Dlg1 Maintains Dendritic Cell Function by Securing Voltage-Gated K+ Channel Integrity.

Dendritic cells (DCs) play key roles in Ab responses by presenting Ags to lymphocytes and by producing proinflammatory cytokines. In this study, we reported that DC-specific knockout of discs large homologue 1 (Dlg1) resulted in a significantly reduced capacity to mediate Ab responses to both thymus-independent and thymus-dependent Ags in Dlg1 fl/flCd11c-Cre-GFP mice. Mechanistically, Dlg1-deficient DCs showed severely impaired endocytosis and phagocytosis capacities upon Ag exposure. In parallel, loss of Dlg1 significantly jeopardized the proinflammatory cytokine production by DCs upon TLR stimulation. Thus, Dlg1-deficient DCs lost their functions to support innate and adaptive immunities. At a cellular level, Dlg1 exhibited an indispensable function to maintain membrane potential changes by securing potassium ion (K+) efflux and subsequent calcium ion (Ca2+) influx events in DCs upon stimulation, both of which are known to be required for proper function of DCs. At a molecular level, Dlg1 did so by retaining the integrity of voltage-gated K+ channels (including Kv1.3) in DCs. The loss of Dlg1 led to a decreased expression of K+ channels, resulting in impaired membrane potential changes and, as a consequence, reduced proinflammatory cytokine production, compromised Ag endocytosis, and phagocytosis. In conclusion, this study provided, to our knowledge, a novel insight into Dlg1 and the voltage-gated K+ channels axis in DC functions.

Effects of prenatal cold stress on maternal serum metabolomics in rats.

Our previous studies have shown that prenatal cold stress leads to placental inflammatory response and induces anxiety-like behavior reduced in offspring rats. However, the role and mechanisms by which prenatal cold stress affects offspring remain unclear. The aim of this study was to determine the metabolic profiles from the maternal serum and helpful in understanding the role and mechanisms by which prenatal cold stress affects the offspring. In this study, liquid chromatography-mass spectrometry (LC/MS) was used to analyze serum metabolites, and PCA, PLS-DA, and OPLS-DA were performed to analyze changes in metabolites in the maternal serum after cold stress of 3 or 7 days. The results showed that 19 metabolites in the CS (cold stress 7 days)-NS (control) group and 23 metabolites in the CT (cold stress 3 days)-NT (control) group were significantly altered. These metabolites were mainly associated with unsaturated fatty acid synthesis, and arachidonic acid, linoleic acid, and glutamine and glutamate metabolism. The data indicated that prenatal cold stress not only affected the maternal neuroendocrine system, but also affected the immune system, and lipid and amino acid metabolism. These results further supported the findings of our previous studies on the effects of prenatal cold stress on the mother and offspring. A more comprehensive understanding of these data may lead to maternal intervention that can reverse the damage of prenatal stressors.

p38α has an important role in antigen cross-presentation by dendritic cells.

The role of the p38 signaling pathway in the innate and adaptive immune responses has been well documented, especially in inflammatory cytokine production by dendritic cells (DCs). However, whether the p38 signaling pathway affects the important antigen (Ag) presentation function of DCs remains largely unknown. In this study, we reported that the deletion of p38α resulted in an impaired cross-presentation ability of CD8+ conventional DCs (cDCs) and a reduction in the direct presentation ability of CD8- cDCs ex vivo. Further study revealed that p38α had a crucial role in Ag processing by CD8+ cDCs but did not affect the Ag uptake or co-stimulation of T cells. Moreover, p38α deficiency led to reduced cross-priming of T cells in vivo. The production of the IL-12p40 and IL-12p70 cytokines by p38α-deficient cDCs was also significantly reduced. Our study identified a new role for p38α in modulating the important antigen cross-presentation function of DCs.

The Novel Toll-Like Receptor 2 Agonist SUP3 Enhances Antigen Presentation and T Cell Activation by Dendritic Cells.

Dendritic cells (DCs) are highly specialized antigen-presenting cells that play crucial roles in innate and adaptive immunity. Previous studies suggested that Toll-like receptor (TLR) agonists could be used as potential adjuvants, as activation of TLRs can boost DC-induced immune responses. TLR2 agonists have been shown to enhance DC-mediated immune responses. However, classical TLR2 agonists such as Pam3CSK4 are not stable enough in vivo, which limits their clinical applications. In this study, a novel structurally stable TLR2 agonist named SUP3 was designed. Functional analysis showed that SUP3 induced much stronger antitumor response than Pam3CSK4 by promoting cytotoxic T lymphocytes activation in vivo. This effect was achieved through the following mechanisms: SUP3 strongly enhanced the ability of antigen cross-presentation by DCs and subsequent T cell activation. SUP3 upregulated the expression of costimulatory molecules on DCs and increased antigen deposition in draining lymph nodes. More interestingly, SUP3 induced less amount of pro-inflammatory cytokine production in vivo compared to other TLR agonists such as lipopolysaccharide. Taken together, SUP3 could serve as a novel promising immune adjuvant in vaccine development and immune modulations.

Generation of mouse and human dendritic cells in vitro.

Dendritic cells (DC) that can orchestrate immune responses and maintain host homeostasis, are indispensable components of the immune system. Although distributed widely in many lymphoid and non-lymphoid tissues, their rarity in number has become a limiting factor for DC related research and therapies. Therefore, methods for efficiently generating large numbers of DC resembling their in vivo counterparts are urgently needed for DC related research and therapies. Herein we summarize the current methods for generating mouse and human DC in vitro and hope that these will facilitate both studies of DC biology and their clinical applications.