Human CD4 T cells are a functional target for lipid nanoparticle-based mRNA vaccines

Area of Science:

• Immunology
• Vaccinology
• Molecular Biology

Background:

• Billions of mRNA vaccine doses for SARS-CoV-2 have been safely administered, yet the precise mechanisms of protection are not fully understood.
• While B and T cell responses are observed, the specific immune cells responsible for mRNA lipid nanoparticle (LNP) uptake and subsequent protein expression remain unidentified.

Purpose of the Study:

• To investigate the cellular targets of mRNA LNP vaccines and elucidate their role in protein expression and immune response generation.
• To determine if CD4 T cells can serve as a primary source of antigen production following mRNA vaccination.

Main Methods:

• Utilized fluorescent reporter mRNA LNPs to track particle uptake and protein expression in immune cells.
• Employed *in vitro* human lymph node-like organoid models and *in vivo* murine immunization models.
• Assessed the capacity of transfected CD4 T cells to generate antibody responses and present antigens.

Main Results:

• Demonstrated that CD4 T cells are a significant, unexpected target for mRNA LNP transfection both *in vitro* and *in vivo*.
• Showed that CD4 T cells transfected with SARS-CoV-2 mRNA vaccines can independently produce sufficient antigen to elicit specific antibody responses.
• Confirmed that while CD4 T cells can produce antigen, they do not effectively present it to other CD4 T cells.

Conclusions:

• Non-antigen-presenting immune cells, specifically CD4 T cells, are a novel and significant target for mRNA-based protein expression.
• mRNA-transfected CD4 T cells can support effective adaptive immune responses, contributing to antigen production outside the injection site.
• These findings suggest potential new vaccination strategies involving direct targeting of CD4 T cells to optimize immune responses or immunotherapies.