Document Type

Article

Publication Date

1-16-2026

Comments

This is the author's final published version in Nature Communications, Volume 17, 2026, Article number 1327.

The published version is available at https://doi.org/10.1038/s41467-025-68080-x. Copyright © The Author(s) 2026.

Abstract

Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines elicit robust CD4+ T cell responses, yet the mechanisms underlying this T cell priming remain unknown. Antigens presented to CD4+ T cells on major histocompatibility complex class II (MHC II) are traditionally acquired by antigen presenting cells (APCs) from extracellular sources. Here we show that vaccine specific CD4+ T cell responses instead rely on antigen directly expressed within APCs, without extracellular transit. Murine APCs treated with mRNA-LNP vaccines activate T cells more efficiently when presenting antigen produced internally, rather than acquired externally. Immunization with mRNA-LNP vaccines engineered to inhibit antigen expression in APCs results in lower antigen-specific CD4+ T cell, T follicular helper cell, and antibody responses in mice. In contrast, excluding vaccine antigen from muscle cells minimally affects CD4+ T cell responses. Our findings demonstrate that endogenous antigen presentation is essential to mRNA-LNP vaccine-induced immune responses and refine paradigms of MHC II-restricted antigen processing and presentation.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Language

English

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