Respiratory syncytial virus impairs T cell activation by preventing synapse assembly with dendritic cells

Abstract

Respiratory syncytial virus (RSV) infection isimmunological synapse ͉ virus evasion ͉ virulence mechanism ͉ adaptive immunity R espiratory syncytial virus (RSV) is the worldwide leading cause of infant hospitalization related to airway diseases. RSV infects Ͼ70% of children in the first year of life and by age 2, almost 100% of children have been infected at least once with this virus (1, 2). In addition, RSV reinfection is extremely frequent, suggesting that naturally acquired adaptive immunity to RSV is either inefficient or transient (2-4). It is thought that clearance of RSV would require the induction of a balanced Th1/Th2 adaptive immune response capable of inducing the production of neutralizing antibodies and IFN-␥-secreting cytotoxic CD8 ϩ T cells (CTLs) (5, 6). However, RSV-specific T cell responses generally fail to efficiently clear infection (7-9). Although functional RSV-specific memory CTLs and helper T cells can be observed in the blood and spleens of infected hosts, these cells show impaired effector function in infected lung tissues (10)(11)(12)(13)(14).Dendritic cells (DCs) are ubiquitous professional antigenpresenting cells (APCs) found in lymphoid and nonlymphoid tissues, where they locate strategically to capture antigens and present them to T cells as peptides bound to either MHC class I or II molecules (15, 16). These features render DCs as key components for the initiation and modulation of T cell immunity against pathogens, such as virus. Thus, several virulent microorganisms have developed molecular mechanisms to impair DC function and prevent clearance by adaptive immunity (17-21). RSV infection causes a significant increase in the number of mature DCs in mouse lungs (22,23) and has the capacity to infect and replicate within these cells (24-27), rendering them inefficient at inducing proliferation and IFN-␥ secretion by antigenspecific T cells (24,25). Inhibition of T cell activation by RSV has been suggested to be mediated by soluble molecules secreted by RSV-infected DCs, which reduce their capacity to induce IFN-␥ secretion by T cells (28). Although recent data indicate that RSV-induced secretion of IFN-and -␣ by human DCs can impair T cell activation (29), this phenomenon could also be observed upon T cell culture with RSV particles or cells expressing RSV antigens on their surface (30, 31). However, whether RSV-mediated inhibition applies to cognate pMHC recognition by T cells and the mechanism responsible for this inhibition remain unknown.Here, we have approached these questions by evaluating the effect of RSV infection on the capacity of murine DCs to activate T cells. We observed that DCs are efficiently infected by RSV and, although these cells mature upon infection, they are rendered unable to promote T cell activation in response to cognate-, allo-, and superantigen stimuli. Upon exposure to RSV-infected DCs, T cell proliferation and IL-2 secretion were significantly impaired, and T cells became unresponsive to subsequent stimulation with anti-CD3. Inhibition was not medi...

Potent High-Affinity Antibodies for Treatment and Prophylaxis of Respiratory Syncytial Virus Derived from B Cells of Infected Patients

“…The low frequency of Abs against this functionally critical region has been reported to persist even after specific immunization with peptides from this region (51). Although the mechanism underlying the poor immunogenicity is unclear (17,18), the fact remains that virus strains surviving in Table I). FIGURE 6.…”

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

“…Purification of OT-I and OT-II T cells from total splenocytes was carried out by negative selection using CD8 + or CD4 + T cell isolation kits (Miltenyi Biotec), respectively. T cell activation was determined as IL-2 secretion in the coculture supernatant after incubation for 24 h by ELISA (35). For determination of T cell proliferation, purified OT-I or OT-II T cells were stained with 5 mM CFSE (Invitrogen) in the presence of 5% heat-inactivated FBS for 5 min at room temperature.…”

“…Levels of IL-6, IL-10, and IL-12 released into the culture supernatant of iDCs and mDCs and IL-2 secreted by T cells into the coculture supernatant were quantified by ELISA as previously described (35). Recombinant murine cytokines were used as standards for quantification.…”

Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

“…Furthermore, hRSV infection reduces the capacity of DCs to induce the expansion of antiviral Th1 effector cells (17)(18)(19). It has been shown that hRSV inhibits naïve T-cell priming by preventing the assembly of the immunological synapse (IS) with DCs (20), which is a supramolecular structure required for the activation of T cells by DCs and other antigen-presenting cells (APCs) (21). Nevertheless, the mechanisms responsible for the inhibition of IS assembly by hRSV infection remain unknown.…”