Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response

We recently demonstrated that the respiratory syncytial virus (rsv) ns1 protein,an antagonist of host type i interferon (ifn-i) production and signaling,has a suppressive effect on the maturation of human dendritic cells (dc) that was only partly dependent on released ifn-i. here we investigated whether ns1 affects the ability of dc to activate cd8+ and cd4+ t cells. human dc were infected with rsv deletion mutants lacking the ns1 and/or ns2 genes and assayed for the ability to activate autologous t cells in vitro,which were analyzed by multi-color flow cytometry. deletion of the ns1,but not ns2,protein resulted in three major effects: (i) an increased activation and proliferation of cd8+ t cells that express cd103,a tissue homing integrin that directs cd8+ t cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of th17 cells,which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of il-4-producing cd4+ t cells - which are associated with enhanced rsv disease - and reduced proliferation of total cd4+ t cells. except for total cd4+ t cell proliferation,none of the t cell effects appeared to be due to increased ifn-i signaling. in the infected dc,deletion of the ns1 and ns2 genes strongly up-regulated the expression of cytokines and other molecules involved in dc maturation. this was partly ifn-i-independent,and thus might account for the t cell effects. taken together,these data demonstrate that the ns1 protein suppresses proliferation and activation of two of the protective cell populations (cd103+ cd8+ t cells and th17 cells),and promotes proliferation and activation of th2 cells that can enhance rsv disease.