Activation of Lymphocytes Induced by Bronchial Epithelial Cells with Prolonged RSV Infection

Abstract

Respiratory syncytial virus (RSV) preferentially infects airway epithelial cells,which might be responsible for susceptibility to asthma; however, the underlying mechanism is not clear. This study determined the activation of lymphocytes and drift of helper T (Th) subsets induced by RSV-infected human bronchial epithelial cells (HBECs) in vitro. HBECs had prolonged infection with RSV, and lymphocytes isolated from human peripheral blood were co-cultured with RSV-infected HBECs. Four groups were established, as follows: lymphocytes (group L); lymphocytes infected with RSV (group RL); co-culture of lymphocytes with non-infected HBECs (group HL); and co-culture of lymphocytes with infected HBECs (group HRL). After co-culture with HBECs for 24 hours, lymphocytes were collected and the following were determined in the 4 groups: cell cycle status; apoptosis rate; and concentrations of IL-4, IFN-γ, and IL-17 in the supernatants. Cell cycle analysis for lymphocytes showed a significant increase in S phase cells, a decrease in G1 phase cells, and a higher apoptosis rate in group HRL compared with the other three groups. In group HRL, the levels of IL-4, IFN-γ, and IL-17 in supernatants were also higher than the other three groups. For further study, lymphocytes were individually treated with supernatants from non-infected and RSV-infected HBECs for 24 h. We showed that supernatants from RSV-infected HBECs induced the differentiation of Th2 and Th17 subsets, and suppressed the differentiation of Treg subsets. Our results showed that HBECs with prolonged RSV infection can induce lymphocyte proliferation and apoptosis, and enhance the release of cytokines by lymphocytes. Moreover, subset drift might be caused by RSV-infected HBECs.

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…92 Stimulation of T cells with hRSV-infected human bronchial epithelial cells (HBEC) induced the production of IFN-g, IL-4, and IL-17, suggesting that hRSV can activate these three T H cell subsets. 93 Consistent with the latter, stimulation of PBMC from healthy donors with hRSV infected A549 cells induced the production of IFN-g and IL-4. 94 In other studies, the concentration of IL-17 in nasopharyngeal aspirates of children during hRSV infection was higher at the moment of discharge of the hospital.…”

“…130 Moreover, hRSV-infected DCs are unable to activate na€ ıve CD4 C T cells in vitro probably due to the impairment of the immunological synapse assembly by the hRSV N protein expressed at the host cell membrane (Fig. 2, upper left box), rendering T cells unresponsive to subsequent TCR engagement.. 27,93,131 Specifically, the Golgi apparatus polarization within T cells, an event needed for a proper immunological synapse assembly, is barely detectable in T cells co-cultured with hRSVinfected DCs, in contrast to T cells co-cultured with mock-inoculated DCs. 27 Moreover, impairing this signaling event significantly decreases tyrosine phosphorylation of TCR-associated CD3z-chain tyrosine-based activation motifs (ITAM) by LCK, 132 in na€ ıve T cells stimulated with a cognate antigen.…”

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

“…RSV-infected human bronchial epithelial cells enhance the expression of the inflammatory transcription factor NF-κB and release multiple chemokines (intercellular adhesion molecule-1, IL-6, IL-8, and RANTES) leading to recruitment and differentiation of neutrophils, eosinophils and T helper cells. Differentiation into Th17 cells is stimulated, while the differentiation into Treg cells is inhibited (84). Moreover, RSV is able to induce a Th2-like effector profile of the Treg cells by inducing GATA-3.…”

CX3CR1 is an important surface molecule for respiratory syncytial virus infection in human airway epithelial cells

“…It has been shown that RSV infection of human airway epithelial cells (HAECs) induces strong cytokine/ chemokine responses, including production of IL-1b, IL-6, IL-8, IP-10, macrophage inflammatory protein (MIP)-1a, monocyte chemotactic protein (MCP)-1 and RANTES (regulated on activation normal T-cell expressed and secreted) (Fonceca et al, 2012;Ioannidis et al, 2012;Olszewska-Pazdrak et al, 1998;Oshansky et al, 2010;Tristram et al, 1998;Villenave et al, 2011), and these cytokines and released viral proteins influence the host immune response to RSV (Chirkova et al, 2013;Ioannidis et al, 2012;McNamara et al, 2013;Qin et al, 2011). RSV G protein has been shown to impair innate and memory immune responses, such as suppressing production of IFN-b (Shingai et al, 2008), lymphoproliferation of T-cells (Ray et al, 2001), and responsiveness of monocytes/macrophages and dendritic cells (Johnson et al, 2012;Polack et al, 2005).…”