Impaired tumor necrosis factor-α secretion by CD4 T cells during respiratory syncytial virus bronchiolitis associated with recurrent wheeze.

Huiqing Yin‐Declue,John P Atkinson,Marilyn K Leung,Maleewan Kitcharoensakkul,Mario Castro,Jonathan S Boomer,Kenneth B Schechtman,Geneline Sajol,Leonard B Bacharier,Jonathan M Green,Brad Wilson

doi:10.1002/iid3.281

Abstract

BackgroundInfants with severe respiratory syncytial virus (RSV) bronchiolitis have an increased risk of recurrent wheezing and asthma. We aimed to evaluate the relationships between regulatory T cell (Treg) percentage and cytokine production of in vitro‐stimulated CD4+ T cells during acute bronchiolitis and the development of recurrent wheezing in the first 3 years of life.MethodsWe obtained peripheral blood from 166 infants hospitalized with their first episode of RSV‐confirmed bronchiolitis. Granzyme B (GZB) expression, and interleukin‐10, interferon‐γ, tumor necrosis factor‐α (TNF‐α), IL‐4, and IL‐5 production by in vitro anti‐CD3/CD28‐ and anti‐CD3/CD46‐activated CD4+ T cells, and percentage of peripheral Treg (CD4+CD25hiFoxp3hi) cells were measured by flow cytometry. Wheezing was assessed every 6 months. Recurrent wheezing was defined as three or more episodes following the initial RSV bronchiolitis.ResultsSixty‐seven percent (n = 111) of children had wheezing after their initial RSV infection, with 30% having recurrent wheezing. The percentage of peripheral Treg (CD4+CD25hiFoxp3hi) cells was not significantly different between the wheezing groups. Decreased TNF‐α production from anti‐CD3/CD28− and anti‐CD3/CD46− activated CD4+ T cells was observed in the recurrent wheezers, compared with nonwheezers (p = .048 and .03, respectively). There were no significant differences in the GZB+ CD4+ T cells and production of other inflammatory cytokines between these groups.ConclusionsWe demonstrated lower TNF‐α production by in vitro stimulated CD4+ T cells during severe RSV bronchiolitis in children that subsequently developed recurrent wheezing, compared with children with no subsequent wheeze. These findings support the role of CD4+ T cell immunity in the development of subsequent wheezing in these children.

Highlights

Respiratory syncytial virus (RSV) bronchiolitis is a common cause of lower respiratory tract infection in infancy
A recent study demonstrated that higher Th2 and Th17 cytokine levels in nasal wash samples obtained during acute respiratory syncytial virus (RSV) bronchiolitis were associated with recurrent wheezing at age one and 2 years.[9]
The purpose of this study was to evaluate a putative relationship between circulating Foxp3+ Tregs and cytokine production of in vitro activated CD4+ T cells in infants with acute severe RSV bronchiolitis and the development of recurrent wheezing in the first 3 years of life

Summary

Introduction

Respiratory syncytial virus (RSV) bronchiolitis is a common cause of lower respiratory tract infection in infancy. Almost all children demonstrate seropositivity to RSV by age 2 years.[1] Severe RSV bronchiolitis is associated with the subsequent development of recurrent wheezing, physician‐diagnosed asthma, and decreased lung function later in life.[2,3]. There appears to be a role of CD4+ T cells in mediating lung inflammation and pathology in RSV‐infected mice.[4,5] Immune dysregulation with an imbalance of Th1 and Th2 responses has been demonstrated in RSV‐ infected mice and children.[6,7,8] A recent study demonstrated that higher Th2 and Th17 cytokine levels in nasal wash samples obtained during acute RSV bronchiolitis were associated with recurrent wheezing at age one and 2 years.[9]. We aimed to evaluate the relationships between regulatory T cell (Treg) percentage and cytokine production of in vitro‐stimulated CD4+ T cells during acute bronchiolitis and the development of recurrent wheezing in the first 3 years of life. Conclusions: We demonstrated lower TNF‐α production by in vitro stimulated CD4+ T cells during severe RSV bronchiolitis in children that subsequently

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