Neonatal Follicular Th Cell Responses Are Impaired and Modulated by IL-4

Debock, Isabelle; Jaworski, Kathy; Chadlaoui, Hanan; Delbauve, Sandrine; Passon, Nicolas; Twyffels, Laure; Léo, Oberdan; Flamand, Véronique

doi:10.4049/jimmunol.1203288

Cited by 56 publications

(71 citation statements)

References 38 publications

(46 reference statements)

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“…ICOS binding is well established to promote differentiation of Tfh [31] and OX40 engagement has been reported to promote generation, proliferation and survival of Tfh [33–36]. Given the impaired generation of Tfh cell responses reported in infants [37–39], targeting these cells holds promise for the development of more potent vaccines.…”

Section: Discussionmentioning

confidence: 99%

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Holbrook

D’Agostino

Aycock

et al. 2017

Vaccine

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Generation of a potent antibody response that can be sustained over time is highly challenging in young infants. Our previous studies using a nursery-reared nonhuman primate model identified R848 conjugated to inactivated influenza virus as a highly immunogenic vaccine for neonates. Here we determined the effectiveness of this vaccine in mother-reared infants as well as its ability to promote improved responses at 6 months compared to vaccination in the absence of R848. In agreement with our nursery study, R848 conjugated to influenza virus induced a higher antibody response in neonates compared to the non-adjuvanted vaccine. Further, the increase in the response relative to that induced by the non-adjuvanted vaccine was maintained at 6 months suggesting the increased antibody secreting cells that resulted from inclusion of conjugated R848 production were capable of surviving long term. There was no significant difference in quality of antibody (i.e. neutralization or affinity), suggesting the beneficial effect of conjugated R848 during vaccination of neonates with inactivated influenza virus is likely manifest during the early generation of antibody secreting cells.

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Section: Discussionmentioning

confidence: 99%

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Holbrook

D’Agostino

Aycock

et al. 2017

Vaccine

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“…Two recent studies in mice sought to determine if newborns can mount effective T FH cell responses (86, 87). Both works showed that CD4 + CXCR5 + PD-1 + T FH cells can be induced in mice neonates subjected to antigenic immunization, but that their full development is impaired.…”

Section: Neonatal Follicular T Helper Cellsmentioning

confidence: 99%

“…Both works showed that CD4 + CXCR5 + PD-1 + T FH cells can be induced in mice neonates subjected to antigenic immunization, but that their full development is impaired. Indeed, neonatal T FH cells expressed lower levels of Bcl6 and IL-21 and were poorly located in GCs, while they were highly present in interfollicular regions (86). This localization outside of GCs correlates with the limited expansion and differentiation in GC T FH cells of newborn T FH cells (87).…”

Section: Neonatal Follicular T Helper Cellsmentioning

confidence: 99%

Unbalanced Neonatal CD4+ T-Cell Immunity

2014

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In comparison to adults, newborns display a heightened susceptibility to pathogens and a propensity to develop allergic diseases. Particular properties of the neonatal immune system can account for this sensitivity. Indeed, a defect in developing protective Th1-type responses and a skewing toward Th2 immunity characterize today the neonatal T-cell immunity. Recently, new findings concerning Th17, regulatory helper T-cell, and follicular helper T-cell subsets in newborns have emerged. In some circumstances, development of effector inflammatory Th17-type responses can be induced in neonates, while differentiation in regulatory T-cells appears to be a default program of neonatal CD4+ T-cells. Poor antibody production, affinity maturation, and germinal center reaction in vaccinated neonates are correlated with a limiting expansion of TFH lymphocytes. We review herein the factors accounting for and the implications of the unbalanced neonatal helper T-cell immunity.

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“…Important contributors to the poor antibody response in infants are impaired accessory cells, i.e., follicular Th (T FH ) cells (23) and follicular DCs (24), as well as inherent defects in B cell survival and differentiation (25). A potential contributor to diminished survival and differentiation is the reduced expression of B cell maturation antigen (BCMA) and BAFF-R on neonate B cells (26).…”

mentioning

confidence: 99%

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

Kim

Holbrook

Hayward

et al. 2015

J Virol

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Influenza virus can cause life-threatening infections in neonates and young infants. Although vaccination is a major countermeasure against influenza, current vaccines are not approved for use in infants less than 6 months of age, in part due to the weak immune response following vaccination. Thus, there is a strong need to develop new vaccines with improved efficacy for this vulnerable population. To address this issue, we established a neonatal African green monkey (AGM) nonhuman primate model that could be used to identify effective influenza vaccine approaches for use in young infants. We assessed the ability of flagellin, a Toll-like receptor 5 (TLR5) agonist, to serve as an effective adjuvant in this at-risk population. Four-to 6-day-old AGMs were primed and boosted with inactivated PR8 influenza virus (IPR8) adjuvanted with either wild-type flagellin or inactive flagellin with a mutation at position 229 (m229), the latter of which is incapable of signaling through TLR5. Increased IgG responses were observed following a boost, as well as at early times after challenge, in infants vaccinated with flagellin-adjuvanted IPR8. Inclusion of flagellin during vaccination also resulted in a significantly increased number of influenza virus-specific T cells following challenge compared to the number in infants vaccinated with the m229 adjuvant. Finally, following challenge infants vaccinated with IPR8 plus flagellin exhibited a reduced pathology in the lungs compared to that in infants that received IPR8 plus m229. This study provides the first evidence of flagellin-mediated enhancement of vaccine responses in nonhuman primate neonates. Influenza virus remains one of the leading causes of morbidity and mortality worldwide. Infants less than 6 months of age are particularly vulnerable to development of severe disease following infection (1). Diseases associated with influenza virus infection in children include otitis media, pneumonia, myositis, and croup. While oseltamivir (Tamiflu), one of the two FDA-approved antiinfluenza drugs, can be used in infants aged 2 weeks and older, concerns exist due to the potential for adverse effects, drug resistance, and limited effectiveness in young infants (2).Currently, there are three approved approaches for vaccination against influenza in the United States: intramuscular (i.m.) administration of inactivated influenza virus, intramuscular administration of recombinant hemagglutinin (HA) proteins, and intranasal administration of a live attenuated influenza virus (LAIV). The first is approved for use in individuals aged 6 months and older, the second for use in individuals aged 18 to 49 years, and the last for use in healthy individuals aged 2 to 49 years. Thus, none are approved for use in the vulnerable neonate population. While the lack of approval for the use of these vaccines in the very young may reflect some safety concerns, a principal factor is the poor immune responses elicited in human neonates (3,4).Previous studies, while limited, have shown that an initia...

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Neonatal Follicular Th Cell Responses Are Impaired and Modulated by IL-4

Cited by 56 publications

References 38 publications

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Unbalanced Neonatal CD4+ T-Cell Immunity

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

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