Distinct components of mRNA vaccines cooperate to instruct efficient germinal center responses
Diana Castaño, Emily Bettini, Binod Kumar, Aleksey Chudnovskiy, Anna Siv, Giulia Protti, Sandra Nakadakari-Higa, Simona Ceglia, Nina De Luna, Joy E. Chiu, Katlyn Lederer, Shuk Hang Li, Hassaan Ibrahim, Hiromi Muramatsu, Thandiswa Mdluli, Edit Ábrahám, Sinem E. Sahingur, Ivan Maillard, Ying K. Tam, Sunny Shin, Scott E. Hensley, Jonathan J. Miner, Zoltán Lipinszki, Andrea Reboldi, Norbert Pardi, Roberto Spreafico, Gabriel D. Victora, Michela Locci
Abstract
Nucleoside-modified messenger RNA (mRNA) vaccines elicit protective antibodies through their ability to promote T follicular helper (Tfh) cell differentiation. The lipid nanoparticles (LNPs) of mRNA vaccines possess inherent adjuvant activity. However, the extent to which the nucleoside-modified mRNA is sensed and contributes to Tfh cell responses remains undefined. Herein, we deconvolute the signals induced by LNPs and mRNA that instruct dendritic cells (DCs) to promote Tfh cell differentiation. We demonstrate that the mRNA drives the production of type I interferons, which act on DCs to enhance their maturation and Tfh cell differentiation, and favors plasma cells and memory B cell responses. In parallel, LNPs, which allow for mRNA uptake by DCs within the draining lymph node, also modulate Tfh cell responses by shaping the localization of CD25 + DCs. Our work unravels distinct adjuvant features of mRNA and LNPs necessary for the induction of Tfh cells, with implications for rational vaccine design.