Cytotoxic CD4 T Cells: Differentiation, Function, and Application to Dengue Virus Infection

Abstract

Dengue virus (DENV) has spread through most tropical and subtropical areas of the world and represents a serious public health problem. The control of DENV infection has not yet been fully successful due to lack of effective therapeutics or vaccines. Nevertheless, a better understanding of the immune responses against DENV infection may reveal new strategies for eliciting and improving antiviral immunity. T cells provide protective immunity against various viral infections by generating effector cells that cooperate to eliminate antigens and memory cells that can survive for long periods with enhanced abilities to control recurring pathogens. Following activation, CD8 T cells can migrate to sites of infection and kill infected cells, whereas CD4 T cells contribute to the elimination of pathogens by trafficking to infected tissues and providing help to innate immune responses, B cells, as well as CD8 T cells. However, it is now evident that CD4 T cells can also perform cytotoxic functions and induce the apoptosis of target cells. Importantly, accumulating studies demonstrate that cytotoxic CD4 T cells develop following DENV infections and may play a crucial role in protecting the host from severe dengue disease. We review our current understanding of the differentiation and function of cytotoxic CD4 T cells, with a focus on DENV infection, and discuss the potential of harnessing these cells for the prevention and treatment of DENV infection and disease.

Keywords: CD4 T cells; cytotoxicity; dengue virus; protection; vaccines.

Figure 1

Regulation of cytotoxic CD4 T cell differentiation by a network of signaling and transcriptional pathways. ThPOK is essential for the lineage specification and stability of CD4 helper T cells and counteracts Runx3, which coordinate the differentiation of CD8 T cells. Nevertheless, signals mediated by antigens, TGF-β, and retinoic acid (RA) can repress ThPOK expression in CD4 T cells, which results in elevated levels of Runx3. Since ThPOK inhibits Eomes, the suppression of ThPOK may also lead to increased Eomes expression. Furthermore, cytokines such as IL-2 and IFN-α, costimulatory molecules including OX40 and 4-1BB, as well as the transmembrane protein CRTAM can increase the expression and/or activities of Eomes as well as additional transcription factors such as Blimp1 and T-bet, which together with Runx3 direct the differentiation program of cytotoxic CD4 T cells.

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.