CCR2- and Flt3-Dependent Inflammatory Conventional Type 2 Dendritic Cells Are Necessary for the Induction of Adaptive Immunity by the Human Vaccine Adjuvant System AS01.

Cedric Bosteels,Catherine Collignon,Manon Vanheerswynghels,Aurélie Chalon,Sofie De Prijck,Arnaud M Didierlaurent,Kaat Fierens,Hamida Hammad,Caroline De Wolf,Justine Van Moorleghem,Bart N Lambrecht

doi:10.3389/fimmu.2020.606805

Abstract

The Adjuvant System AS01 contains monophosphoryl lipid A (MPL) and the saponin QS-21 in a liposomal formulation. AS01 is included in recently developed vaccines against malaria and varicella zoster virus. Like for many other adjuvants, induction of adaptive immunity by AS01 is highly dependent on the ability to recruit and activate dendritic cells (DCs) that migrate to the draining lymph node for T and B cell stimulation. The objective of this study was to more precisely address the contribution of the different conventional (cDC) and monocyte-derived DC (MC) subsets in the orchestration of the adaptive immune response after immunization with AS01 adjuvanted vaccine. The combination of MPL and QS-21 in AS01 induced strong recruitment of CD26+XCR1+ cDC1s, CD26+CD172+ cDC2s and a recently defined CCR2-dependent CD64-expressing inflammatory cDC2 (inf-cDC2) subset to the draining lymph node compared to antigen alone, while CD26-CD64+CD88+ MCs were barely detectable. At 24 h post-vaccination, cDC2s and inf-cDC2s were superior amongst the different subsets in priming antigen-specific CD4+ T cells, while simultaneously presenting antigen to CD8+ T cells. Diphtheria toxin (DT) mediated depletion of all DCs prior to vaccination completely abolished adaptive immune responses, while depletion 24 h after vaccination mainly affected CD8+ T cell responses. Vaccinated mice lacking Flt3 or the chemokine receptor CCR2 showed a marked deficit in inf-cDC2 recruitment and failed to raise proper antibody and T cell responses. Thus, the adjuvant activity of AS01 is associated with the potent activation of subsets of cDC2s, including the newly described inf-cDC2s.

Highlights

Recombinant proteins are often combined with adjuvants in vaccines to enhance immunogenicity with the aim of conferring protection against disease
Dependency on the CCR2 chemokine receptor for monocyte bone marrow egress was initially considered as a defining characteristic of monocyte-derived cells [26], we found that inf-cDC2s were dependent on CCR2, and cautioned that CCR2-dependency did not equalize with monocyte origin [23]
We stained for the dipeptidyl peptidase CD26, identifying all contribution of the different conventional (cDC), whereas monocyte-derived DC (MC) were identified as CD26-CD64+ cells expressing the complement receptor CD88 [22, 23, 29]

Summary

Introduction

Recombinant proteins are often combined with adjuvants in vaccines to enhance immunogenicity with the aim of conferring protection against disease. Adjuvants trigger the innate immune system, which in turn shapes the nature of the adaptive immune response. MPL promotes the production of pro-inflammatory cytokines and directly activates antigen-presenting cells (APCs) [3, 4]. QS-21 enhances antibody responses in humans [5], and cytotoxic CD8+ T lymphocyte (CTL) responses in mice through modified antigen cross-presentation by cDCs [6,7,8]. By activating multiple innate pathways, both immunostimulants in AS01 synergistically enhance antigen-specific T cell responses producing interferon-gamma (IFN-g) and antibody switching toward IgG2c antibodies in mice [3, 9, 10]. AS01 is included in the recombinant herpes zoster (Shingrix) and the malaria vaccines [13,14,15] as well as in other candidate vaccines against viruses and intracellular pathogens, such as HIV and tuberculosis [16, 17]

Objectives

Methods

Results

Conclusion