DENV-specific CD4 T-cells dominantly recognize capsid-derived epitopes and display a cytotoxic phenotype

Abstract

While DENV-specific CD8⁺ T cell responses have been extensively studied, the breadth and specificity of CD4⁺ T cell responses remains to be defined. Here we map CD4 T cell responses in individuals previously exposed to dengue virus. To identify HLA class II candidates, we utilized a panel of algorithms for sixteen common HLA DR molecules representative of the main DR super types. These efforts led to the identification of 365 epitopes derived from all 10 DENV proteins. In contrast to CD8 T cell targets, the highest number of epitopes was associated with the structural capsid protein (C), followed by nonstructural NS3, NS2A, NS5 and envelope proteins (E). Phenotyping of the responding CD4⁺ T cell subset revealed a DENV specific T cell subset, specifically expanded in donors carrying an allele associated with protection from severe disease and which is absent in DENV negative donors. This subset of DENV specific CD4 T cells is associated with markers of cytotoxic T cells such as Granzyme B, Perforin, CD107a, T bet, Eomes and co-expression of CD8α. We are currently establishing specific gene expression signatures associated with these characteristic phenotypes, as a function of different HLA restricting alleles. Detailed knowledge of phenotype and function of DENV-specific T cells will aid in the establishment of correlates of protection against severe disease.