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Summary Respiratory syncytial virus (RSV)-specific CD81 T cell responses do not protect against reinfection. Activation of mammalian target of rapamycin (mTOR) impairs memory CD8 1 T cell differentiation. Our hypothesis was that RSV inhibits the formation of CD8 1 T cells memory responses through mTOR activation. To explore this, human and mouse T cells were used. RSV induced mTOR phosphorylation at Ser2448 in CD8 T cells. mTOR activation by RSV was completely inhibited using rapamycin. RSV-infected children presented higher mTOR gene expression on nasal washes comparing to children infected with metapneumovirus and rhinovirus. In addition, RSV-infected infants presented a higher frequency of CD8 1 pmTORser2448 1 T cells in nasal washes compared to RSV-negative infants.Rapamycin treatment increased the frequency of mouse CD8 RSV-M 282-90 pentamer-positive T cells and the frequency of RSV-specific memory T cells precursors. These data demonstrate that RSV is activating mTOR directly in CD8 T cells, indicating a role for mTOR during the course of RSV infection.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1 year. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV‐specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via interleukin (IL) 21 secretion. In this study, we evaluated whether RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL‐21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL‐21/interleukin‐21 receptor (IL‐21R) in Tfh cells and upregulated programmed death‐ligand 1 (PD‐L1) expression in dendritic cells (DCs) and B cells. PD‐L1 blockade during infection recovered IL‐21R expression in Tfh cells and increased the secretion of IL‐21 in a DC‐dependent manner. IL‐21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs in the lung. It also decreased regulatory follicular T cells, and increased Tfh cells, B cells, antibody avidity and neutralization capacity, leading to an overall improved anti‐RSV humoral response in infected mice. Passive immunization with purified immunoglobulin G from IL‐21‐treated RSV‐infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD‐L1 expression on antigen‐presenting cells, highlighting the importance of an IL‐21–PD‐L1 axis for the generation of protective responses to RSV infection.

The generation of memory is a cardinal feature of the adaptive immune response, involving different factors in a complex process of cellular differentiation. This process is essential for protecting the second encounter with pathogens and is the mechanism by which vaccines work. Epigenetic changes play important roles in the regulation of cell differentiation events. There are three types of epigenetic regulation: DNA methylation, histone modification, and microRNA expression. One of these epigenetic changes, DNA methylation, occurs in cytosine residues, mainly in CpG dinucleotides. This brief review aimed to analyse the literature to verify the involvement of DNA methylation during memory T and B cell development. Several studies have highlighted the importance of the DNA methyltransferases, enzymes that catalyse the methylation of DNA, during memory differentiation, maintenance, and function. The methylation profile within different subsets of naïve activated and memory cells could be an interesting tool to help monitor immune memory response.

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