Specific human cytotoxic T cells recognize B-cell lines persistently infected with respiratory syncytial virus.

Bangham, Charles R. M.; McMichael, Andrew J.

doi:10.1073/pnas.83.23.9183

Cited by 71 publications

(41 citation statements)

References 46 publications

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“…Cytotoxicity assays measure CTL responses by CD8 ϩ cells and reflect a more accurate effector function of CMI. However, little data are available on CTL responses in infants during RSV infection (29,30).…”

Section: Discussionmentioning

confidence: 99%

Natural Reinfection with Respiratory Syncytial Virus Does Not Boost Virus-Specific T-Cell Immunity

et al. 2002

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To determine the role of respiratory syncytial virus (RSV)-specific cell-mediated immunity during natural reinfection, we investigated whether RSV-specific T-cell responses protect against reinfection and, subsequently, whether reinfection boosts virusspecific memory. In a cohort of 55 infants who were hospitalized for RSV bronchiolitis, RSV-specific lymphoproliferative responses in the peripheral blood were measured at three time-points: on admission, 4 wk after admission, and 1 y later, after the second winter season. Memory was defined as a stimulation index (SI) Ͼ2. During the second winter season, nasal secretions were collected in every case of a runny nose. Reinfection was diagnosed if immunofluorescence or PCR was positive for RSV. Virus-specific memory was found in one child on admission for primary RSV infection, whereas 4 wk later 44 infants (80%) had memory. Reinfection with RSV was found in 23 infants (43%) during the second winter season. After the second season, memory was found in 20 infants (38%). No differences in SI after the second winter season were found between infants with and without reinfection (2.3 versus 2.1). However, a highly significant correlation was found between SI measured 4 wk after primary RSV infection and SI after the second winter season (r ϭ 0.40, p ϭ 0.001). In conclusion, RSV-specific T-cell responses did not provide protection against reinfection. Moreover, reinfection did not boost RSV-specific T-cell proliferation. To explain both findings, it is hypothesized that RSV-specific T cells fail to expand in vivo upon reinfection. RSV is one of the most important respiratory pathogens in infancy causing the majority of lower respiratory tract infections during the winter season. Hospitalization rates for RSV illness are 1-30 cases per 1000 infants Ͻ1 y of age (1-3). In hospitalized infants with RSV bronchiolitis, mechanical ventilation is required in 7-21% of cases (4 -6). Mortality in RSV-infected infants with lower respiratory tract symptoms is Ͻ1% (7).Reinfection with RSV occurs frequently and usually has a mild character with symptoms of uncomplicated upper respiratory tract infection (8). Neutralizing antibodies induced by primary RSV infection appear to provide only partial protection for a limited period of time, which does probably not last until the subsequent RSV season (8,9). Evidence that intact cell-mediated responses play a role in clearance of the virus and protection against reinfection was derived from animal studies (10). In humans, little information is available on the role of virus-specific CMI induced during primary infection in the protection against reinfection with RSV.Currently, no vaccine for RSV is available. In the 1960s, a formalin-inactivated vaccine was used in infants (11). No protection against naturally acquired RSV was observed. In contrast, enhanced disease and increased mortality were observed during RSV infection after vaccination. CMI has been implicated in the pathogenesis of this phenomenon (12

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Section: Discussionmentioning

confidence: 99%

Natural Reinfection with Respiratory Syncytial Virus Does Not Boost Virus-Specific T-Cell Immunity

et al. 2002

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“…HRSV Infection of the Human JY Epstein-Barr-Transformed Cell Line-JY cells (HLA-DRB1*0404, -DRB4*0101, -DRB1*1301, and -DRB3*0101 or -DRB3*0201) were incubated with the HRSV Long strain and assayed at different time points for the presence of HRSV antigens using flow cytometry, as previously described, with either Epstein-Barr-transformed human B-cell lines (11) or other cell lines (12), to obtain a persistently infected JY-cell line that synthesized HRSV viral proteins and secreted infectious virus several months after infection (13).…”

Section: Methodsmentioning

confidence: 99%

Structural and Nonstructural Viral Proteins Are Targets of T-Helper Immune Response against Human Respiratory Syncytial Virus

Lorente

Barriga

Barnea

et al. 2016

Molecular & Cellular Proteomics

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Newly synthesized HLA class II molecules from antigenpresenting cells associate with the class II invariant chain (Ii). These complexes are eventually transported to specialized endosomal compartments where the Ii is progressively proteolyzed until only a fragment known as the class-II-associated invariant chain peptide (CLIP) 1 remains bound in the HLA class II peptide-binding groove to prevent it from binding to cellular peptides or pathogen peptides from the endogenous pathways. Interaction of HLA class II/CLIP complexes with the accessory molecule HLA-DM induces conformational changes in HLA class II molecules. Additionally, the release of CLIP results in peptide-receptive HLA class II molecules. This compartment fuses with a late endosome that contains exogenous proteins and/or viral particles that were previously endocytosed. Thus, the binding of antigen-processed peptides of different lengths, but with specific major anchor residues that can be deeply accommodated into specific pockets of the antigen recognition site of the HLA class II molecule, produces the stabilization of the nascent HLA class II/peptide complexes and allows for their subsequent transport to the cell membrane where they are exposed for T cell recognition (1).Human respiratory syncytial virus (HRSV) (2), which is included in the Paramyxoviridae family of the Mononegavirales order, presents a single-stranded, negative-sense RNA genome that codes for 11 proteins. This enveloped pneumovirus causes repeat infections throughout life, and although in healthy adults mild infections are generally reported, the health risk in infected pediatric, immunocompromised, and elderly populations is much more serious. HRSV is the main cause of hospitalization for bronchiolitis and pneumonia in infants and young children, with infection rates approaching 70% in the first year of life (3). Worldwide, at least 3.4 million hospital admissions each year are associated with severe HRSV disease, and the global mortality rate was estimated at more than a quarter of a million deaths in 2010, mainly in developing countries (4).The immune mechanisms involved in HRSV disease and protection are not completely understood; however, it is known that infection induces mucosal and systemic humoral and cellular responses. Studies evaluating CD4 ϩ and CD8 ϩ T-lymphocyte subsets individually or together showed that both effector MHC class I-and helper MHC class II-restricted cellular responses are particularly important in clearing infections (5). Previously, some HRSV epitopes that are restricted by different HLA class II molecules were identified using T cells from seropositive individuals (6 -9). However, these experiments were performed with overlapping synthetic pepFrom the ‡Centro Nacional

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“…In BALB/c mice, previous studies have demonstrated that virus-specific CTL are sufficient for effective virus clearance during primary infection (3,4) and matrix 2 (M2), fusion (F), and N proteins of RSV are major target Ags for MHC class I-restricted CTL activity (5)(6)(7). In humans, RSV-specific CTL develop in response to natural infection (8,9), and F and N proteins are reported to be primary targets for MHC class I-restricted CTL responses (6,10,11). In addition to the role in the clearance of virus, it has been suggested that CD8 ϩ T cells play an important role in the regulation of the differentiation and activation of Th2 CD4 ϩ T cells, which mediate the enhanced lung pathology by the recruitment of eosinophils into the lungs during RSV infection (12,13).…”

Section: R Espiratory Syncytial Virus (Rsv)mentioning

confidence: 99%

Visualization and Characterization of Respiratory Syncytial Virus F-Specific CD8+ T Cells During Experimental Virus Infection

Chang

Srikiatkhachorn

Braciale

2001

The Journal of Immunology

108

130

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CTL play a major role in the clearance of respiratory syncytial virus (RSV) during experimental pulmonary infection. The fusion (F) glycoprotein of RSV is a protective Ag that elicits CTL and Ab response against RSV infection in BALB/c mice. We used the strategy of screening a panel of overlapping synthetic peptides corresponding to the RSV F protein and identified an immunodominant H-2Kd-restricted epitope (F85–93; KYKNAVTEL) recognized by CD8+ T cells from BALB/c mice. We enumerated the F-specific CD8+ T cell response in the lungs of infected mice by flow cytometry using tetramer staining and intracellular cytokine synthesis. During primary infection, F85–93-specific effector CD8+ T cells constitute ∼4.8% of pulmonary CD8+ T cells at the peak of the primary response (day 8), whereas matrix 2-specific CD8+ T cells constituted ∼50% of the responding CD8+ T cell population in the lungs. When RSV F-immune mice undergo a challenge RSV infection, the F-specific CD8+ T cell response is accelerated and dominates, whereas the primary response to the matrix 2 epitope in the lungs is reduced by ∼20-fold. In addition, we found that activated F-specific effector CD8+ T cells isolated from the lungs of RSV-infected mice exhibited a lower than expected frequency of IFN-γ-producing CD8+ T cells and were significantly impaired in ex vivo cytolytic activity compared with competent F-specific effector CD8+ T cells generated in vitro. The significance of these results for the regulation of the CD8+ T cell response to RSV is discussed.

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Specific human cytotoxic T cells recognize B-cell lines persistently infected with respiratory syncytial virus.

Cited by 71 publications

References 46 publications

Natural Reinfection with Respiratory Syncytial Virus Does Not Boost Virus-Specific T-Cell Immunity

Natural Reinfection with Respiratory Syncytial Virus Does Not Boost Virus-Specific T-Cell Immunity

Structural and Nonstructural Viral Proteins Are Targets of T-Helper Immune Response against Human Respiratory Syncytial Virus

Visualization and Characterization of Respiratory Syncytial Virus F-Specific CD8+ T Cells During Experimental Virus Infection

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