Central Role of CD169+ Lymph Node Resident Macrophages in the Adjuvanticity of the QS-21 Component of AS01

Abstract

Saponins represent a promising class of vaccine adjuvant. Together with the TLR4-ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the malaria and zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169+ resident macrophages of the draining lymph node where it elicited a local innate immune response. Depletion of these cells abrogated QS-21-mediated innate cell recruitment to the lymph node, dendritic cell (DC) phenotypic maturation as well as the adjuvant effect on T-cell and antibody responses to co-administered antigens. DCs rather than lymph node-resident macrophages were directly involved in T-cell priming by QS-21, as revealed by the decrease in antigen-specific T-cell response in Batf3−/− mice. Further analysis showed that the adjuvant effect of QS-21 depended on the integration of Caspase-1 and MyD88 pathways, at least in part through the local release of HMGB1. Taken together, this work unravels the key role of lymph node sentinel macrophage in controlling the adjuvant effect of a molecule proven to improve vaccine response in humans.

MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2

“…Following infection or vaccination, innate immune cells are recruited to lymphoid tissues [5,[47][48][49]. Myeloid-derived cells can have suppressive effects on adaptive immunity, depending on the local inflammatory milieu.…”

Selection of adjuvants for vaccines targeting specific pathogens

“…In another study, LN-resident CD11b + CD169 + macrophages played a key role in the adjuvant activity of QS-21. Upon intramuscular injection in mice, QS-21 leads to rapid induction of local innate immune responses in the dLNs and co-localises with LN-resident macrophages that are crucial for innate and effector responses to antigens formulated with QS-21 (via Caspase 1/11 and inflammasome activation) [40].…”

Natural compounds that regulate lymph node sinus macrophages: Inducing an anti-tumor effect by regulating macrophage activation

“…[13][14][15] Recent progress in anti-tumor therapy has revealed the significance of anti-tumor immune responses in tumor progression and clinical course in several kinds of malignant tumors. The draining lymph node is an important immune system component that contains a number of antigen-presenting cells, which induce rapid immune responses to foreign antigens.…”