Influenza‐specific CD4 effectors utilize perforin for cytolytic function and protection in vivo

Abstract

Our laboratory previously demonstrated that CD4 effectors generated in vitro could promote survival against a highly pathogenic influenza virus via an antibody independent mechanism that involved class II restricted, perforin‐mediated cytotoxicity. The present study set out to determine whether influenza specific CD4 cells could acquire cytolytic activity in vivo and the role of perforin in CD4 T cell responses to influenza. Surprisingly, influenza PR8 infection induced a population of cytolytic CD4 effectors that resided in the lung, but not the draining LN. These cells expressed granzyme B (GrB), were CD62L low and required perforin to lyse peptide pulsed targets. CD4 cells isolated from the lungs of infected mice were able to confer protection to a lethal dose of influenza PR8; however, cells isolated from the DLN were more effective at promoting survival. This was attributed to the ability of DLN CD4 cells to further differentiate to cytolytic GrB+ cells upon re‐infection. Lethally infected mice given flu specific CD4 cells deficient in perforin showed greater weight loss and slower time to recovery compared to mice given wildtype flu specific CD4 cells, suggesting that CD4 mediated cytolytic activity may play a role in protection to lethal infection. Studies are underway to determine whether perforin is required for B cell independent protection mediated by CD4 effectors in B cell deficient mice. Supported by PHS grants AI‐0672, AG‐21600 and the Trudeau Institute.