effector functions, like cytotoxic natural killer cells, as well as anti-inflammatory cytokine activity peak during daytime wakefulness. Although it is difficult to entirely dissect the influence of sleep from that of the circadian rhythm, comparisons of the effects of nocturnal sleep with those of 24-h periods of wakefulness suggest that sleep facilitates the extravasation of T cells and their possible redistribution to lymph nodes. Moreover, such studies revealed a selectively enhancing influence of sleep on cytokines promoting the interaction between antigen presenting cells and T helper cells, like interleukin-12. Sleep on the night after experimental vaccinations against hepatitis A produced a strong and persistent increase in the number of antigen-specific Th cells and antibody titres. Together these findings indicate a specific role of sleep in the formation of immunological memory. This role appears to be associated in particular with the stage of slow wave sleep and the accompanying pro-inflammatory endocrine milieu that is hallmarked by high growth hormone and prolactin levels and low cortisol and catecholamine concentrations.

Fig. 1

Concept: Sleep supports the initiation of an adaptive immune response. The invading antigen is taken up and processed by antigen presenting cells (APC) which present fragments of the antigen to T helper (Th) cells, with the two kinds of cells forming an ‘immunological synapse’. The concomitant release of interleukin (IL)-12 by APC induces a Th1 response that supports the function of antigen-specific cytotoxic T cells and initiates the production of antibodies by B cells. This response finally generates long-lasting immunological memory for the antigen. Sleep, in particular slow wave sleep (SWS), and the circadian system act in concert to generate a pro-inflammatory hormonal milieu with enhanced growth hormone and prolactin release as well as reduced levels of the anti-inflammatory stress hormone cortisol. The hormonal changes in turn support the early steps in the generation of an adaptive immune response in the lymph nodes. In analogy to neurobehavioural memory formed in the central nervous system, the different phases of immunological memory might be divided in an encoding, a consolidation and a recall phase. In both the central nervous system and the immune system, sleep specifically supports the consolidation stage of the respective memory types. Modified from Lange and Born [71]

Fig. 2

Combined impact of sleep, the circadian rhythm and associated release of cortisol and epinephrine on rhythms and redistribution of leukocyte subsets. Sleep compared with nocturnal wakefulness enhances the homing of naïve T helper (Th) cells to lymph nodes which leads to slightly reduced numbers of these cells circulating in blood during sleep. The mechanisms of this enhanced homing of cells during sleep are not understood. During daytime wakefulness, the circadian rise in cortisol induces an increase in CXCR4 expression on undifferentiated or less differentiated leukocytes, like naïve Th cells, which in turn enables the redistribution of these cells to the bone marrow. On the other hand, epinephrine controls the rhythm of highly differentiated leukocytes, like cytotoxic natural killer (NK) cells, acting as effector cells. During daytime wakefulness, the enhanced activation of β2-adrenoceptors by epinephrine attenuates CX3CR1/CD11a signalling, which leads to an enhanced mobilisation of theses cells from the marginal pool during daytime. Reduced epinephrine levels during sleep (compared to nocturnal wakefulness) allow the margination of these cells, which results in lower cell numbers in peripheral blood. Modified from Lange and Born [71]

Fig. 3

Sleep compared to nocturnal wakefulness selectively enhances the production of interleukin (IL)-12 by pre-myeloid dendritic cells (pre-mDC) which is important for the initiation of adaptive immune responses, whereas it does not influence the levels of interferon (IFN)-α that is released as an early response of the innate immune system upon viral infection. a The percentage of pre-mDC producing IL-12 measured after lipopolysaccharide stimulation of peripheral blood samples from healthy young men during a regular sleep–wake cycle (black circle) and during 24 h of continuous wakefulness (white circle). Analyses were performed by flow cytometry. b IFN-α production of plasmacytoid DC (pDC). Values indicate IFN-α concentrations measured by ELISA in whole blood samples after herpes simplex virus 1 stimulation, divided by the number of pDC. Means (±SEM) are shown. Shaded area indicates bed time. **p < .01, *p < .05 for pairwise comparison between conditions at single time points. Modified from Dimitrov et al. [33]

Fig. 4

Sleep enhances the hepatitis A virus (HAV)-specific T helper (Th) cell response to vaccination which is strongly predicted by EEG slow wave activity during slow wave sleep (SWS) and associated release of immune regulatory hormones during early SWS-rich sleep. a Emergence of CD40L⁺ HAV-specific Th cells (percentage of total Th cells) after HAV vaccination (three shots at weeks 0, 8 and 16—vertical syringes) in two groups of subjects who either slept (black circle, thick line) or stayed awake (white circle, thin line) in the night following inoculations. y-axis log transformed. Means ± SEM are indicated. n = 12–27 for both groups. **p < 0.01, *p < 0.05, (*)p < 0.1 for comparisons between sleep and wake conditions. b Scatter plots of the correlations between slow wave activity (averaged across the three post-inoculation nights) and the frequency of CD40L⁺ HAV-specific Th cells (percentage of total Th cells) at weeks 18–20 (left panel) and week 52 (right panel). c Correlation coefficients between average GH, prolactin and cortisol concentrations during the early, SWS-rich part (0:30–2:00 a.m.) of post-inoculation nights and frequency of HAV-specific Th cells at weeks 8, 12, 16, 18 and 20 and 1 year after HAV vaccination. (Analyses performed across sleep and wake groups.) Note the most robust correlations for an ‘Adjuvant Factor’ describing the synergistic action of the three hormones of interest by the formula GH × prolactin/cortisol. ***p < 0.001, **p < 0.01, *p < 0.05. Modified from Lange et al. [75]