Inflammation regulates the differentiation of CD4 T cells with cytolytic potential (P6088)

Abstract

Abstract Cytolytic CD4 T cells have been described during viral infections; however, the factors necessary for driving the cytolytic phenotype have not been identified. Our data indicate IL-2 regulates granzyme B (GrB) expression in CD4 T cells but IL-12 and IL-6 enhance GrB expression and promote perforin-mediated cytotoxicity in CD4 effectors. To further dissect the role of inflammation in CD4 CTL generation in vivo, we used an adoptive transfer system and infection with highly pathogenic influenza virus PR8, compared to x31 with lower pathogenicity. At relatively low doses (1000 EID50), Ova specific CD4 cells expressing GrB differentiated in PR8/Ova infected mice but not x31/Ova infected mice. This pattern was observed at 10-fold higher dose of x31/Ova compared to PR8/Ova. In addition, CD4 T cell influx to the lung and IFN-γ expression was increased in mice infected with PR8/Ova compared to x31/Ova. Importantly, these differences were seen in the endogenous, polyclonal population of CD4 T cells. Inflammatory mediators including IL-6, CXCL-9, CXCL-10 and MIP1β were 3-5 fold higher in PR8/Ova infected lungs at day 4 post infection compared to x31/Ova infected lungs. Whether these inflammatory cytokines are responsible for inducing CD4 CTL is being investigated. These data suggest that CD4 CTL are induced in vivo by strong inflammatory responses and may provide an extra layer of protection against highly pathogenic IAV infection.