Sleep restriction prior to antigen exposure does not alter the T cell receptor repertoire but impairs germinal center formation during a T cell-dependent B cell response in murine spleen

Cornelia Tune,Julia Hahn,Stella E Autenrieth,Martin Meinhardt,Rene Pagel,Andrea Schampel,Lisa-Kristin Schierloh,Kathrin Kalies,Juergen Westermann

doi:10.1016/j.bbih.2021.100312

Cornelia Tune, Julia Hahn + Show 7 more

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https://doi.org/10.1016/j.bbih.2021.100312

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Abstract

It is well known that sleep promotes immune functions. In line with this, a variety of studies in animal models and humans have shown that sleep restriction following an antigen challenge dampens the immune response on several levels which leads to e.g. worsening of disease outcome and reduction of vaccination efficiency, respectively. However, the inverse scenario with sleep restriction preceding an antigen challenge is only investigated in a few animal models where it has been shown to reduce antigen uptake and presentation as well as pathogen clearance and survival rates. Here, we use injection of sheep red blood cells to investigate the yet unknown effect on a T cell-dependent B cell response in a well-established mouse model. We found that 6 h of sleep restriction prior to the antigen challenge does not impact the T cell reaction including the T cell receptor repertoire but dampens the development of germinal centers which correlates with reduced antigen-specific antibody titer indicating an impaired B cell response. These changes concerned a functionally more relevant level than those found in the same experimental model with the inverse scenario when sleep restriction followed the antigen challenge. Taken together, our findings showed that the outcome of the T cell-dependent B cell response is indeed impacted by sleep restriction prior to the antigen challenge which highlights the clinical significance of this scenario and the need for further investigations in humans, for example concerning the effect of sleep restriction preceding a vaccination.

Highlights

It is a long known phenomenon of everyday life that sleep promotes protective functions of the immune system and well documented by a plethora of human and animal studies (reviewed e.g. by (Bryant et al, 2004) and (Besedovsky et al, 2019))
After 3 d and 10 d, respectively, spleens were harvested and cell proliferation visualized via histochemical staining for Ki-67 and B220, which allows us to assess both T and B cell proliferation within the T cell zone (TCZ) and the developing germinal center (GC), respectively
This effect became significant during full GC development at 10 d p.i. (Fig. 1D, U 1⁄4 3, p < 0.0001), and was validated by two-way ANOVA (interaction: F (1,18) 1⁄4 20.11, p 1⁄4 0.0001; time: F 1⁄4 295.9, p < 0.0001, sleep: F 1⁄4 22.88, p < 0.0001; sleep vs awake, 3 d: ns, 10 d: p < 0.0001)

Summary

Introduction

It is a long known phenomenon of everyday life that sleep promotes protective functions of the immune system and well documented by a plethora of human and animal studies (reviewed e.g. by (Bryant et al, 2004) and (Besedovsky et al, 2019)). Sleep has a regulatory effect on the host defense system, as it impacts tissue distribution and functionality of basically all types of immune cells (Benedict et al, 2007; Bonacho et al, 2001; Born et al, 1997; Dimitrov et al, 2007, 2009; Esquifino et al, 2004). While the majority of these studies determined quantitative blood parameters like lymphocyte numbers, cytokine levels and antibody titers in humans, we used mice to investigate sleep effects on the milieu of secondary lymphoid organs (SLO) and found its impact to be more pronounced in spleen than in lymph nodes (Tune et al, 2020). We determined the effects of sleep on the response to sheep red blood cells (SRBC), a blood born antigen processed in spleen. When 6 h of sleep restriction followed the antigen challenge we found synchronized

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