The conservation of T cell epitopes in human influenza A virus has prompted the development of T cell-inducing influenza vaccines. However, the selection pressure mediated by memory CD8 T cells upon influenza virus has not been directly measured. Using a droplet digital PCR technique to distinguish wild-type and an epitope-mutant PR8 influenza viruses in vivo , this study quantifies the viral replicative fitness of a CD8 T cell-escaping mutation in the immunodominant influenza NP 366-374 epitope in C57BL/6 (B6) mice under different settings of cellular immunity. Although this mutation does not result in a viral fitness defect in vitro or during the early stages of in vivo infection in naïve B6 mice, it does confer a moderate but consistent advantage to the mutant virus following heterosubtypic challenge of HKx31-immunized mice. In addition, this advantage was maintained under increased MHC diversity but became more substantial when the breadth of epitope recognition is limited. Finally, we showed that lung-resident, but not circulating, memory CD8 T cells are the primary source of cellular immune pressure early during infection, prior to the induction of a secondary effector T cell response. Integrating the data with an established modeling framework, we show that the relatively modest immune pressure mediated by memory CD8 T cells is one of the important factors responsible for the conservation of CD8 T cell epitopes in influenza A viruses that circulate among humans. Thus, a T cell-inducing vaccine that generates lung-resident memory CD8 T cells covering a sufficient breadth of epitopes may transiently protect against severe pathology without driving the virus to rapidly evolve and escape.
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