title: Distinct TLR-mediated cytokine production and immunoglobulin secretion in human newborn naïve B cells.
abstract: Neonatal innate immunity is distinct from that of adults, which may contribute to increased susceptibility to infection and limit vaccine responses. B cells play critical roles in protection from infection and detect PAMPs via TLRs, that, when co-activated with CD40, can drive B-cell proliferation and Ab production. We characterized the expression of TLRs in circulating B cells from newborns and adults, and evaluated TLR- and CD40-mediated naïve B-cell class-switch recombination (CSR) and cytokine production. Gene expression levels of most TLRs was similar between newborn and adult B cells, except that newborn naïve B cells expressed more TLR9 than adult naïve B cells. Neonatal naïve B cells demonstrated impaired TLR2- and TLR7- but enhanced TLR9-mediated cytokine production. Significantly fewer newborn naïve B cells underwent CSR to produce IgG, an impairment also noted with IL-21 stimulation. Additionally, co-stimulation via CD40 and TLRs induced greater cytokine production in adult B cells. Thus, while newborn naïve B cells demonstrate adult-level expression of TLRs and CD40, the responses to stimulation of these receptors are distinct. Relatively high expression of TLR9 and impaired CD40-mediated Ig secretion contributes to distinct innate and adaptive immunity of human newborns and may inform novel approaches to early-life immunization.
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Pettengill
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Simon D
authors.initials: SD
authors.lastname: van Haren
authors.affiliation: Department of Immunology and Rheumatology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dowling
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Bergelson
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jop
authors.initials: J
authors.lastname: Jans
authors.affiliation: Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Gerben
authors.initials: G
authors.lastname: Ferwerda
authors.affiliation: Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA ofer.levy@childrens.harvard.edu.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000328:Adult; D000818:Animals; D000917:Antibody Formation; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D058501:Enzyme-Linked Immunospot Assay; D006801:Humans; D007113:Immunity, Innate; D017578:Immunoglobulin Class Switching; D007156:Immunologic Memory; D007231:Infant, Newborn; D007378:Interleukins / Q000378:metabolism; D008213:Lymphocyte Activation; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D007378:Interleukins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D000098546:Interleukin-21
keywords: B lymphocyte; TLR; class-switch recombination; cytokine; neonatal