Dengue-specific CD8+ T cell subsets display specialized transcriptomic and TCR profiles

Accumulating evidence demonstrates that CD8+ T cells contribute to protection from severe dengue virus (DENV) disease and vaccine efficacy. Nevertheless, molecular programs associated with DENV-specific CD8+ T cell subsets have not been defined. Here, we studied the transcriptomic profiles of human DENV-specific CD8+ T cells isolated after stimulation with DENV epitopes from donors who had been infected with DENV multiple times and would therefore be expected to have significant levels of adaptive immunity. We found that DENV-specific CD8+ T cells mainly consisted of effector memory subsets, namely CD45RA-CCR7- effector memory (Tem) and CD45RA+CCR7- effector memory re-expressing CD45RA (Temra) cells, which enacted specific gene expression profiles upon stimulation with cognate antigens. DENV-specific CD8+ T cell subsets in general, and Temra cells in particular, were fully activated and polyfunctional, yet associated with relatively narrow transcriptional responses. Furthermore, we found that DENV-specific CD8+ Tem and Temra cells showed some unique T cell receptor features in terms of overlap and variable (V) gene usage. This study provides a transcriptomic definition of DENV-specific activated human CD8+ T cell subsets and defines a benchmark profile that vaccine-specific responses could aim to reproduce.