Toll-like Receptor agonists and alpha-galactosylceramide synergistically enhance the production of interferon-gamma in murine splenocytes

Abstract

Vα14 natural killer T (iNKT) cells activated by alpha-galactosylceramide (GalCer) secrete a large amount of cytokines. Toll-like receptors (TLRs) play a critical role in the innate immune responses via the recognition of pathological antigen. Previously we demonstrated that the iNKT cells activated by GalCer augmented LPS-induced NO production in peritoneal cells. In this study, we examined the effect of GalCer and TLR agonists by IFN-γ production from splenocytes. Splenocytes pretreated with GalCer induced TLR3, 4, 7/8, and 9 agonists in vitro, resulting in the enhancement of IFN-γ mRNA expression. In particular, IFN-γ stimulated by GalCer and LPS was increased in NK cells and CD8 T cells, and inhibited by a neutralizing anti-IL-12 antibody. Pretreatment with GalCer enhanced the phosphorylation of IκB-α induced by LPS stimulation. The present study showed that co-stimulation of GalCer and TLR agonists powerfully induced the production of IFN-γ from splenocytes.

Activated NKT Cells Can Condition Different Splenic Dendritic Cell Subsets To Respond More Effectively to TLR Engagement and Enhance Cross-Priming

“…The observation that activation of NKT cells can condition APCs to manufacture more cytokines in response to TLR ligands is consistent with a previous study conducted on splenocytes in vitro (50). Our results are significant in that they show that this conditioning can apply to many APCs and has an impact on induced T cell responses.…”

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 + T cells through IL-12 and TGF-β1

“…The adaptation of DCs to changing metabolic states resulted from a mechanism of "metabolic checkpoint," an active signaling process involved in sensing metabolic alteration and subsequently signaling transaction and execution (56). Recent studies indicated that a Tolllike receptor signaling-mediated metabolic reprogramming is required for DC maturation and antigen presentation (57)(58)(59). Moreover, the dysregulated mTORC1 or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity results in an impaired DC development and maturation, indicating a metabolic checkpoint sensing amino acids and intracellular ATP during DC development and maturation (58,60).…”

An autologous leukemia cell vaccine prevents murine acute leukemia relapse after cytarabine treatment

“…73 Although we have not directly compared a-GalCer and toll-like receptor ligands in this model, the two approaches are not mutually exclusive, and it is possible that these adjuvants may synergize to provide enhanced therapy. 74,75 In summary, an a-GalCer-adjuvanted whole leukemia cell vaccine that is effective at preventing leukemia development in naïve animals is ineffective in the presence of established leukemia because of the suppressive activities of Tregs, MDSCs, and the leukemia cells themselves. However, in the setting of remission after cytarabine treatment, the vaccination leads to durable protection For personal use only.…”