Transforming Growth Factor Beta Is a Major Regulator of Human Neonatal Immune Responses following Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality. Previous studies have suggested that T-cell responses may contribute to RSV immunopathology, which could be driven by dendritic cells (DCs). DCs are productively infected by RSV, and during RSV infections, there is an increase of DCs in the lungs with a decrease in the blood. Pediatric populations are particularly susceptible to severe RSV infections; however, DC responses to RSV from pediatric populations have not been examined. In this study, primary isolated DCs from cord blood and adult peripheral blood were compared after RSV infection. Transcriptional profiling and biological network analysis identified transforming growth factor beta (TGF-␤) and associated signaling molecules as differentially regulated in the two age groups. TGF-␤1 was decreased in RSV-infected adult-blood DCs but increased in RSV-infected cord blood DCs. Coculture of adult RSV-infected DCs with autologous T cells induced secretion of gamma interferon (IFN-␥), interleukin 12p70 (IL-12p70), IL-2, and tumor necrosis factor alpha (TNF-␣). Conversely, coculture of cord RSV-infected DCs and autologous T cells induced secretion of IL-4, IL-6, IL-1␤, and IL-17. Addition of purified TGF-␤1 to adult DC-T-cell cocultures reduced secretion of IFN-␥, IL-12p70, IL-2, and TNF-␣, while addition of a TGF-␤ chemical inhibitor to cord DC-T-cell cocultures increased secretion of IL-12p70. These data suggest that TGF-␤ acts as a major regulator of RSV DC-T-cell responses, which could contribute to immunopathology during infancy.Human respiratory syncytial virus (RSV), an enveloped negative-strand RNA virus in the family Paramyxoviridae, is the most common viral cause of severe bronchiolitis and pneumonia in infants and young children (10). RSV mainly infects cells of the nasopharynx and lung but can also be detected in circulating blood mononuclear cells (16). Both adaptive and innate responses play a role in protecting hosts from RSV disease. Antibodies do not appear to play a major role in controlling primary infection (25). However, studies using depletion of B lymphocytes indicate that antibodies are necessary for preventing reinfection, and the level of passively acquired anti-RSV maternal antibodies appears to correlate with de-

Alveolar Macrophages Contribute to the Pathogenesis of Human Metapneumovirus Infection while Protecting against Respiratory Syncytial Virus Infection

“…These cytokines have been shown to be involved in the various aspects of pathogenesis of respiratory diseases and in human natural and experimental RSV infections by regulating lung inflammation, mucus production, oxidative response, airway neutrophilia, AHR, T cell responses, and viral replication (25,(37)(38)(39)(40)(41).…”

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

“…Th17-type immunity can be promoted by a combined exposure to TGF-β and inflammatory cytokines (25), factors also elevated in RSV and following maternal inflammation (4,25). Inflammatory neutrophils, which are prominent in the lungs of LPS-exposed mice, could potentially promote Th17-type immunity through direct interactions with Th17 cells (26).…”

The Innate Immune System of the Perinatal Lung and Responses to Respiratory Syncytial Virus Infection

“…54,134,140 Proliferation and differentiation of CD4þ T cells are blocked by TGF-b, which may be associated with a general dysregulation of Th1/Th2 response in infants. 138 TGF-b also plays a role in immunoglobulin production and class switching. 134 With RSV infection, TGF-b expression is decreased in term lambs.…”

“…RSV-infected DCs co-cultured with T cells of either adults or umbilical cord blood elicited markedly different cytokine profiles, with the primary differences attributed to differences in response to TGF-b. 138 In mice, neonatal lungs have a deficit in conventional and plasmacytoid dendritic cells along with a shift of cytokines and transcription factors toward Th2 responses. 115 Furthermore, infecting neonatal mice with RSV results in enhanced TNF-a initially followed by increased IL-13, mucus hyperproduction, and airway hyperreactivity.…”