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LT-K63 Enhances B Cell Activation and Survival Factors in Neonatal Mice That Translates Into Long-Lived Humoral Immunity

LT-K63 Enhances B Cell Activation and Survival Factors in Neonatal Mice That Translates Into Long-Lived Humoral Immunity


Title: LT-K63 Enhances B Cell Activation and Survival Factors in Neonatal Mice That Translates Into Long-Lived Humoral Immunity
Author: Aradottir Pind, Audur Anna
Molina Estupiñan, Jenny Lorena
Magnusdottir, Gudbjorg Julia
Del Giudice, Giuseppe
Jonsdottir, Ingileif   orcid.org/0000-0001-8339-150X
Bjarnarson, Stefania P.
Date: 2020-10-23
Language: English
Scope:
University/Institute: University of Iceland
Landspitali - The National University Hospital of Iceland
School: Health Sciences
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: Frontiers in Immunology; 11()
ISSN: 1664-3224
DOI: https://doi.org/10.3389/fimmu.2020.527310
Subject: adjuvant; APRIL (TNFSF13); B cell subsets; BAFF - B-cell activating factor; BAFF-R; BCMA; neonatal vaccination; plasma cell survival; Immunology and Allergy; Immunology
URI: https://hdl.handle.net/20.500.11815/3424

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Citation:

Aradottir Pind , A A , Molina Estupiñan , J L , Magnusdottir , G J , Del Giudice , G , Jonsdottir , I & Bjarnarson , S P 2020 , ' LT-K63 Enhances B Cell Activation and Survival Factors in Neonatal Mice That Translates Into Long-Lived Humoral Immunity ' , Frontiers in Immunology , vol. 11 , 527310 . https://doi.org/10.3389/fimmu.2020.527310

Abstract:

Adjuvants enhance magnitude and duration of immune responses induced by vaccines. In this study we assessed in neonatal mice if and how the adjuvant LT-K63 given with a pneumococcal conjugate vaccine, Pnc1-TT, could affect the expression of tumor necrosis factor receptor (TNF-R) superfamily members, known to be involved in the initiation and maintenance of antibody responses; B cell activating factor receptor (BAFF-R) and B cell maturation antigen (BCMA) and their ligands, BAFF, and a proliferation inducing ligand (APRIL). Initially we assessed the maturation status of different B cell populations and their expression of BAFF-R and BCMA. Neonatal mice had dramatically fewer B cells than adult mice and the composition of different subsets within the B cell pool differed greatly. Proportionally newly formed B cells were most abundant, but they had diminished BAFF-R expression which could explain low proportions of marginal zone and follicular B cells observed. Limited BCMA expression was also detected in neonatal pre-plasmablasts/plasmablasts. LT-K63 enhanced vaccine-induced BAFF-R expression in splenic marginal zone, follicular and newly formed B cells, leading to increased plasmablast/plasma cells, and their enhanced expression of BCMA in spleen and bone marrow. Additionally, the induction of BAFF and APRIL expression occurred early in neonatal mice immunized with Pnc1-TT either with or without LT-K63. However, BAFF+ and APRIL+ cells in spleens were maintained at a higher level in mice that received the adjuvant. Furthermore, the early increase of APRIL+ cells in bone marrow was more profound in mice immunized with vaccine and adjuvant. Finally, we assessed, for the first time in neonatal mice, accessory cells of the plasma cell niche in bone marrow and their secretion of APRIL. We found that LT-K63 enhanced the frequency and APRIL expression of eosinophils, macrophages, and megakaryocytes, which likely contributed to plasma cell survival, even though APRIL+ cells showed a fast decline. All this was associated with enhanced, sustained vaccine-specific antibody-secreting cells in bone marrow and persisting vaccine-specific serum antibodies. Our study sheds light on the mechanisms behind the adjuvanticity of LT-K63 and identifies molecular pathways that should be triggered by vaccine adjuvants to induce sustained humoral immunity in early life.

Description:

Funding text 1 AA was a recipient of a doctoral study grant from the University of Iceland Research Fund (2015–18). This study was financially supported by grants from the Icelandic Research Fund (130675051-53), The University of Iceland Research Fund (2014–17) and the Landspitali Science Fund A-2015-083, A2015-084, A-2016-067, A-2017-069. Funding text 2 Part of the work presented in this paper was presented as posters at the European Congress of Immunology, Vienna, Austria, 6?9. September 2015 (abstract no P.A.27.14 and P.A.27.15) and at V?sindi a? hausti, scientific conference at Landsp?tali - the National University Hospital of Iceland, Reykjav?k, 7. October 2020 (abstract number 8). Funding. AA was a recipient of a doctoral study grant from the University of Iceland Research Fund (2015?18). This study was financially supported by grants from the Icelandic Research Fund (130675051-53), The University of Iceland Research Fund (2014?17) and the Landspitali Science Fund A-2015-083, A2015-084, A-2016-067, A-2017-069. Publisher Copyright: © Copyright © 2020 Aradottir Pind, Molina Estupiñan, Magnusdottir, Del Giudice, Jonsdottir and Bjarnarson.

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