Concomitant Cytotoxic Effector Differentiation of CD4⁺ and CD8⁺ T Cells in Response to EBV-Infected B Cells

Most people infected by EBV acquire specific immunity, which then controls latent infection throughout their life. Immune surveillance of EBV-infected cells by cytotoxic CD4⁺ T cells has been recognized; however, the molecular mechanism of generating cytotoxic effector T cells of the CD4 subset remains poorly understood. Here we compared phenotypic features and the transcriptome of EBV-specific effector-memory CD4⁺ T cells and CD8⁺ T cells in mice and found that both T cell types show cytotoxicity and, to our surprise, widely similar gene expression patterns relating to cytotoxicity. Similar to cytotoxic CD8⁺ T cells, EBV-specific cytotoxic CD4⁺ T cells from human peripheral blood expressed T-bet, Granzyme B, and Perforin and upregulated the degranulation marker, CD107a, immediately after restimulation. Furthermore, T-bet expression in cytotoxic CD4⁺ T cells was highly correlated with Granzyme B and Perforin expression at the protein level. Thus, differentiation of EBV-specific cytotoxic CD4⁺ T cells is possibly controlled by mechanisms shared by cytotoxic CD8⁺ T cells. T-bet-mediated transcriptional regulation may explain the similarity of cytotoxic effector differentiation between CD4⁺ T cells and CD8⁺ T cells, implicating that this differentiation pathway may be directed by environmental input rather than T cell subset.