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

SIMPLE SUMMARY: The Epstein–Barr virus (EBV) is a γ-herpes virus that primarily infects human B cells, and more than 90% of adults have experienced infection. EBV(+) B cells express several viral proteins, transmitting signals important for the transformation and tumorigenesis of the infected B cells. Immune surveillance by the host immune system is important to suppress such abnormal expansion of EBV-infected B cells. Here we found that both CD4(+) T cells and CD8(+) T cells show similar gene expression patterns relating to cytotoxicity towards EBV-infected B cells. EBV-specific cytotoxic CD4(+) T cells markedly expressed T-bet, Granzyme B, and Perforin alongside killing activity, which could reflect mechanisms shared with cytotoxic CD8(+) T cells. Our findings support the concept that, upon EBV and perhaps other viral infections, T cells of different subsets can be drawn into common pathways mediating immune surveillance through cytotoxicity. ABSTRACT: 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.