Castadno, Diana and Bettini, Emily and Kumar, Binod and Chudnovskiy, Aleksey and Siv, Anna and Protti, Giulia and Nakadakari-Higa, Sandra and Ceglia, Simona and De, Luna Nina and Chiu, Joy E. and Lederer, Katlyn and Li, Shuk Hang and Ibrahim, Hassaan and Muramatsu, Hiromi and Mdluli, Thandiswa and Ábrahám, Edit and Sahingur, Sinem E. and Maillard, Ivan and Tam, Ying K. and Shin, Sunny and Hensley, Scott E. and Miner, Jonathan J. and Lipinszki, Zoltán and Reboldi, Andrea and Pardi, Norbert and Spreafico, Roberto and Victora, Gabriel D. and Locci, Michela (2025) Distinct components of mRNA vaccines cooperate to instruct efficient germinal center responses. CELL, 188 (26). pp. 7461-7480. ISSN 0092-8674
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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.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: NIH [R01AI153064, R01AI168312, T32AI055400, R01AI146101, P01AI158571, U19AI181968, DP1AI144248, R01AI173086, R01-AI091627, R01-CA278976, 5R01AI158832, R01AI155727, T32AI055428, 75N93021C00015]; National Laboratory for Biotechnology [2022-2.1.1-NL-2022-00008]; Hungarian Academy of Sciences [LP2017-7/2017]; NRDI Office, Hungary [2021-1.1.4-GYORSITOSAV-2022-00008]; Bulgari Women & Science Fellowship; Damon Runyon Postdoctoral Fellowship; Commonwealth of Pennsylvania Health Research Formula Fund; American Association of Immunologists Careers in Immunology Fellowship Program; Charles A. King Trust Postdoctoral Research Funding text: M.L. was supported by NIH grants R01AI153064 and R01AI168312. E.B. was supported by NIH grant T32AI055400. N.P. was supported by NIH grants R01AI146101, R01AI153064, P01AI158571, and U19AI181968. Z.L. was supported by the National Laboratory for Biotechnology (2022-2.1.1-NL-2022-00008) , the Hungarian Academy of Sciences (LP2017-7/2017) , and partially by the 2021-1.1.4-GYORSITOSAV-2022-00008 project of NRDI Office, Hungary. G.D.V. was supported by NIH grants DP1AI144248 and R01AI173086. S.N.-H. was supported by a Bulgari Women & Science Fellowship. A.C. was supported by a Damon Runyon Postdoctoral Fellowship. G.D.V. is an HHMI investigator. I.M. was supported by NIH grants R01-AI091627 and R01-CA278976 and a Commonwealth of Pennsylvania Health Research Formula Fund. S.C. was supported by the American Association of Immunologists Careers in Immunology Fellowship Program and the Charles A. King Trust Postdoctoral Research. A.R. was supported by NIH grants 5R01AI158832 and R01AI155727. K.L. was supported by NIH grant T32AI055428. S.E.H. was supported by NIH contract no. 75N93021C00015. We thank Dr. A.J. Minn and M. Klapholz for providing RIG-I-deficient mice and Dr. Florin Tuluc and Jennifer Murray at the Children's Hospital of Pennsylvania Flow Cytometry Core for technical assistance. R.S. would like to thank the UCLA QCB Collaboratory community directed by Matteo Pellegrini. The following reagent was obtained through the NIH Tetramer Core Facility: I-Ab HA91-107 PE-labeled tetramers. Figures were created with the use of BioRender.com . We acknowledge the use of Grammarly, Inc. for removing grammatical mistakes, spelling errors, and typos. |
| Uncontrolled Keywords: | Inflammation; IN-VIVO; ANTIGEN; RECOGNITION; Toll-Like Receptors; Dendritic cell; INNATE; Biochemistry & Molecular Biology; Helper; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia Q Science / természettudomány > QH Natural history / természetrajz > QH426 Genetics / genetika, örökléstan Q Science / természettudomány > QR Microbiology / mikrobiológia Q Science / természettudomány > QR Microbiology / mikrobiológia > QR180 Immunology / immunológia Q Science / természettudomány > QR Microbiology / mikrobiológia > QR355 Virology / víruskutatás |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 10 Feb 2026 12:43 |
| Last Modified: | 10 Feb 2026 12:43 |
| URI: | https://real.mtak.hu/id/eprint/233652 |
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