Sleep supports immune defense. In the first half of nocturnal sleep, slow wave sleep (SWS) and the circadian system act in concert to induce a pro-inflammatory milieu, while immunosuppressive mediators are at lowest levels. This pro-inflammatory milieu boost and facilitates T helper (Th) 1 immune responses, like an adjuvant. On the other side, pro-inflammatory and Th1 cytokines feed back to the brain and enhance SWS. Sleep and the circadian system also regulate leukocyte traffic and organize the immune system in time and space. We hypothesize that SWS serves to facilitate the interaction between antigen-presenting cell and Th cell in the lymph node and thereby promotes the transfer of antigenic information into a long-term store. Like the nervous system the immune system takes advantage from the offline condition during SWS to foster the formation of long-term memory for antigens.
Infections increase the propensity to sleep. Research addressing this issue revealed that immune mediators are not only involved in sleep induction during immune activation but also in normal physiological sleep regulation [1,2] (see also section ‘Cytokines, sleep regulation and disturbances’). On the other hand, sleep regulates immune functions [3-5]. Our review will focus on this latter aspect. We will present a conceptual view that sleep and the circadian system act in concert to organize immune functions in time and space in order to effectively shape immune defense against infectious challenges, simultaneously maintaining internal stability (homeostasis) of the immune system (as for example indicated by leukocyte blood counts and cytokine levels within normal physiological ranges). After briefly introducing the physiology of sleep, the circadian system and the immune system (Sections 2-4), we will outline that sleep evokes a pro-inflammatory state that promotes Th1 immune responses and immunological memory formation (Sections 5-6). Subsequently, we will elucidate that cytokines feed back to the brain (Section 7) and that sleep impacts leukocyte traffic (Section 8). Growth hormone, prolactin, cortisol, and catecholamines will be discussed as the primary mediators of sleep-immune interactions, and in Section 9 we will also go into some other potential mechanisms. We conclude with discussing immunological effects of chronic sleep loss and with the clinical implications arising from sleep-immune interactions (Sections 10-11).
2. Sleep physiology
Sleep is a recurrent physiological state hallmarked by a reversible loss of consciousness, reduced sensory and motor activity and characteristic changes in brain electroencephalographic (EEG) activity, neurotransmission and hormonal activity. By means of polysomnographic recordings we can differentiate wake from shallow NonREM (non-rapid eye movement) sleep stages (1 and 2), deep NonREM sleep stages (3 and 4), aka SWS, and REM sleep  (Figure 1).
Figure 1. Sleep in the laboratory. Sleep is monitored by polysomnography, including electro-encephalography (EEG), electrooculography (EOG) and electromyography (EMG), which allows the differentiation of four NonREM (non-rapid eye movement) sleep stages (1 to 4) and REM sleep. Deep sleep stages 3 and 4 are summarized to slow wave sleep (SWS). The ‘hypnogram’ shows the succession of sleep stages during nocturnal sleep from 2300 h to 0700 h, with SWS predominating the first half and REM sleep predominating the second half of the sleep period, respectively. An indwelling forearm catheter is connected to a long thin tube, enabling blood sampling from an adjacent room without disturbing the subject’s sleep. The neurobehavioral and immunological functions of SWS and REM sleep are indicated in the blue and green box, respectively.
SWS predominates the first half of nocturnal sleep in humans and is characterized in the EEG by high amplitude-low frequency activity, i.e., slow wave activity (SWA, sometimes termed delta activity, 0.5-4 Hz) including the slow oscillations with a spectral peak of ~0.8 Hz. In addition, SWS is characterized by minimum central nervous cholinergic tone, minimum activity of the hypothalamus-pituitary-adrenal (HPA) stress axis, lowered (but not minimal) noradrenergic activity and by an upsurge in the release of growth hormone (GH) and prolactin [7,8] (Figure 2). SWS has been shown to co-ordinate the system consolidation of psychological memories for experienced events, i.e., a process that by reactivating newly encoded memories promotes the transfer of these memories from neuron networks serving as temporary storage to other networks serving as long-term storage . SWS is also assumed to fulfill recovery functions on cellular (e.g., replenishment of macromolecules and transmitter vesicles) and system levels (e.g., restoration of neuronal and endocrine networks) . REM sleep predominates the second half of nocturnal sleep and is characterized by low amplitude-mixed frequency EEG activity (>12 Hz beta activity and also 4-8 Hz theta activity), muscular atonia, high wake-like central nervous cholinergic activity and local increases in plasticity-related immediate-early genes  (Figure 1). Noradrenergic activity in the brain is at its lowest levels, paralleled by minimum levels of epinephrine and norepinephrine in circulating blood . REM sleep might favour enduring synaptic changes that involve long-term potentiation (LTP), synaptic consolidation  and may also generally support plasticity and brain maturation during development.
Figure 2. Rhythms of blood hormone levels and cytokine production. Blood levels of growth hormone (GH), prolactin, cortisol, epinephrine and norepinephrine, as well as production of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL-12 and IL-10 by stimulated monocytes and of IL-12 by stimulated myeloid dendritic cell precursors show characteristic changes during a 24-hour period including regular sleep between 2300 h and 0700 h (blue area). Pro-inflammatory mediators (depicted in blue) show peak levels/production during sleep whereas anti-inflammatory mediators (depicted in orange) show nadir levels/production during this time. On top of circadian influences, sleep and specifically slow wave sleep (SWS) was shown to promote the upsurge in the release of GH and prolactin and to suppress cortisol to nadir levels. Accordingly, in comparison with nocturnal wakefulness sleep enhances GH and prolactin levels and decreases cortisol levels (indicated by arrows). Catecholamine levels are also lower during regular sleep than during nocturnal wakefulness with intermediate levels during SWS and lowest levels during rapid eye movement (REM) sleep. Sleep in comparison to a nocturnal vigil enhances the production of TNF-alpha and IL-12, whereas the production of IL-10 is suppressed. Generally, the effects of sleep as indicated by arrows are present during night-time. The production of IL-6 seems to be mediated solely by circadian influences, as there are no differences between sleep and nocturnal wakefulness. Of note the rhythms of IL-12 and IL-10 production are completely dependent on sleep. Schematic presentation of original data derived from several studies in healthy volunteers.
The role of sleep in memory and underlying neuronal plasticity was substantiated in numerous experiments since the beginnings of experimental psychological memory research [11-13]. Memory traces that are encoded during daytime activity are re-activated in the offline state of sleep enabling processes of system consolidation during SWS and of synaptic consolidation during subsequent REM sleep. In addition, sleep probably fulfils a pro-active function to facilitate encoding during subsequent wakefulness by globally down-scaling potentiated synapses and the erasure of unnecessary memories . At a subjective level, one of the most obvious functions of sleep is to recover from feelings of sleepiness . The mechanisms behind this are not fully understood: it is assumed that during waking sleep regulatory substances (SRS) accumulate as a function of increased neuronal activity and information processing in the brain. Some of these SRS are released by glia cells and thus keep track of neuronal activity. SRS induce sleepiness, sleep pressure and eventually SWS. SWS in turn leads to a degradation of SRS, which explains why we wake up feeling well-rested the next morning [2,16]. Aside from cognitive impairment and sleepiness, acute sleep loss impacts other brain functions like mood, thermoregulation and pain perception [17-19]. However, most bodily functions appear to remain rather unaffected which might explain why the crucial role of sleep in immunity was initially less clear and discovered only recently . A milestone in sleep-immune research was the finding that prolonged sleep deprivation in rodents is lethal due to a breakdown of immune defense and septic invasion of bacteria [21,22]. Thus, sleep is essential for survival by maintaining proper immune function.
Research on sleep-immune interactions has focused on SWS. Immune activation induces SWS via cytokines like interleukin-1 (IL-1) and tumor necrosis factor (TNF)-alpha that were identified as SRS, and are also involved in physiological SWS regulation . During the first half of nocturnal sleep when SWS predominates, a unique immuno-supportive endocrine milieu develops with high GH and prolactin levels but low cortisol levels which are paralleled by profound changes in cytokine production (see below). On the other hand, only a small number of studies have addressed the impact of REM sleep on immune functions which overall did not reveal a consistent picture [23-26]. Moreover, as these studies were performed mostly in animals and investigations of this issue in humans are almost completely missing, here we will concentrate on the effects of SWS on immune functions. Note, however, this is not meant to exclude that REM sleep might exert effects on immune functions separate from or additive to those of SWS.
3. Sleep and the circadian system
Sleep is intimately linked to the circadian system, which over a period of approximately 24 hrs., regulates periodic changes in behavioral and physiological parameters to anticipate environmental changes linked basically to the light-dark cycle . The molecular basis of the circadian rhythm is an interlocked feedback loop of clock genes and their transcripts that, under constant light conditions, takes somewhat longer than 24 hours for a full cycle (hence the term circa-dian). Such clocks tick in the hypothalamic suprachiasmatic nuclei (SCN) but also in many, if not all, cells throughout the body. The SCN is the master clock that receives external cues about the time, i.e., zeitgebers, allowing the endogenous clocks to be trained to the 24-hour light-dark cycle and corresponding social rhythms of activity. The SCN synchronizes cellular clocks in the body periphery mainly via two effector pathways, i.e., cortisol release and the sympathetic nervous system (SNS). In addition, peripheral clocks are indirectly entrained by activity related changes in food intake and body temperature  (Figure 3). If cells are isolated, for example by drawing blood and putting leukocytes into culture, they keep on ticking in their endogenous ‘free running’ rhythm for several days . Sleep and the circadian system are interconnected, because the SCN signals to sleep centers and regulates sleep propensity and physiology . On the other hand, sleep itself can entrain circadian rhythms due to the fact that when we sleep we lay down and close our eyes and thus determine the impact of the zeitgeber-signal ‘light’. Sleep and associated neurotransmitter, hormonal and temperature changes can also directly influence the SCN [9,31,32]. Sleep, the SCN and clock genes regulate immune functions , and immune mediators feedback to sleep regulatory centers, the SCN, clock genes, the HPA axis and the SNS [1,34,35]. Thus, we are facing a complex systemic network that maintains immune homeostasis despite ongoing immune challenges. In this network the circadian system appears to anticipate these immune challenges and thereby serves in a predictive way to maintain homeostasis (‘predictive homeostasis’), whereas the neuroendocrine feedback mechanisms that are elicited by immune activation (e.g., induction of SWS, activation of the HPA-axis) prevent insufficient and overshooting immune reactions (‘reactive homeostasis’; Figure 3) [36-38].
Figure 3. Sleep and the circadian system. In the hypothalamus sleep regulatory centers interact with the suprachiasmatic nuclei (SCN). This master clock receives time cues ‘zeitgeber’ (light) from the retina enabling the adjustment of endogenous rhythms to the 24-hour light-dark cycle. In turn the SCN synchronizes peripheral cellular clocks. The circadian system helps to prepare the organism for the ‘stress’ of daytime activity (Predictive homeostasis). On top of these circadian influences, sleep exerts synergistic actions on specific parameters, e.g., slow wave sleep (SWS) contributes to the suppression of cortisol during the early night. The syringe illustrates an immunological stressor (e.g., antigen) inducing an immune activation (e.g., increased cytokine release) that is followed by neuroendocrine responses (e.g., increase in cortisol levels). In addition, immune and neuroendocrine mediators feed back to cellular clocks, the SCN and sleep regulatory centers to prevent insufficient or exaggerated immune responses (Reactive homeostasis). SNS = sympathetic nervous system.
4. The adaptive immune response
A hallmark of the vertebrate immune system is its ability to adapt over time. It is the principle of vaccination that after a first encounter with a pathogen the antigenic information is memorized in a long-term store, so that upon re-encounter with the pathogen the immune response is facilitated. This ‘memory’ resides within lymphocytes, but in the last decades the outstanding role of antigen-presenting cells (APC) in the initiation of an adaptive immune response was elucidated. APC, like macrophages and dendritic cells (DC), represent an important link between the innate and adaptive immune system. They act as sentinels in tissues, take up the antigen and migrate to the draining lymph node to present fragments of the antigen to antigen-specific Th cells, thereby forming the immunological synapse. The APC provides the Th cell with three signals: the antigenic information, co-stimulatory signals and cytokines that determine the type of Th cell differentiation (e.g., into interferon-γ (IFN-γ) producing Th1 cells or into IL-4 producing Th2 cells). Th cells then provide ‘help’ for B cells to produce antibodies and for cytotoxic T cells to eliminate infected cells [39,40]. Antigen-specific Th cells, cytotoxic T cells, B cells and antibodies are the effectors of adaptive immunity and hence reflect immunological memory (Figure 4). APC and Th cells are the key players of an adaptive immune response which we will focus on here. Because APC fully differentiate and exert their function mainly in the tissue, they are rarely detected in peripheral blood. Therefore, to assess effects on APC in human studies sometimes monocytes are taken as surrogate markers, as these cells are precursors of APC and easily identified in circulating blood.
Figure 4. Slow wave sleep (SWS) supports the immunological synapse. The circadian system and SWS act in concert to enhance growth hormone (GH) and prolactin release and to suppress cortisol levels. This pro-inflammatory milieu during the first half of nocturnal sleep facilitates the production of interleukin (IL)-12 by stimulated antigen-presenting cells (APC). The APC-T helper (Th) cell interaction (immunological synapse) determines the magnitude and type of the subsequent Th cell and antibody response. GH, prolactin and IL-12 act at this cellular level to enhance Th1 immune responses. We therefore propose that SWS – like an adjuvant – supports the immunological synapse and fosters the initiation of Th1 immune responses. In analogy to the neurobehavioral domain an adaptive immune response can be divided into the processes of encoding (uptake of the antigen), consolidation (transfer of antigenic information into a long-term store) and recall (facilitated response upon antigen re-encounter) with SWS specifically supporting the process of consolidation. Additionally, during an ongoing immune response pro-inflammatory and Th1 cytokines feed back to the brain to enhance SWS.
In the neurobehavioral domain, memory encoding and recall are most effective during waking, whereas the consolidation and formation of long-term memory takes place more effectively during sleep . It is tempting to generalize this conceptual view to the immune system : encoding and referring to the uptake of antigens by APC, consolidation to the transfer of antigenic information from the APC to the Th cell (immunological synapse) and recall to the facilitated immune response upon antigen re-encounter provided by antigen-specific T- and B cells and antibodies (Figure 4). Thus, it is possible that sleep specifically supports the consolidation of immunological memories. In the next sections we will highlight how sleep, and specifically SWS, fulfils this function at the cellular level of the immunological synapse.
5. SWS is a pro-inflammatory state
In an early study, Halberg et al. reported on the rhythm of lipopolysaccharide (LPS) induced death rates in mice, showing a peak when LPS was administered during the diurnal rest period (~80 % versus ~10 % lethality during the nocturnal activity period) . In a more recent animal study, splenic macrophages showed rhythmic variations in clock gene expression and in transcription of genes that are involved in immune activation, together with a peak in stimulated TNF-alpha and IL-6 secretion during the rest period . Hence, the increased susceptibility of mice to die after LPS was injected during the rest span might well relate to an over-production of pro-inflammatory cytokines . In healthy humans, the LPS-stimulated production of IL-6, TNF-alpha and IL-12 by monocytes and myeloid DC precursors (pre-myeloid DC) also peaked during nocturnal sleep [8,33,45,46] (Figure 2). In contrast, release of the anti-inflammatory cytokine IL-10 by monocytes showed an opposing rhythm with peak activity during daytime in the active phase . The observed peak in pro-inflammatory cytokine production during the rest phase may reflect an enhanced release of GH and prolactin during this period together with coordinated inactivation of the HPA-axis and the SNS, in addition to immediate influences of cellular clock genes [47-51]. Indeed, correlation analyses and in vitro experiments identified high prolactin and low cortisol levels as the factors most strongly contributing to the nocturnal upsurge of IL-12 production [8,46] (Figure 2).
Are these rhythms in cytokines and hormones governed by the circadian system or by sleep? To dissect these influences, rhythms under regular sleep conditions are to be compared with those under conditions of continuous wakefulness. This approach revealed that except for the production of IL-6 by monocytes , all the rhythms of interest in cytokine production and hormonal release, are dependent on sleep, although to varying degrees. In comparison with continuous wakefulness, sleep robustly enhances the nocturnal release of TNF-alpha, IL-12, GH and prolactin whereas production of IL-10 and levels of cortisol and catecholamines are suppressed [8,33,46,52,53] (Figure 2). Of note, rhythms of IL-12 and IL-10 secretion entirely depend on sleep, and disappear when subjects stay awake at night [8,46].
The flow cytometry method applied in those studies offers the advantage that cytokine production is measured on a per cell level. This allows to control for possible confounding changes in cell subset composition within the stimulated sample which can itself be substantially influenced by the clock time and sleep [46,54]. Whereas the peaks in the production of IL-12 and TNF-alpha occurring during nocturnal sleep represent quite robust findings [48,55-57], such methodological issues might explain why results from studies that assessed cytokine production simply in culture supernatants have often yielded discrepant results regarding the effects of sleep and sleep deprivation [54,58]. Likewise, mixed results were obtained when spontaneous cytokine release or cytokine serum levels were measured, rather than using the more widespread measurement of cytokine production where cytokines are determined after stimulating the samples [45,57-61] (Table 1).
Table 1. Effects of acute and chronic sleep loss on neuroendocrine and immune parameters. + Indicates enhanced, – suppressed, nc not changed; the time period in which these changes are present is indicated in brackets. aDue to experimental sleep restriction for several days [59,84,128-130,139], in clinical conditions that are associated with sleep curtailment (insomnia, alcoholism, depression [132-134,136-138]) or in the course of aging [62,141-143]. bNote that opposite effects on SNS activity are observed during daytime after one night of sleep deprivation [145,146] cAs cell composition can confound measures of stimulated cytokine production in cell culture the table concentrates on studies that assessed cytokine production in monocytes or dendritic cells by flow cytometry methods. dNote that IL-6 serum levels can be confounded by the blood drawing procedure via an intravenous catheter .
In the experiments discussed previously, the effects of sleep, in comparison with continuous wakefulness, were most pronounced during the first half of nocturnal sleep, i.e. the sleep period with predominant SWS. SWS plays a causal role for the suppression of cortisol as well as for the strongly enhanced release of GH and prolactin during this period [52,62-64]. Although direct evidence is missing so far it is tempting to speculate that SWS is the driving force for the peak in pro-inflammatory cytokine production characterizing the nocturnal rest period Alternatively, it could be argued that rather than reflecting a specific action of SWS, deprivation of SWS and sleep used in these studies as control condition per se acts as non-specific stressors that suppresses the release of pro-inflammatory hormones and cytokines. However, this is an unlikely explanation for several reasons: (i) In contrast to animals, humans voluntarily participate in the experimental procedures of sleep deprivation making these conditions less uncontrollable and stressful. (ii) Cortisol and catecholamine levels typically show only rather slight activation of stress axes. Although significant, this hormonal activation is far from reaching the concentrations that are normally observed during daytime activity [52,53]. (iii) The effects of sleep in comparison with continuous wakefulness on pro-inflammatory cytokine production and hormone levels concentrate during the first half of nocturnal sleep. In contrast, sleep pressure, feelings of fatigue and associated strain gradually increase during the nocturnal vigil and peak not until the second half of the night . It seems therefore justified to assume that it is SWS that actively enhances pro-inflammatory activity early in the night. Interestingly, the pro-inflammatory action of sleep is still evident at the end of the nocturnal sleep period, although less pronounced [8,46]. This prolonged effect makes it in fact difficult to interpret results from partial sleep deprivation studies, especially when in these studies sleep is restricted to the latter half of the night, such that onset of SWS is delayed and elevations of GH and prolactin as well as a suppression of cortisol levels are still present in the early morning hours [66,67]. Thus, increases in TNF-alpha production of monocytes observed at 0800 h after depriving early night sleep could reflect effects of sleep loss but, could as well reflect continuing effects of SWS that became shifted to the morning [68,69].
Does the SWS-associated peak in pro-inflammatory cytokine production that is observed in peripheral blood reflect comparable conditions in secondary lymphatic tissues? As mentioned in the beginning of this section, splenic macrophages indeed produce high amounts of TNF-alpha and IL-6 when stimulated with LPS ex-vivo during the rest period . Further evidence comes from an animal study showing that sleep deprivation attenuates TNF-alpha production after LPS challenge in vivo in both blood and – more importantly – also in spleen and brain .
In contrast to the clear effect of sleep on IL-12 production in monocytes and pre-myeloid DC, production of IL-6 by monocytes is not influenced by sleep . Likewise, IFN-alpha production of herpes simplex virus-stimulated plasmocytoid DC did not differ between conditions of sleep and continuous wakefulness . Thus, sleep does not generally enhance pro-inflammatory actions of leukocytes, but specifically acts on certain cell subtypes and cytokines. Such differential effects on APC derived cytokines might help to further unravel the mediators and molecular mechanisms that are involved in the sleep-dependent activation of pro-inflammatory cell systems. The anti-inflammatory milieu that develops in the early morning and during daytime activity is probably important for shutting down the pro-inflammatory immune activity prevailing during early sleep, thus ensuring homeostasis over the 24-hour cycle. In this way, immune defense might specifically benefit from conditions where pro- and anti-inflammatory actions are limited in time and take place in succession. An idea that is also supported by findings showing that prolactin and cortisol are capable of reducing tumor growth in animals, only, however, when these hormones are administered sequentially with a defined time delay in between .
6. SWS supports Th1 immune responses
IL-12, GH and prolactin, whose release is increased during SWS, are endogenous adjuvants that are proven to enhance the immune response after vaccination in animals [72-74]. In contrast, cortisol, which is suppressed during SWS, shows opposite effects impairing the immune response to vaccination . In this background we examined a recent study in healthy humans, whether the pro-inflammatory milieu during sleep, and in particular during early SWS-rich sleep, suffices to boost an adaptive immune response after vaccination. The participants received three shots of a combined hepatitis A/B vaccine in the morning at weeks 0, 8 and 16. On the night following the inoculations half of the subjects were allowed to sleep, while the other half stayed awake and did not sleep until the second night after vaccination. In comparison with the waking condition, sleep indeed enhanced the emergence of antigen-specific Th cells. Interestingly SWA, as well as the combined influence of high GH and prolactin levels and low cortisol levels during early sleep after vaccination, were very strong predictors of the vaccine-driven Th cell response. Correlation of coefficients were greater than r = 0.8 with an increase in antigen specific Th cells one year later (unpublished data).
Endogenous and exogenous adjuvants enhance an adaptive immune response by acting on the immunological synapse that is formed between APC and Th cells in lymph nodes [39,76]. Timing is critical in this process. The immunomodulating influences of prolactin and cortisol are most pronounced within the first 24 hours after inoculation of the antigen [74,75]. Thus, in our vaccination experiments discussed above, the first night after vaccination was obviously the most effective time window for sleep (in comparison with wakefulness) to exert its adjuvant-like action on APC-Th cell interactions (Figure 4). After forming the immunological synapse, Th cells produce IL-2, proliferate and differentiate to Th1 or Th2 cells. When measured in polyclonally stimulated whole blood and in isolated Th cell cultures, cell proliferation as well as production of IL-2 and IFN-gamma show parallel rhythms with a peak during nocturnal sleep [38,48,77-79] (Figure 5). In lymph nodes of animals nonstimulated and stimulated cell proliferation, as well as nonstimulated IFN-gamma production are likewise at highest levels during the rest period, but it is not clear to what extent these rhythms reflect Th cell functions [80-83]. Interestingly, IFN-gamma production in lymph nodes correlates positively with GH and prolactin plasma concentrations . Some studies have revealed an enhancing effect of sleep on nocturnal lymphocyte proliferation and IL-2 production [54,77], but others failed [78,79]. It seems that the kind of stimulus and the involvement of APC in lymphocyte activation are important factors that determine differences in sleep effects on lymphocyte proliferation and respective cytokine production [38,54,55,77,78]. Moreover, because Th cell proliferation and differentiation is a rather slow and gradual process, the immunosupporting effects of sleep on Th cells might become evident only with some delay and with longer periods of culturing the cells [54,79].
Figure 5. Rhythms of T cell functions. Stimulated T helper (Th) cell proliferation and production of interleukin (IL)-2 and interferon (IFN)-γ show parallel rhythms peaking during regular sleep (from 2300 h to 0700 h; blue area). When compared with nocturnal wakefulness, only the production of IL-2 in stimulated whole blood cell cultures is enhanced by night-time sleep (indicated by arrows). Schematic presentation of original data derived from several studies in healthy volunteers.
Vaccination against hepatitis A elicits a prominent Th1 immune response. Accordingly, the supporting effect of sleep after vaccination in the experiments mentioned previously was revealed to be most pronounced for IFN-gamma producing Th1 cells (unpublished data). Similarly, in two other vaccination studies that showed higher antibody titers after vaccination due to regular sleep in comparison to acute sleep deprivation or prolonged sleep restriction [53,84], the antibody response was mainly of the immunoglobulin (Ig) G1 and IgG3 subtypes (opsonizing antibodies) which are considered to depend on Th1 function in humans . These findings are well in line with observations of a sleep induced increase in IL-12 production in APC which is the most important signal for Th1 cell differentiation [39,46,72]. Moreover, in comparison with continuous wakefulness, sleep favors a shift in the Th1/Th2 cytokine balance towards Th1 cytokine activity, although restricted to the early SWS-rich part of nocturnal sleep . Emphasizing again, in vitro studies show that such shift towards Th1 cytokine activity can result from high GH and prolactin levels as well as low cortisol levels [85,86] (Figure 4).
Clinical evidence for the notion that sleep supports Th1 immunity comes from a sleep deprivation study in patients with allergic rhinitis. Wheal reactions to a skin prick test and spontaneous IgE production of peripheral blood mononuclear cells (PBMC) were increased after sleep deprivation, indicating a shift towards Th2 immune defense . In 2001, Petrovsky speculated that as “…Th1 responses are associated with inflammation, swelling, pain, immobility and malaise,…it would be advantageous … to restrict Th1 responses to inactive ‘healing’ periods (night-time in humans) and not to active periods when maximum mobility is required for hunting, gathering and ‘fight or flight’ responses” . An analogous idea has been proposed in neurobehavioral research that brain functions such as the reprocessing of memories during consolidation, which are incompatible with the high demands of information processing during daytime activity, are shifted to the offline state of sleep .
We showed in this section that sleep enhances the immune response to vaccination in humans and, thus, facilitates immunological memory formation. SWS plays a major role in this process by evoking a pro-inflammatory milieu that boosts the production of APC derived IL-12 and in turn Th1 immunity (Figure 4). At a first glance, the robust findings in humans in this regard appear to contrast with findings from vaccination experiments in animals which yielded overall conflicting results with enhancing but also suppressing effects of sleep on immune responses [88-90]. However, unlike the human studies examining primary responses to vaccination, these studies focused on secondary immune responses, i.e., the effect of sleep on efficacy of pre-existing immunity to eliminate a pathogen upon re-encounter. The exact role sleep plays for such immunological recall functions remains to be elucidated.
7. Pro-inflammatory and Th1 cytokines induce SWS
As discussed in the beginning of this article, SRS keep track of prior neuronal activity, accumulate during wakefulness, induce sleepiness and can, eventually, promote SWS. IL-1, TNF-alpha, adenosine, GH releasing hormone (GHRH), brain derived neurotrophic factor (BDNF) and prostaglandins are SRS. It is assumed that in normal physiological conditions these signals are released within the brain in a cascade-like manner: high levels of neurotransmission during waking produce an accumulation of extracellular adenosine triphosphate (ATP) that is partly metabolized to adenosine. Adenosine via binding to neuronal A1 receptors induces SWS, whereas ATP via P2 receptors on glia cells induces the production of IL-1 and TNF-alpha. These cytokines stimulate, in a positive feedback loop, their own production, and additionally downstream signals like adenosine, GHRH, BDNF and prostaglandins which all per se promote SWS [2,91]. Indeed, administration of IL-1 and TNF-alpha and other pro-inflammatory Th1 cytokines like IL-2 and IFN-gamma have been demonstrated to increase SWS, whereas anti-inflammatory Th2 cytokines like IL-4 and IL-10 suppress SWS .
During infections, toll like receptors (TLR) recognize microbial structures and directly stimulate production of IL-1 and TNF-alpha. Animal experiments indicate that the subsequent increase in SWS helps to fight the pathogen, as it has been described for other aspects of sickness behavior [92,93]. Muramyl dipeptide and LPS are not only specific TLR ligands that induce SWS but also act as adjuvants on APC to facilitate Th1 immune responses [76,93-95]. Thus, these and similar pro-inflammatory signals may act in parallel in the brain and in the immune system to promote SWS and Th1 immunity, respectively.
8. Does SWS support APC and T cell homing?
Sleep not only impacts leukocyte function but also leukocyte migration. During regular sleep, absolute numbers of monocytes, T cells and natural killer (NK) cells in circulating blood are significantly lower than during nocturnal wakefulness . A closer look on functional cell subsets reveals that these reductions in cell counts result from traffic patterns to various compartments which distinctly differ among the subsets. Also, epinephrine and cortisol play differential roles for the migratory behavior of these subsets as outlined in Figure 6. Subsets with immediate cytotoxic effector functions, like pro-inflammatory monocytes (CD14dimCD16+), terminally differentiated effector cytotoxic T cells (CD62L–CD45RA+) and cytotoxic NK cells (CD16+CD56dim) show lowest blood counts during the night, and these counts are further suppressed when the person sleeps [33,46]. The rhythm of these cells is controlled mainly by epinephrine that releases the cells from the marginal pool by attenuating adhesive fractalkine receptor (CX3CR1) and CD11a signaling [96,97]. Epinephrine concentrations are higher during waking than in sleep which explains that a nocturnal vigil increases cytotoxic effector cell numbers in circulating blood (Figure 6).
In contrast to cells with immediate cytotoxic effector function, cells that are less differentiated, like naive and central memory T cells, show an opposing circadian rhythm with highest numbers of circulating cells at night. Their rhythm seems to be mainly controlled by cortisol. Cortisol leads to an upregulation of the chemokine receptor CXCR4 on these cells which facilitates their redistribution to the bone marrow [96,98]. On top of this circadian rhythm, nocturnal sleep, compared with wakefulness induces a slight but significant reduction in circulating numbers of naive and central memory T cells . This might well reflect a redistribution of these cells to the lymph nodes by a different cortisol-related mechanism described below (Figure 6). As in humans, rodent peripheral blood lymphocyte and T cell counts show a pronounced 24-hour rhythm with highest levels at the beginning of the rest period [99-101]. Interestingly, this rhythm runs in parallel with those found in spleen and lymph nodes for lymphocyte numbers and Th cell percentages, both peaking during the rest period [81,100]. Together, these observations suggest a fast and efficient redistribution of T cells from the vascular compartment to secondary lymphatic tissues during sleep. However, other studies revealed less consistent rhythms of T cells in spleen and lymph nodes, also greatly differing among different rat strains [43,102].
T cells are home in the lymph node via high endothelial venules involving adhesion molecules and chemokine receptors (CD62L, CCR7 and CD11a on T cells). Cortisol is known to impair the evasion of lymphocytes across the high endothelial venules presumably via effects on the endothelium . Therefore, nadir cortisol levels during nocturnal sleep do not only enable the release of T cells from bone marrow but probably also ease the traffic to lymph nodes. In addition, two reports, one in sheep  and the other in humans , point towards a reduced efflux of lymphocytes from lymph nodes during sleep. It is therefore tempting to speculate that sleep favours the accumulation of lymphocytes in lymph nodes thereby enhancing the rate of APC-Th cell interactions. However, so far there is only one study in rats confirming that lymphocyte counts in lymph nodes are indeed increased after recovery sleep . In addition to keeping cortisol at a low level, sleep might facilitate T cell homing via sympathetic and peptidergic innervation of lymph nodes, via influences on blood flow and on cytokine release [47,106].
The migratory pattern of APC is different from that of T cells, and can hardly be inferred from peripheral blood cell numbers. Unlike naive T cells that continuously recirculate (via blood – lymph nodes – efferent lymphatics – blood), fully differentiated APC are not present in blood, but only as precursors in pre-myeloid DC, plasmocytoid DC and monocytes. These cells typically circulate only for a short time and then extravasate to tissues . Pre-myeloid DC, plasmocytoid DC and pro-inflammatory monocytes show rhythms in blood with quite different peak times, i.e., at 0200 h, 0800 h and 1400 h, respectively . Lower numbers of pro-inflammatory monocytes and of plasmocytoid DC during nocturnal sleep could reflect margination of these cells due to low epinephrine levels during this period [46,97]. Pre-myeloid DC numbers were not found to be influenced by sleep . On the other hand, another report showed an accumulation of monocytes in the spleen during the rest period . Overall effects of sleep on APC trafficking and tissue homing are not well studied. To reveal a consistent picture further research is required.
Figure 6. Rhythms of T cell subset numbers in circulating blood. Cortisol and epinephrine govern rhythms of undifferentiated and differentiated T cell subsets, respectively. Daytime increases of cortisol lead to an upregulation of CXCR4 on, e.g., naive T helper (Th) cells which facilitates the redistribution of these cells to the bone marrow. Conversely, nadir cortisol levels during sleep enable the release of naive Th cells from the bone marrow into the circulation. Animal studies point to a fast equilibrium between cell numbers in the circulating pool and in secondary lymphatic tissues like the lymph nodes during the rest period. Based on available evidence it is justified to assume that sleep facilitates the entry of naive Th cells to the lymph nodes which leads to reduced cell numbers in circulating blood (thick line), when compared with nocturnal wakefulness (thin line). On the other hand, daytime increases of epinephrine attenuate adhesive CX3CR1/CD11a signaling which mobilizes highly differentiated leukocytes, e.g., terminally differentiated effector cytotoxic T cells, from the marginal pool. During nocturnal sleep lower epinephrine levels allow demargination of these cells resulting in lower cell numbers (thick line) in comparison to nocturnal wakefulness (thin line).
To summarize, the two major stress axes – specifically HPA-driven release of cortisol and SNS-driven release of epinephrine – organize the immune system in time and space defining two entities of cells that exert different functions within different compartments at different times of the day. During nocturnal sleep, leukocytes at early stages of differentiation, like naive and central memory T cells, are released from the bone marrow and redistributed to lymph nodes, a compartment that shows high proliferative activity and cytokine production at this time. This homing process in conjunction with a boost of pro-inflammatory mediators supports APC-Th cell interactions and thereby prompts the formation of an adaptive immune response. In contrast, leukocytes at terminal stages of differentiation with high cytotoxic effector potential are mobilized from the marginal pool during daytime activity presumably to strengthen immediate immune defense against pathogens invading the organism preferentially during the activity period [107,108].
9. Further potential mediators, molecular mechanisms and genetics
We have focused here on the role of GH, prolactin, the HPA axis and the SNS in SWS-immune interactions. However, there are numerous further signals that, on the one hand, are influenced by sleep and circadian oscillators and, on the other hand, impact immunity, amongst them melatonin, leptin, orexin, gonadal hormones, prostaglandins, histamine, dopamine and the parasympathetic nervous system [19,41,47,48,50]. SWS predominating in early nocturnal sleep and the circadian system orchestrate these mediators to induce a pro-inflammatory Th1-supporting milieu. Redundancy in this regulation hinders the identification of the ‘ultimate’ mediator in the SWS-immune relationship. However, a systems view can provide clues as to how the central nervous system and the immune system are intertwined to optimize immune defense.
SWS and the circadian system do not only influence blood levels of hormones and cytokine production, but also the expression of receptors for these and other immunoregulating signals, i.e., adhesion molecules, chemokine receptors, costimulatory molecules, antigen presenting molecules, CD3 and alike [45,96,109-112]. Finally, leukocyte metabolism and energy supply [113,114] as well as oxidative stress  are basic processes that are regulated by sleep and have also a major impact on the efficacy of immune defense.
In the molecular machinery underlying the interaction between SWS and immune function nuclear factor κB (NFκB) seems to be a most important player [2,68]. The transcription factor mediates the promoting influence of several pro-inflammatory signals on SWS and is also a downstream signal upon TLR activation and a regulator of Th1 differentiation [116,117]. Interestingly, the impact of immune activation on sleep via NFκB is gated by clock genes . Sleep patterns show a high heritability , a fact that has to be considered when SWS-immune interactions are compared across different strains of mice [120,121]. In humans, polymorphism of the clock gene period3 (PER3) influences diurnal preference and the response to sleep deprivation. Approximately 10% of the population is homozygous for the 5-repeat allele (PER35/5). These subjects show a morning preference and, after prolonged wakefulness, more pronounced signs of sleep pressure than subjects with PER34/4 genotypes. They also demonstrate a greater cognitive decline and higher increases in sympathetic activity, theta EEG activity during wake and SWA during recovery sleep [122,123]. A potential link to the immune system is provided by the fact that the PER35/5 genotype is also associated with increased IL-6 serum levels and probably to an increased risk of cancer . The role of genetic influences on the inflammatory stress-response as well as on circadian rhythms and their sensitivity to desynchronizing influences are currently a matter of intense debate. Both a stress-like inflammatory response and disruption of circadian rhythms represent adverse effects also of prolonged sleep loss (see next section).
10. Effects of chronic in comparison with acute sleep loss
We have so far concentrated on the acute effects of sleep and SWS on immune functions, in comparison to nocturnal wakefulness. However, one night of sleep deprivation, as most often used to assess sleep functions, represents a rather short-lived challenge to homeostasis, with cytokine release and cell counts typically recovering baseline levels already at the end of the 24-hour period [8,46]. Also, in modern society sleep disturbances prevail which typically persists over longer time periods and, thus, may induce continuing deviations of hormone levels and immune functions [125,126]. As sleep entrains circadian rhythms (see Section 3), prolonged sleep curtailment may additionally lead to circadian disruption with phase shifts of endocrine and immune rhythms and, eventually, a flattening of rhythm amplitudes [127-129]. Such effects might explain why, when sleep debt accumulates over prolonged time periods, some neuro-endocrine immune changes that are observed during acute sleep deprivation (see Section 5) are more robust and become evident even during daytime hours (Table 1). Similar to the effects of acute sleep deprivation, the endocrine changes accompanying chronic sleep loss are characterized by increased levels of cortisol and sympathetic activity [126,130,131] and decreases in GH and prolactin levels . These neuroendocrine alterations are likewise observed in clinical conditions with continuing sleep disturbances [132-134]. Also in accordance with findings following acute sleep deprivation (see Sections 5 and 6), prolonged sleep loss is reported to induce immunodeficiency. Thus, rats failed to eradicate invading bacteria and toxins due to prolonged sleep deprivation . In humans, chronic sleep loss suppresses the immune response after vaccination and induces a shift towards Th2 immunity and these findings have been obtained in numerous studies in both experimental and clinical settings [84,134,136-138] (Table 1).
In addition, chronic sleep loss is most consistently associated with elevated serum levels of TNF-alpha and IL-6. Increases in these cytokines were revealed in conditions of experimental sleep restriction [59,139] and they were likewise observed in chronic sleep disturbances accompanying insomnia, alcoholism and depression [132,134,138] (Table 1). At first glance such increase in pro-inflammatory cytokine activity stands in contrast to the findings, discussed in the previous sections, that sleep and particularly SWS promotes a pro-inflammatory cytokine milieu. However, SWS acutely supports cytokine production of ex-vivo stimulated cells, whereas the increase in cytokine serum levels that is observed after several days of sleep curtailment emerges spontaneously in the absence of discrete antigenic stimulation, and likely reflects an up-regulation of an ongoing systemic low-grade inflammation. Presently, it is unclear how this inflammatory response is triggered and which cells produce these cytokines. One explanation could be that prolonged sleep loss leads to bacterial invasion thereby inducing an inflammatory response , but endothelial cells and adipose tissue are discussed as additional sources of pro-inflammatory cytokines . Increased serum levels of TNF-alpha and IL-6 in conditions of chronic sleep loss were in most cases assessed during the active daytime period and are associated with feelings of fatigue and sleepiness. How prolonged sleep curtailment affects ex-vivo stimulated cytokine production is presently not clear. One study in depressive patients showed a higher TNF-alpha production of stimulated monocytes during daytime that was however not related to sleep disturbances . The neuroendocrine-immune changes that are observed in the process of aging and resemble the changes characterizing acute and prolonged sleep deprivation will be discussed at the end of the next section [62,141-143].
11. Conclusions, clinical implications and aging
Sleep regulates immune functions. The finding that sleep and specifically SWS has immuno-supporting effects on Th1 immune responses (Sections 5 and 6) has broad immunological and clinical implications. It offers the opportunity to optimize vaccination strategies (e.g., in the timing of inoculation)  the use of endogenous adjuvants  and it likely explains immunodeficiency and Th2 shifts that are observed with sleep loss due to insomnia, depression or alcoholism [134,136-138] (Table 1). In addition, the sleep-associated changes in hormones and cytokine production may help to elucidate the mechanisms contributing to the early morning peak of disease symptoms such as joint pain and stiffness in rheumatoid arthritis  and to improve the timing of anti-inflammatory drug therapy .
Prolonged sleep curtailment induces a stress-like inflammatory response with increases in blood levels of cortisol, catecholamines, IL-6, TNF-alpha and in neutrophil counts that is likewise observed not only in insomnia and depression [132,134] (Section 10), but also in obstructive sleep apnea, obesity, metabolic syndrome and diabetes [59,114,152]. C-reactive protein, fibrinogen and apolipoproteins are additional biomarkers of this inflammatory response. All these signals are involved in atherosclerotic pathways providing a potential mechanism how sleep curtailment can lead to cardiovascular disease . Here we have proposed that systemic low-grade inflammation provides the key link between chronic sleep loss on the one hand and metabolic and cardiovascular diseases on the other hand. Along this line, a quite extensive prospective clinical trial has been initiated that assesses the effects of sleep extension (from lower than 6.5 hours to approximately 7.5 hours) in obese subjects on body weight, hormones and cytokines .
Sleep disturbances are accompanied by disruption of circadian rhythms, conversely, circadian misalignment (e.g., due to shift work) induces sleep disturbances. Such alterations of the circadian system are again associated with an inflammatory response with metabolic and cardiovascular consequences and also with an increased risk of cancer [114,154-156]. All these clinical aspects of sleep loss inducing immunodeficiency and inflammation are further corroborated by reports showing that sleep duration and efficiency predict the susceptibility to the common cold , the incidence of obesity, diabetes  and coronary artery calcification  as well as all-cause mortality [159,160].
The process of aging nicely illustrates how decrements in SWS are paralleled by circadian disturbances, low GH and prolactin levels, increases in HPA and SNS activity, impaired T cell functions and vaccine-driven immune responses, a shift towards Th2 cytokines, and systemic low-grade inflammation [62,141,143]. Of note, DC of elderly subjects show enhanced spontaneous production of pro-inflammatory cytokines that could well contribute to systemic inflammation. Unlike spontaneous production, the stimulated cytokine production of DC is significantly impaired in the elderly . The stimulated production of TNF-alpha and IL-12 by DC correlated with the immune response after influenza vaccination such that older subjects with reduced cytokine production showed lower seroconversion rates and lower seroprotection . These signs of immunodeficiency and inflammation in elderly subjects are summarized as immunosenescence and are very similar to the changes that are observed following experimentally induced acute and chronic sleep deprivation in young volunteers (Table 1). It is therefore tempting to speculate that the age-associated decline in SWS contributes to immunosenescence, although direct experimental evidence has yet to be observed .
The challenging aim of future studies should be to decipher the exact effects of SWS on APC functions. As reviewed here, APC functions, whether stimulated or nonstimulated, and (spontaneous) cytokine production, seem to be the key processes that regulate sleep-immune interactions. As to the SWS-induced increase in cytokine production of stimulated APC, this effect well explains how SWS fosters immunological memory formation and why acute and chronic sleep loss are associated with immunodeficiency. As to the sleep deprivation induced increase in nonstimulated cytokine production of APC, this effect could well explain the low-grade systemic inflammation and related metabolic and cardiovascular diseases observed under these conditions or in elderly subjects.
T Lange – Department of Neuroendocrinology, University of Luebeck, Luebeck, Germany
J Born – Department of Neuroendocrinology, University of Luebeck, Luebeck, Germany
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