Abstract
Respiratory syncytial virus (RSV) is the most common cause of hospitalization due to lower respiratory tract infection in infants. While the majority of infants experience symptoms of a normal common cold, three percent of the entire birth cohort requires hospitalization due to severity of symptoms. While both CD4+ T cells
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and CD8+ T cells play an important role in clearing RSV infections, both T cell subsets might also augment disease. In a vaccine trial in the 1960s infants were vaccinated with formalin inactivated RSV. Upon natural infection, vaccinated infants experienced more severe disease leading to 80% hospitalisation and some deaths. This lead to a major setback in vaccine development. For the development of a safe vaccine in the future, more insight in this immune enhanced pathology is needed. Therefore, we investigated the role of both CD4+ T cells and CD8+ T cells during human RSV infections. To be able to study RSV specific responses, we identified new CD4+ T cell and CD8+ T cell epitopes. We found that infants with severe primary RSV infection elicited a mixed Th1-Th2 CD4+ T cell response against two overlapping peptides derived from the viral G protein that were presented by HLA-DPB1*0401 and *0402. The newly identified CD8+ T cell epitopes were used to study the RSV specific CD8+ T cell responses during severe primary RSV infections in bronchoalveolar lavage (BAL) and PBMC of infants. Highly activated RSV specific T cells were identified in BAL samples of 95% of infants, with an average of 0.58% of CD8+ T cells. There was no correlation between the percentage of RSV specific CD8+ T cells and time of sampling or disease severity. However, in PBMC the highest percentage of activated virus specific CD8+ T cells correlated with disease severity. Next we investigated CD8+ T cell dynamics upon secondary respiratory infections. Early during heterologous infections, RSV and influenzavirus specific CD8+ T cells disappeared from blood, to re-appear several days later. To investigate whether these cells were recruited to the lungs we followed the CD8+ T cell dynamics in tracheal aspirate of children with a tracheostoma. Indeed, we showed the influx of a small percentage of RSV or influenzavirus specific cells upon heterologous infections of the respiratory tract, that disappeared within 14 days. Upon infection with homologous virus (RSV), both duration and magnitude of the RSV-specific response exceeded the bystander RSV-specific responses. During secondary RSV infection RSV specific CD8+ T cells peaked after two weeks, with an average of 1.3% of CD8+ T cells. Finally, we investigated the RSV specific CD8+ T cell responses in the elderly. While influenzavirus specific memory CD8+ T cells remain at stable levels throughout age, RSV specific CD8+ T cell numbers gradually decline, and were undetectable without in vitro expansion in PBMC of elderly people. In conclusion, the ability to study RSV specific T cell responses in different patient groups and healthy individuals provided important insight in the presence of memory and effector T cell types during health and disease, which might contribute to development of vaccines.
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