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

• Published in: Immunity, Inflammation and Disease Inflammation and Disease, 2020-03, Vol.8 (1), p.30-39
• Main Authors: Kitcharoensakkul, Maleewan, Bacharier, Leonard B., Yin‐Declue, Huiqing, Boomer, Jonathan S., Sajol, Geneline, Leung, Marilyn K., Wilson, Brad, Schechtman, Kenneth B., Atkinson, John P., Green, Jonathan M., Castro, Mario
• Format: Article
• Language: English
• Subjects: Age; Asthma; Bronchiolitis, Viral - immunology; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Children & youth; Cytokines; Cytokines - metabolism; Emergency medical care; Families & family life; Female; Flow cytometry; Guardians; Humans; Infant; Lymphocytes; Male; Necrosis; Original Research; recurrent wheeze; Respiratory Sounds - etiology; Respiratory syncytial virus; respiratory syncytial virus bronchiolitis; Respiratory Syncytial Virus Infections - complications; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Viruses - isolation & purification; Software; Tregs; tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF
• ISSN: 2050-4527; 2050-4527
• DOI: 10.1002/iid3.281

Background Infants 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. Methods We 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. Results Sixty‐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. Conclusions We 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. Infants with severe respiratory syncytial virus (RSV) bronchiolitis have increased risks of recurrent wheezing and asthma. We demonstrated lower tumor necrosis factor‐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.