Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

Abstract

Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection in a high percentage of the population worldwide. CMV induces the strongest and most durable CD8⁺ T cell response known in human clinical medicine. Due to its unique properties, the virus represents a promising candidate vaccine vector for the induction of persistent cellular immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) expressing an MHC-I restricted epitope from influenza A virus (IAV) H1N1 within the immediate early 2 (ie2) gene. Only mice that were immunized intranasally (i.n.) were capable of controlling IAV infection, despite the greater potency of the intraperitoneally (i.p.) vaccination in inducing a systemic IAV-specific CD8⁺ T cell response. The protective capacity of the i.n. immunization was associated with its ability to induce IAV-specific tissue-resident memory CD8⁺ T (CD8T_RM) cells in the lungs. Our data demonstrate that the protective effect exerted by the i.n. immunization was critically mediated by antigen-specific CD8⁺ T cells. CD8T_RM cells promoted the induction of IFNγ and chemokines that facilitate the recruitment of antigen-specific CD8⁺ T cells to the lungs. Overall, our results showed that locally applied MCMV vectors could induce mucosal immunity at sites of entry, providing superior immune protection against respiratory infections. Vaccines against influenza typically induce immune responses based on antibodies, small molecules that recognize the virus particles outside of cells and neutralize them before they infect a cell. However, influenza rapidly evolves, escaping immune recognition, and the fastest evolution is seen in the part of the virus that is recognized by antibodies. Therefore, every year we are confronted with new flu strains that are not recognized by our antibodies against the strains from previous years. The other branch of the immune system is made of killer T cells, which recognize infected cells and target them for killing. Influenza does not rapidly evolve to escape T cell killing; thus, vaccines inducing T-cell responses to influenza might provide long-term protection. We introduced an antigen from influenza into the murine cytomegalovirus (MCMV) and used it as a vaccine vector inducing killer T-cell responses of unparalleled strength. Our vector controls influenza replication and provides relief to infected mice, but only if we administered it through the nose, to activate killer T cells that will persist in the lungs close to the airways. Therefore, our data show that the subset of lung-resident killer T cells is sufficient to protect against influenza.