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.

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 â€‹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.

Effects of sleep on the splenic milieu in mice and the T cell receptor repertoire recruited into a T cell dependent B cell response.

Sleep is known to improve immune function ranging from cell distribution in the naïve state to elevated antibody titers after an immune challenge. The underlying mechanisms still remain unclear, partially because most studies have focused on the analysis of blood only. Hence, we investigated the effects of sleep within the spleen in female C57BL/6J mice with normal sleep compared to short-term sleep-deprived animals both in the naïve state and after an antigen challenge. Lack of sleep decreased the expression of genes associated with immune cell recruitment into and antigen presentation within the spleen both in the naïve state and during a T cell dependent B cell response directed against sheep red blood cells (SRBC). However, neither T cell proliferation nor formation of SRBC-specific antibodies was affected. In addition, the T cell receptor repertoire recruited into the immune response within seven days was not influenced by sleep deprivation. Thus, sleep modulated the molecular milieu within the spleen whereas we could not detect corresponding changes in the primary immune response against SRBC. Further studies will show whether sleep influences the secondary immune response against SRBC or the development of the B cell receptor repertoire, and how this can be compared to other antigens.

Targeted overexpression of IL-18 binding protein at the central nervous system overrides flexibility in functional polarization of antigen-specific Th2 cells.

The current study shows that functional polarization of Ag-specific CD4(+) Th2 cells entering the CNS during the accelerating phase of experimental autoimmune encephalomyelitis is flexible and dependent on the cytokine milieu there. Thus, targeted cell/gene therapy by Ag-specific T cells overexpressing IL-18 binding protein overrides this flexibility and induces infectious spread of T cell tolerance. Using a congenic system, we demonstrated that at this time, Ag-specific Th2 cells accumulate at the CNS but then arrest of IL-4 production. A manipulation of targeted cell/gene delivery was then used to detect whether this function is dependent on the cytokine milieu there. Targeted overexpression of IL-18 binding protein, a natural inhibitor of IL-18, restored the ability of these Ag-specific Th2 cells to produce IL-4 and subsequently induce protective spread of Th2 polarization. These findings not only suggest a novel way of therapy, but also explain why shifting the balance of Ag-specific T cells toward Th2 suppresses ongoing experimental autoimmune encephalomyelitis, whereas a direct transfer of these cells is ineffective.

Lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1 expression on B-cell subsets and the effects of splenectomy-experimental studies.

There is an abundance of data dealing with recirculation of T cells in the rats, but relatively little is known about the traffic of B cells. The adhesion molecules expressed on the surface membrane are of great significance for recirculation of lymphocytes. However, very little is known about the expression of various adhesion molecules on B-cell subsets. Here we show that in normal rats various adhesion molecules are differentially expressed on B-cell subsets and that the level of their expression changes after the entry of B lymphocytes from the blood into the lymphoid tissues. In splenectomized rats, the surface expression of LFA-1 and ICAM-1 is selectively reduced on B-cell subsets in blood and lymph node, which is accompanied by a selective increase in the number of all B-cell subsets in the blood. The decreased surface expression of adhesion molecules results in faster migration of B lymphocytes through lymph nodes with subsequent accumulation of these cells in the blood.