Optimal murine CD4⁺ T cell priming by mRNA-lipid nanoparticle vaccines requires endogenous antigen processing

Area of Science:

• Immunology
• Vaccinology
• Molecular Biology

Background:

• Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines induce strong CD4+ T cell responses.
• The mechanisms of T cell priming by these vaccines are not fully understood.
• Conventional understanding posits CD4+ T cell antigens are acquired extracellularly by antigen-presenting cells (APCs) for presentation on MHC class II molecules.

Purpose of the Study:

• To investigate the mechanism of CD4+ T cell priming induced by mRNA-LNP vaccines.
• To determine whether endogenous or exogenous antigen presentation is critical for vaccine-specific T cell responses.

Main Methods:

• Utilized murine models immunized with mRNA-LNP vaccines.
• Engineered vaccines to either inhibit or exclude antigen expression in APCs or muscle cells.
• Assessed CD4+ T cell, T follicular helper cell, and antibody responses.

Main Results:

• Antigen presentation from internally synthesized proteins within APCs, not external acquisition, is essential for robust CD4+ T cell activation.
• mRNA-LNP vaccines engineered to block antigen expression in APCs led to diminished T cell, T follicular helper cell, and antibody responses.
• Excluding vaccine antigen from muscle cells had minimal impact on CD4+ T cell responses.

Conclusions:

• Endogenous antigen presentation by APCs is a critical pathway for mRNA-LNP vaccine-induced CD4+ T cell immunity.
• These findings challenge traditional paradigms of MHC class II-restricted antigen processing and presentation in the context of vaccination.
• The study highlights the importance of intracellular antigen synthesis for effective mRNA vaccine immunogenicity.