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 antibody 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 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.

An R848 adjuvanted influenza vaccine promotes early activation of B cells in the draining lymph nodes of non‐human primate neonates

“…They found that many of the TLR, including TLR7, were expressed at levels similar to those in adult cells . Further, cord blood B cells responded to R848 stimulation by production of cytokines and up‐regulation of co‐stimulatory molecules, although certainly some of these responses were diminished compared with adult cells . The data presented here add further evidence for the ability of R848 to promote neonate B‐cell activation and suggest that this is an important contributor to the in vivo adjuvant function of R848 in this population.…”

“…assessed TLR expression in cord‐blood‐derived B cells. They found that many of the TLR, including TLR7, were expressed at levels similar to those in adult cells . Further, cord blood B cells responded to R848 stimulation by production of cytokines and up‐regulation of co‐stimulatory molecules, although certainly some of these responses were diminished compared with adult cells .…”

“…27,28 Increased antibody production may occur through indirect effects of R848 on CD4 + T cells or directly through its ability to activate B cells. [29][30][31][32][33][34][35][36][37][38] The capacity for R848 to signal through TLR8 in addition to TLR7 is an attractive attribute given reports that TLR8 agonists suppress regulatory T cells 39 in addition to inducing robust T helper type 1-biasing cytokines in neonatal antigenpresenting cells. 40 Hence, R848 has the potential to overcome two obstacles associated with neonates, T helper type 2 skewing and increased regulatory T cells.…”

The Impact of the Gut Microbiota on Humoral Immunity to Pathogens and Vaccination in Early Infancy

“…Given the dynamic nature of the infant gut microbiota and the importance of robust humoral immunity to protection against life-threatening pathogens, future pediatric vaccine research should evaluate the manipulation of the infant microbiome to modulate desirable immune responses. Not only are the developing immune systems of infants distinct from those in adults, but the composition and influence of the gut microbiome on infant immune system is also unique [35]. Therefore, the infant microbiome should be explored as potential source of immune response modulation and enhancement of vaccine efficacy.…”

TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth

“…Of note, 3M-052 + PCV13 expanded atypical PnPS-specific CD27 -B cells, also known as "naive-mature B cells," thought to represent direct precursors to multiple phenotypically distinct memory B cells, including germinal center-dependent Ab-secreting memory B cells with relatively high proliferation and somatic hypermutation (44). As 3M-052 is a dual TLR7/8A, direct activation of naive B cells through TLR7 may also contribute to the observed effects of this adjuvant (45).…”