Targeting Xcr1 on Dendritic Cells Rapidly Induce Th1-Associated Immune Responses That Contribute to Protection Against Influenza Infection

Demo Yemane Tesfaye,Bjarne Bogen,Sonja Bobic,Ranveig Braathen,Arnar Gudjonsson,Anna Lysén,Even Fossum,Peter Csaba Huszthy

doi:10.3389/fimmu.2022.752714

Demo Yemane Tesfaye, Bjarne Bogen + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2022.752714

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Abstract

Targeting antigen to conventional dendritic cells (cDCs) can improve antigen-specific immune responses and additionally be used to influence the polarization of the immune responses. However, the mechanisms by which this is achieved are less clear. To improve our understanding, we here evaluate molecular and cellular requirements for CD4+ T cell and antibody polarization after immunization with Xcl1-fusion vaccines that specifically target cDC1s. Xcl1-fusion vaccines induced an IgG2a/IgG2b-dominated antibody response and rapid polarization of Th1 cells both in vitro and in vivo. For comparison, we included fliC-fusion vaccines that almost exclusively induced IgG1, despite inducing a more mixed polarization of T cells. Th1 polarization and IgG2a induction with Xcl1-fusion vaccines required IL-12 secretion but were nevertheless maintained in BATF3-/- mice which lack IL-12-secreting migratory DCs. Interestingly, induction of IgG2a-dominated responses was highly dependent on the early kinetics of Th1 induction and was important for optimal protection in an influenza infection model. Early Th1 induction was dominant, since a combined Xcl1- and fliC-fusion vaccine induced IgG2a/IgG2b polarized antibody responses similar to Xcl1-fusion vaccines alone. In summary, our results demonstrate that targeting antigen to Xcr1+ cDC1s is an efficient strategy for enhancing IgG2a antibody responses through rapid Th1 induction, which can be utilized for improved vaccine design.

Highlights

Conventional dendritic cells capture and process foreign antigens for presentation of antigen-specific T cells
While Xcl1-fusion vaccines target the Xcr1 receptor which is expressed on cDC1s [5, 6, 29], the surface receptor for fliC, TLR5, has been reported to be expressed on CD11b+ cDC2s (Supplementary Figure 1B) [23]
Intradermal (i.d.) DNA vaccination using Xcl1- or fliC-fusion vaccines containing hemagglutinin (HA) from influenza A/Puerto Rico/8/34 (PR8) as an antigen demonstrated that fliC-HA induced almost exclusively antibodies of the IgG1 subclass, while Xcl1-HA induced higher titers of IgG2a and IgG2b (Figures 1A, B and Supplementary Figure 1D) [22]

Summary

Introduction

Conventional dendritic cells (cDCs) capture and process foreign antigens for presentation of antigen-specific T cells Through this function, cDCs have a central role in the initiation phase of the cellular immune response and can as a consequence influence the polarization of the ensuing immune responses [1]. Antigens can be targeted directly to cDCs by fusion to antibodies, chemokines, or other ligands that bind surface receptors expressed on the cDCs [reviewed in [1, 11, 12]]. Such approaches have been shown to enhance antigen-specific immune responses in mice as well as in larger animals [13–17]. FliC is a ligand for the intracellular NLRC4– NAIP5 inflammasome activating complex [26, 27]

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