Figure 2.

The generation of cytotoxic CD4 T cells following DENV infections. DENV-specific naïve CD4 T cells are activated during primary DENV infection and acquire an effector phenotype and the ability to produce inflammatory cytokines such as IFN-γ. Following reexposure to secondary heterologous infections, DENV-specific CD4 T cells receive repeated antigenic signals and differentiate into cytotoxic CD4 T cells, which display a CD45RA^highCCR7^low Temra phenotype and are characterized by their expression of the chemokine receptor CX3CR1. Cytotoxic CD4 T cells also upregulate the expression of CD8α and CD226, as well as the transcription factors T-bet and Eomes, which may cooperate with additional transcription regulators to induce the production of cytotoxic molecules such as CD107a, perforin, and granzyme B. In addition to recurring antigens, costimulatory molecules, cytokines, and other environmental cues are all likely to modulate the differentiation of cytotoxic CD4 T cells.