Sleep after Vaccination Boosts Immunological Memory Tanja Lange, Stoyan Dimitrov, Thomas Bollinger, Susanne Diekelmann and Jan Born This information is current as of September 28, 2021. J Immunol 2011; 187:283-290; Prepublished online 1 June 2011; doi: 10.4049/jimmunol.1100015 http://www.jimmunol.org/content/187/1/283 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2011/06/01/jimmunol.110001 Material 5.DC1 References This article cites 50 articles, 6 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/187/1/283.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Sleep after Vaccination Boosts Immunological Memory Tanja Lange,*,† Stoyan Dimitrov,*,1 Thomas Bollinger,‡ Susanne Diekelmann,* and Jan Born* Sleep regulates immune functions. We asked whether sleep can influence immunological memory formation. Twenty-seven healthy men were vaccinated against hepatitis A three times, at weeks 0, 8, and 16 with conditions of sleep versus wakefulness in the following night. Sleep was recorded polysomnographically, and hormone levels were assessed throughout the night. Vaccination-induced Th cell and Ab responses were repeatedly monitored for 1 y. Compared with the wake condition, sleep after vaccination doubled the frequency of Ag-specific Th cells and increased the fraction of Th1 cytokine-producing cells in this population. Moreover, sleep markedly increased Ag-specific IgG1. The effects were followed up for 1 y and were associated with high sleep slow-wave activity during the postvaccination night as well as with accompanying levels of immunoregulatory hormones (i.e., increased growth hor- mone and prolactin but decreased cortisol release). Our findings provide novel evidence that sleep promotes human Th1 immune responses, implicating a critical role for slow-wave sleep in this process. The proinflammatory milieu induced during this sleep stage Downloaded from apparently acts as adjuvant that facilitates the transfer of antigenic information from APCs to Ag-specific Th cells. Like the nervous system, the immune system takes advantage of the offline conditions during sleep to foster adaptive immune responses resulting in improved immunological memory. The Journal of Immunology, 2011, 187: 283–290. he immune system and the CNS share the ability to re- we show for the first time that sleep indeed enhances the vaccine- spond to external stimuli and to form memory (1). Vac- driven induction of immunological memory in the expansion, http://www.jimmunol.org/ T cination induces a multistep immune response eventually contraction, and maintenance phase as reflected by increased leading to differentiation of Ag-specific memory T and B cells as formation of Ag-specific Th cells and IgG1. effectors of immune protection (2, 3). After vaccination, APCs take up the Ag and migrate to lymphatic tissues to present part of the Ag at the cell surface to Th cells, thereby forming the so-called Materials and Methods Subjects immunological synapse and initiating the transfer of the antigenic information into long-term storage in Ag-specific T and B cells (1, Participants were 27 healthy, nonsmoking young men with a mean (6 SEM) 3). Formation of the immunological synapse represents an early age of 26.1 6 0.7 y (body weight: 81.4 6 1.9 kg; body mass index: 24.5 6 stage in the immune response that determines quantity and quality 0.5). They presented with a normal nocturnal sleep pattern and did not take by guest on September 28, 2021 any medication at the time of the experiments. None had a medical history of immunological memory, and it is at this stage adjuvants act to of any chronic disease or mental disorder. Acute illness was excluded enhance the immunogenicity of the vaccine (4). by physical examination and routine laboratory investigation, including Sleep generally regulates immune functions in a supportive chemistry panel, C-reactive protein concentration ,6 mg/l, and a WBC , manner (5–7). Sleep impacts APC and Th cell traffic and facili- count 9000/ml. Naive immune status against HAV and hepatitis B virus was explored by medical history and vaccination card and confirmed by tates the release of endogenous adjuvants like growth hormone HAV–Ab levels ,5 IU/ml and hepatitis B virus surface Ag (HBs)–Ab (GH), prolactin, and APC-derived IL-12, whereas it lowers the re- levels of 0 IU/ml, respectively. In addition, HBs and hepatitis B core–Ab lease of immunosuppressive hormones like cortisol (7–9). In this were negative in all subjects. study, we used an experimental vaccination approach against The men were synchronized by daily activities and nocturnal rest. They hepatitis A virus (HAV) to examine whether these effects of sleep had a regular sleep–wake rhythm for at least 6 wk before the experiments. All subjects were adjusted to the experimental setting by spending at least can boost immunological memory formation. To our knowledge, one adaptation night in the laboratory that took place before the experi- ment proper. The presence of signs of sleep disturbances including apnea and nocturnal myoclonus was excluded by interview and by recordings during this adaptation night. For private reasons, three subjects dropped off *Department of Neuroendocrinology, University of Lu¨beck, 23538 Lu¨beck, Ger- at the second vaccination and two further subjects at the third vaccination. many; †Department of Internal Medicine, University of Lu¨beck, 23538 Lu¨beck, Germany; and ‡Department of Microbiology and Hygiene, University of Lu¨beck, Twelve subjects were available at a follow-up examination 1 y later. The 23538 Lu¨beck, Germany study was approved by the Ethics Committee of the University of Lu¨beck. 1 All men gave written informed consent prior to participating in accordance Current address: Department of Psychiatry, University of California, San Diego, La with the Declaration of Helsinki. Jolla, CA. Received for publication January 4, 2011. Accepted for publication May 3, 2011. Experimental design and procedure at days of vaccination This work was supported by a grant from the Deutsche Forschungsgemeinschaft The participants were randomly assigned to a condition of sleep and a (SFB 654: Plasticity and Sleep). condition of continuous wakefulness (wake). Both groups were comparable Address correspondence and reprint requests to Dr. Tanja Lange, Department for age, body weight, and body mass index (p . 0.5). Each participant in of Neuroendocrinology, University of Lu¨beck, Ratzeburger Allee 160, Haus 50, both groups was injected with a vaccine into the deltoid muscle of the 23538 Lubeck, Germany. E-mail address: [email protected] ¨ nondominant arm at 8 AM three times (i.e., at weeks 0, 8, and 16), with 1 The online version of this article contains supplemental material. ml of a hepatitis A vaccine that was combined with a hepatitis B vaccine Abbreviations used in this article: Cy7, cyanin 7; EEG, electroencephalography; GH, (Twinrix, 720 IU HAV, 20 mg HBs; GlaxoSmithKline Biologicals, Rix- growth hormone; HAV, hepatitis A virus; HBs, hepatitis B virus surface Ag; REM, ensart, Belgium) (see Fig. 1B for study protocol). All primary vaccinations rapid eye movement; SWA, slow-wave activity; SWS, slow-wave sleep. were performed in February and March, and the third shot was done in June or July 2007, with no difference in timing between the sleep and wake Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 groups (p . 0.6). After immunizations, subjects were instructed to refrain www.jimmunol.org/cgi/doi/10.4049/jimmunol.1100015 284 SLEEP AND IMMUNOLOGICAL MEMORY from physical or psychological stress and not to nap during the daytime. surface Ag (VP1–VP4, attenuated strain HM175, final concentration for Adherence to these instructions was confirmed by questionnaires. The each peptide 1.8 mg/ml, PEPscreen; ProImmune, Oxford, U.K.). The HBs participants returned to the laboratory at 9 PM for preparing blood sam- peptide pool consisted of 54 peptides of 15 aa overlapping by 11 made pling and, in the regular sleep condition, for standard polysomnographic from HBs (adw serotype, final concentration for each peptide 3 mg/ml, recordings. PEPscreen; ProImmune). Sleep in the sleep group was allowed between 11 PM (lights off) and 6:30 After a stimulation period of 6 h cells were surface-stained for CD3 AM (lights on) in the morning. In the wake condition, subjects stayed awake and CD4 for 15 min at room temperature. After washing, fixation, and in bed during this period in a half-supine position, watching TV, reading, permeabilization according to the manufacturer’s instructions (Cytofix/ listening to music, and talking to the experimenter at normal room light Cytoperm Kit; BD Biosciences), cells were stained intracellularly for (∼300 lx). Subjects of the wake condition were not allowed to sleep until 8 cytokines and CD154/CD40L (which detects both intracellular and surface PM the following day. For hormonal analyses, blood was sampled re- Ag) (12, 13). The following combination of mAb reagents were used in the peatedly during the experimental nights via an i.v.