Influenza infection results in local expansion of memory CD8+ T cells with antigen non‐specific phenotype and function

Summary Primary viral infections induce activation of CD8+ T cells responsible for effective resistance. We sought to characterize the nature of the CD8+ T cell expansion observed after primary viral infection with influenza. Infection of naive mice with different strains of influenza resulted in the rapid expansion of memory CD8+ T cells exhibiting a unique bystander phenotype with significant up‐regulation of natural killer group 2D (NKG2D), but not CD25, on the CD44highCD8+ T cells, suggesting an antigen non‐specific phenotype. We further confirmed the non‐specificity of this phenotype on ovalbumin‐specific (OT‐I) CD8+ T cells, which are not specific to influenza. These non‐specific CD8+ T cells also displayed increased lytic capabilities and were observed primarily in the lung. Thus, influenza infection was shown to induce a rapid, antigen non‐specific memory T cell expansion which is restricted to the specific site of inflammation. In contrast, CD8+ T cells of a similar phenotype could be observed in other organs following administration of systemic agonistic anti‐CD40 and interleukin‐2 immunotherapy, demonstrating that bystander expansion in multiple sites is possible depending on whether the nature of activation is either acute or systemic. Finally, intranasal blockade of NKG2D resulted in a significant increase in viral replication early during the course of infection, suggesting that NKG2D is a critical mediator of anti‐influenza responses prior to the initiation of adaptive immunity. These results characterize further the local bystander expansion of tissue‐resident, memory CD8+ T cells which, due to their early induction, may play an important NKG2D‐mediated, antigen non‐specific role during the early stages of viral infection.