H2-M and H2-O as Targeting Vehicles for the MHC Class II Processing Compartment Promote Antigen-Specific CD4+ T Cell Activation.

Lucia Lapazio,Monika Braun,Kaj Grandien

doi:10.3390/vaccines9101053

Abstract

CD8 and CD4 T cell activation are both required for a strong and long-lasting T cell immune response. Endogenously expressed proteins are readily processed by the MHC class I antigen presentation pathway, enabling activation of CD8+ T cells. However, the MHC class II antigen presentation pathway, necessary for CD4+ T cell activation, is generally not sufficiently accessible to endogenously expressed proteins, limiting the efficiency of mRNA- or DNA-based vaccines. In the current study, we have evaluated the feasibility of using antigen sequences fused to sequences derived from the H2-M and H2-O proteins, two complexes known to participate in MHC class II antigen processing, for the enhancement of CD4 T-cell activation. We analyzed T cell activation after genetic immunization with mRNA-encoding fusion proteins with the model antigen ovalbumin and sequences derived from H2-M or H2-O. Our results show that H2-M- or H2-O-derived sequences robustly improve antigen-specific CD4 T-cell activation when fused to the antigen of interest and suggest that the approach could be used to improve the efficiency of mRNA- or DNA-based vaccines.

Highlights

An efficient vaccination strategy, leading to a strong and durable immunological memory, requires a specific and potent interaction between antigen-specific T cells and professional antigen-presenting cells (APCs), such as dendritic cells (DCs), and activation of both CD4+ and CD8+ T cells [1]
Our study demonstrates for the first time that the coupling of antigen-derived prosequences to H2-M or H2-O protein sequences promotes the activation and prolifercell proliferation was measured at days post-DC transfer by flow cytometry after the staining. ation of CD4 T cells
Our study demonstrates for the first time that the coupling of antigen-derived protein sequences to H2-M or H2-O protein sequences promotes the activation and proliferation of CD4 T cells

Summary

Introduction

An efficient vaccination strategy, leading to a strong and durable immunological memory, requires a specific and potent interaction between antigen-specific T cells and professional antigen-presenting cells (APCs), such as dendritic cells (DCs), and activation of both CD4+ and CD8+ T cells [1]. Experimental vaccination campaigns using live-attenuated viruses for infectious disease indications or cancer immunotherapy have focused mainly on activating cytotoxic CD8+ T cells, using MHC class I-restricted antigens. In contrast to infectious (live) vaccines, subunit Ag are notoriously poor in eliciting protective CD8 T-cell responses, presumably because subunit antigens become insufficiently cross-presented by dendritic cells (DCs) and because the latter need to be activated to acquire competence for cross-priming. MHC class II antigen presentation and the subsequent activation of CD4 T cells are essential to obtain a strong and long-lasting immune response [1]. Efficient activation of CD4+ T cells may be a particular challenge for intracellular proteins which are, in general, poorly presented to CD4+ T cells, since they are not naturally directed to endosomal–lysosomal antigen-processing compartments to generate peptide–MHC class II complexes and activate naive CD4+ T cells [5]

Methods

Results

Conclusion