Immunological Level

C4

Effects of sleep on quantitative and qualitative aspects of CD4 T-cell memory


Kalies, Kathrin, Dr.rer.nat.
Institut für Anatomie, Universität Lübeck,
Ratzeburger Allee 160, D-23538 Lübeck

Telefon: +49-451-500-4045
E-Mail: kalies@anat.uni-luebeck.de

Westermann, Jürgen, Prof. Dr. med.
Institut für Anatomie, Universität Lübeck,
Ratzeburger Allee 160, D-23538 Lübeck

Telefon: +49-451-500-4000
E-Mail: westermann@anat.uni-luebeck.de


Summary
It is now well accepted that sleep improves immunological memory. However, the molecular mechanisms responsible for this interaction are still ill defined. In the previous funding periods we developed a new concept for CD4 T-cell memory. It states that there are no specialized memory CD4 T cells. Instead, after an immune response activated CD4 T cells revert back to resting CD4 T cells. Thus, CD4 T-cell memory is stored in the resting (long lived) CD4 population by an increased frequency of CD4 T cells of the required specificity. Meanwhile we and others have been able to provide experimental evidence that strongly supports the new memory concept in vivo. In the present funding period we focus on three topics. We continue the previous work by studying whether in mice sleep increases the frequency of antigen-specific CD4 T cells among the resting CD4 T-cell population, and which molecular signals mediate such effects. Tetanus toxoid and sheep red blood cells will be used as antigens. The results will reveal whether this is the mechanism by which sleep consolidates immunological memory. We extent our approach by analyzing in mice whether sleep affects the T-cell receptor repertoire which is recruited into an immune response. These data will show whether this is a mechanism by which sleep contributes to encoding of immunological memory. Finally, we will use our newly created two-scale mathematical model for migration of antigen-specific T-cells to predict in silico, and then analyze in vivo, how sleep influences the course of a secondary immune response (recall of immunological memory). Thus, by uncovering the molecular mechanisms that mediate the positive effects of sleep on immunological memory they can be used clinically for the benefit of future atients.

C5

The functions of the gp130-signaling-family for sleep and plasticity


Prof. Dr. Rose-John, Stefan

Institute of Biochemistry, University Kiel
Olshausenstr. 40, 24098 Kiel

Telefon: 49-431-880-3336
Telefax: 49-431-880-5007
E-Mail: rosejohn@biochem.uni-kiel.de


Summary
The cytokine interleukin-6 (IL-6) acts on target cells via a membrane bound IL-6 receptor (IL-6R), which forms a complex with the signaling receptor gp130, leading to classic IL-6 signaling. Most cells of the body, however, do not express the IL-6R and can only be stimulated via a soluble IL-6R (sIL-6R), a process we have named transsignaling. The sIL-6R is mostly generated by proteolytic cleavage by the metalloproteinase ADAM17. Interestingly, IL-6 trans-signaling differs from classic signaling in its kinetics often leading to fundamentally different cellular responses. We have generated designer proteins to specifically induce or inhibit IL-6 trans-signaling. Furthermore, we have generated transgenic mice, which overexpress the IL-6 trans-signaling blocking protein sgp130Fc in the periphery or in the central nervous system. Using these protein tools and the transgenic mouse strains together with IL-6-/- mice and hypomorphic ADAM17 mice, the role of IL-6 classic and trans-signaling in the regulation of sleep and related behavior will be analyzed. Using neuro-inflammatory mouse models we will define the role of IL-6 classic and trans-signaling in the brain under normal and pathophysiologic conditions. Finally, we want to address the question whether the cytokine system in the periphery communicates with the cytokine system in the central nervous system. The results will not only help us to better understand the complexity of IL-6 signaling between periphery and brain and the role of sleep therein, but also will yield novel therapeutic principles for the treatment of cerebral inflammatory diseases.

C6

Sleep effects on the initiation, maintenance and recall of T cell memory in humans


Lange, Tanja, Dr. med.

Medizinische Klinik I, UKSH – Campus Lübeck,
Ratzeburger Allee 160, 23538 Lübeck

Telefon: +49-451-500-2306
E-Mail: lange@uni-luebeck.de

Rammensee, Hans-Georg, Prof. Dr. rer. nat.
Interfakultäres Institut für Zellbiologie, Abteilung Immunologie
Auf der Morgenstelle 15, 72076 Tübingen

Telefon: +49-7071-29 87628
E-Mail: rammensee@uni-tuebingen.de

Summary
Sleep after vaccination enhances the antigen-specific Th1 immune response in humans. Our previous findings suggest that this adjuvant-like action is mediated by slow wave sleep (SWS) and its associated hormonal changes that facilitate pro-inflammatory cytokine production by antigen-presenting cells (APC) and lymph node homing of naive T cells. In this way, SWS strengthens the immunological synapse between APC and T cells in lymph nodes and therefore memory consolidation, i.e., the transfer of antigenic information from a temporary (APC) to a long-term store (T cell). In the third funding period, yellow fever vaccination in healthy volunteers will serve as a model of an acute viral infection to study the effects of SWS on this early stage of T cell memory formation in a comprehensive manner. We hypothesize that SWS boosts pro-inflammatory cytokine release and extravasation of naive T cells and that these acute changes improve T cell memory formation and maintenance later on. The recall of T cell memory is amongst others represented by terminally differentiated cytotoxic effector T cells that exert immediate defense in peripheral tissues upon re-encounter of the antigen. Their blood numbers drop during sleep as they reside in the marginal pool due to low epinephrine levels at this time. In order to elucidate if in parallel their activity is silenced by sleep we will measure numbers and functions of antigen-specific cytotoxic effector T cells in healthy subjects with chronic cytomegalovirus infection. We expect that low epinephrine levels during rapid eye movement (REM) sleep quieten cytotoxic effector defense as a prerequisite for efficient T cell memory recall during daytime wakefulness.

C7

Interactions between sleep and complement-driven regulation of intestinal dendritic cell functions


Köhl, Jörg, Prof. Dr.
Institut für Systemische Entzündungsforschung, Universität Lübeck
Ratzeburger Allee 160, 23538 Lübeck

Telefon: +49-451-500-3067
E-Mail: joerg.koehl@uk-sh.de

Autenrieth, Stella, Eugenie, Dr.
Institut für Zellbiologie, Universität Tübingen
Auf der Morgenstelle 15, 72076 Tübingen

Telefon: +49-7071-29-77624
E-Mail: stella.autenrieth@medizin.uni-tuebingen.de

Summary
The cross-talk between complement and other innate immune sensor systems, like the Toll- (TLR) and Nod-like receptors (NLR) regulates antigen-presenting cells (APCs) functions at the interface between innate and adaptive immunity. We found a circadian rhythm for complement and observed its regulation by sleep. Previously, the NLR ligand muramyldipeptide (MDP) has been identified as a sleep-promoting factor in humans and animals, which accumulates during the active period to eventually induce slow wave sleep (SWS). The source of MDP is still unknown. It has been suggested that intestinal bacteria enter the lamina propria (LP) and that bioactive MDP is released upon bacterial degradation, which in turn triggers the release of sleep-promoting cytokines including IL-1β and TNF-α. In addition, viable bacteria can be found in mesenteric lymph nodes (MLN) following sleep deprivation. We propose that intestinal APCs play an important role in this context, as they are known to sample and digest bacteria from the intestinal lumen. We further propose that APCs and their regulation by complement, TLRs and NLRs are simultaneously subjected to a top-down control by central nervous sleep and circadian processes. In the upcoming funding period, we aim to define the impact of sleep on the frequency and function of circulating, intestinal tissue and secondary lymphoid APCs with a particular focus on the crosstalk between innate sensing systems. In addition, we will assess the impact of intestinal bacterial colonization/translocation on the sleep-wake cycle.

C8

Sleep-circadian oscillations in cytokine regulation


Solbach, Werner, Prof. Dr.
Institut für Medizinische Mikrobiologie und Hygiene, Universität Lübeck,
Ratzeburger Allee 160, D-23538 Lübeck

Telefon: +49-451-5002800
E-Mail: werner.solbach@uksh.de

Oster, Henrik, Prof. Dr.
Medizinische Klinik I, UKSH-Lübeck, Universität Lübeck
Ratzeburger Allee 160, D-23538 Lübeck

Telefon: +49-451-5000
E-Mail: henrik.oster@uksh.de

Summary
During the current funding period we have established functional links between sleep, the circadian timing system, and CD4+ T cell function. We have shown that the expression of many pro- and anti-inflammatory cytokines by human CD4+ T cells is, both, (day-)time- and sleep-dependent. We have also shown that murine CD4+ T cells and thymocytes harbor intrinsic circadian pacemakers as evidenced by self-sustained rhythmic expression of the core circadian clock protein PER2 in thymocytes, in organotypic thymus and lymph node slices, and in cell culture. PER2 rhythmicity is closely associated with rhythmic expression of CD40L and IFN-γ. Now we want to analyze how T cell clock activity and sleep interact in the regulation of T cell-mediated immune responses, with a focus on CD4+ T cells. Specifically, it remains to be shown, at which level – systemic or local – the circadian clock impinges on T cell function in vivo and how this regulation is affected by sleep state. Our previous results suggest two different scenarios: (i) Nocturnal sleep represents a permissive state that facilitates the circadian regulation of immune function, or (ii) sleep itself – or the absence thereof – acts as a Zeitgeber for immune cell clocks, thus synchronizing T cell activity to the rest-activity cycle.

C9

Influence of sleep on pathogenic T and B cell responses and autoimmunity


Ehlers, Marc, Prof. Dr. rer. nat.
Institut für Systemische Entzündungsforschung (ISEF), Universität Lübeck
Ratzeburger Allee 160, 23538 Lübeck

Tel.: +49-451-500-3462
E-Mail: marc.ehlers@uksh.de

Summary
The circadian sleep-wake cycle influences immune cells via the timed release of pro- and anti-inflammatory signals. The pro-inflammatory signals growth hormone (GH) and prolactin are mainly released during slow wave sleep (SWS) whereas the immunosuppressive hormone cortisol is mainly released during the early hours of the active period. Accordingly, in patients with rheumatoid arthritis (RA), symptoms are strong in the early morning after sleep and moderate in the evening. Here, we want to analyze the influence of sleep on the induction of pathogenic T and B cell responses and autoimmunity. More specifically we want to analyze the influence of sleep and in particular of SWS, of sleep regulating/regulated factors such as GH, prolactin, interleukin-6 (IL-6) and cortisol, and the circadian system on the development of pro-inflammatory Th1 and Th17 cells and de-galactosylated IgG antibodies in mice. To this end mice will be immunized with chicken ovalbumin (OVA) plus adjuvant or the chicken collagen II induced RA mouse model will be analyzed. Furthermore we want to analyze the influence of sleep (SWS) on pro-inflammatory T cells in diabetes type I patients and the development of pro-inflammatory de-galactosylated IgG antibodies after vaccination of humans. These studies will contribute to our understanding of whether SWS has an influence on the induction of pro-inflammatory T and B cell responses and autoimmunity.

Last Update: 26.06.2013