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<p>Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines elicit robust CD4<sup>+</sup> T cell responses, yet the mechanisms underlying this T cell priming remain unknown. Antigens presented to CD4<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cell, T follicular helper cell, and antibody responses in mice. In contrast, excluding vaccine antigen from muscle cells minimally affects CD4<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Julia E. Rood,
  • Suh Kyung Yoon,
  • Mary K. Heard,
  • Stephen D. Carro,
  • Emma J. Hedgepeth,
  • Mary E. O’Mara,
  • Michael J. Hogan,
  • Nhu Le,
  • Hiromi Muramatsu,
  • Kieu Lam,
  • Petra Schreiner,
  • Coral Kasden,
  • Hansell H. Stedman,
  • Ryan A. Langlois,
  • James Heyes,
  • Norbert Pardi,
  • Laurence C. Eisenlohr

摘要

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.