Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity (VIR1P.1126)

Abstract

Abstract The frequency of infection with any of the four dengue viruses (DENV 1-4) has increased dramatically in the last few decades, and the lack of a vaccine has led to significant morbidity and mortality worldwide. Dengue virus is a pathogen with unusual pathogenesis and protective immunity is poorly understood. While DENV-specific CD8+ T cell responses have been extensively studied, the breadth and specificity of CD4+ T cell responses remains to be defined. In effort to define HLA-restricted CD4+ T cell responses resulting from natural infection with DENV, we endeavored to map T cell responses in individuals from Sri Lanka where DENV is hyper-epidemic. Characterization of the phenotype of the responding CD4+ T cells revealed a DENV specific T cell subset that is specifically expanded in donors carrying an allele associated with protection from severe DENV disease. Analysis of DENV-specific CD4+ T cells revealed that the virus specific cells were highly polarized, with a strong bias towards a CX3CR1+ Eomes+ Tbet+ perforin+ granzyme B+ CD45RA+ CD4 CTL phenotype. Importantly, frequency of these cells correlated with a protective HLA DR allele and we demonstrate these cells have direct DENV-specific cytolytic activity. We speculate that cytotoxic dengue-specific CD4+ T cells may play a role in control of dengue infection in vivo, and this immune correlate may be a key target for dengue virus vaccine development.