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Toll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses

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  • Jonathan H. Lam

    (University of California Davis
    University of California Davis
    University of California Davis)

  • Nicole Baumgarth

    (University of California Davis
    University of California Davis
    University of California Davis
    Johns Hopkins Bloomberg School of Public Health)

Abstract

Extrafollicular plasmablast responses (EFRs) are considered to generate antibodies of low affinity that offer little protection from infections. Paradoxically, high avidity antigen-B cell receptor engagement is thought to be the main driver of B cell differentiation, whether in EFRs or slower-developing germinal centers (GCs). Here we show that influenza infection rapidly induces EFRs, generating protective antibodies via Toll-like receptor (TLR)-mediated mechanisms that are both B cell intrinsic and extrinsic. B cell-intrinsic TLR signals support antigen-stimulated B cell survival, clonal expansion, and the differentiation of B cells via induction of IRF4, the master regulator of B cell differentiation, through activation of NF-kB c-Rel. Provision of sustained TLR4 stimulation after immunization shifts the fate of virus-specific B cells towards EFRs instead of GCs, prompting rapid antibody production and improving their protective capacity over antigen/alum administration alone. Thus, inflammatory signals act as B cell fate-determinants for the rapid generation of protective antiviral extrafollicular responses.

Suggested Citation

  • Jonathan H. Lam & Nicole Baumgarth, 2023. "Toll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39734-5
    DOI: 10.1038/s41467-023-39734-5
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    1. Sudhir Pai Kasturi & Ioanna Skountzou & Randy A. Albrecht & Dimitrios Koutsonanos & Tang Hua & Helder I. Nakaya & Rajesh Ravindran & Shelley Stewart & Munir Alam & Marcin Kwissa & Francois Villinger &, 2011. "Programming the magnitude and persistence of antibody responses with innate immunity," Nature, Nature, vol. 470(7335), pages 543-547, February.
    2. James D. Phelan & Ryan M. Young & Daniel E. Webster & Sandrine Roulland & George W. Wright & Monica Kasbekar & Arthur L. Shaffer & Michele Ceribelli & James Q. Wang & Roland Schmitz & Masao Nakagawa &, 2018. "A multiprotein supercomplex controlling oncogenic signalling in lymphoma," Nature, Nature, vol. 560(7718), pages 387-391, August.
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