RvD1 treatment during primary infection modulates memory response increasing viral load during respiratory viral reinfection.

Resolvin D1 (RvD1), which is biosynthesized from essential long-chain fatty acids, is involved in anti-inflammatory activity and modulation of T cell response. Memory CD8+ T cells are important for controlling tumor growth and viral infections. Exacerbated inflammation has been described as impairing memory CD8+ T cell differentiation. This study aimed to verify the effects of RvD1 on memory CD8+ T cells in vitro and in vivo in a respiratory virus infection model. Peripheral blood mononuclear cells were treated at different time points with RvD1 and stimulated with anti-CD3/anti-CD28 antibodies. Pre-treatment with RvD1 increases the expansion of memory CD8+ T cells. The IL-12 level, a cytokine described to control memory CD8+ T cells, was reduced with RvD1 pre-treatment. When the mTOR axis was inhibited, the IL-12 levels were restored. In a respiratory virus infection model, Balb/c mice were treated with RvD1 before infection or after 7 days after infection. RvD1 treatment after infection increased the frequency of memory CD8+ T cells in the lung expressing II4, II10, and Ifng. During reinfection, RvD1-treated and RSV-infected mice present a high viral load in the lung and lower antibody response in the serum. Our results show that RvD1 modulates the expansion and phenotype of memory CD8+ T cells but contributed to a non-protective response after RSV reinfection.

Respiratory syncytial virus reduces STAT3 phosphorylation in human memory CD8 T cells stimulated with IL-21.

Respiratory syncytial virus (RSV) is a common cause of childhood lower respiratory tract infections. The recent failure of a vaccine candidate based on recombinant F protein underlines the urgent need to better understand the protective human memory immune response against RSV. Signal transducer and activator of transcription 3 (STAT3) protein is a transcription factor that promotes the maturation of the memory CD8 T cell response in cooperation with IL-10 and IL-21. However, the role of STAT3 in the memory CD8 T cell response during RSV infection remains to be elucidated. We found that in infants with bronchiolitis infected with RSV, the expression of STAT3 detected in nasal washes is reduced when compared to that in infants infected by other viruses. In vitro, RSV impairs STAT3 phosphorylation induced by IL-21 in purified human memory CD8 T cells. In addition, RSV decreases granzyme B production by memory CD8 T cells, reducing its cytotoxic activity against RSV-infected epithelial pulmonary cell lines. Together, these data indicate that RSV modulates the IL-21/STAT3 pathway in human memory CD8 T cells, and this could be a mechanism to be further explored to improve the memory response against the infection.