Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma

Abstract

Immune tolerance is instituted early in life, during which time regulatory T (Treg) cells have an important role. Recurrent infections with respiratory syncytial virus (RSV) in early life increase the risk for asthma in adult life. Repeated infection of infant mice tolerized to ovalbumin (OVA) through their mother’s milk with RSV induced allergic airway disease in response to OVA sensitization and challenge, including airway inflammation, hyper-reactivity and higher OVA-specific IgE, as compared to uninfected tolerized control mice. Virus infection induced GATA-3 expression and T helper type 2 (TH2) cytokine production in forkhead box P3 (FOXP3)+ Treg cells and compromised the suppressive function of pulmonary Treg cells in a manner that was dependent on interleukin-4 receptor α (IL-4Rα) expression in the host. Thus, by promoting a TH2-type inflammatory response in the lung, RSV induced a TH2-like effector phenotype in Treg cells and attenuated tolerance to an unrelated antigen (allergen). Our findings highlight a mechanism by which viral infection targets a host-protective mechanism in early life and increases susceptibility to allergic disease.

Maternal inflammation modulates infant immune response patterns to viral lung challenge in a murine model

“…We also determined pronounced expression of FoxP3, the cognate transcription factor for Treg cells, in lung CD4 cells of both neonates and weanling mice exposed to maternal LPS. Interestingly, increased numbers of lung Treg cells with impaired suppressor function have been reported in weanling mice with exacerbated inflammation in recurrent RSV (21). Although beyond the scope of the present studies, the effect of maternal inflammation on postnatal Treg function would be important to determine in the context of subsequent infection and is a current focus of investigation.…”

The role of Th17 and Treg responses in the pathogenesis of RSV infection

“…Moreover, RSV is able to induce a Th2-like effector profile of the Treg cells by inducing GATA-3. This results in the loss of the Treg cell's normal suppressive function and causes allergic airway disease (85). The exact mechanisms by which RSV exerts its effect on T-cell differentiation is yet to be clarified.…”

Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells

“…+ CD25 + Tregs, as a distinct T cell subset, had an important role in pulmonary inflammatory disease including ALI (53)(54)(55). For example, one group reported that intrapulmonary delivery of human umbilical cord mesenchymal stem cells could attenuate the development of ALI through Treg (56).…”