Cytolytic CD4(+) T cells in viral immunity

Abstract

It is generally believed that the role of CD4(+) T cells is to coordinate the different arms of the adaptive immune system to shape an effective response against a pathogen and regulate nonessential or deleterious activities. However, a growing body of evidence suggests that effector CD4(+) T cells can directly display potent antiviral activity themselves. The presence of cytolytic CD4(+) T cells has been demonstrated in the immune response to numerous viral infections in both humans and in animal models and it is likely that they play a critical role in the control of viral replication in vivo. This article describes the current research on virus-specific cytolytic CD4(+) T cells, with a focus on HIV-1 infection and the implications that this immune response has for vaccine design.

Figure 1. Cytolytic CD4⁺ T-cell lineage

Cytolytic CD4⁺ T cells can resemble both Th1 cells and regulatory T cells. However, it is unknown whether a cytolytic phenotype represents a highly differentiated effector state that can be assumed by different CD4⁺ subsets, or if cytolytic CD4⁺ T cells represent an entirely unique CD4⁺ T-cell lineage instead (dotted line). Although acquisition of cytolytic potential seems to be at least partially dependent on IL-2, the underlying transcriptional pathways have not been determined. Based on the similarities of cytolytic CD4⁺ T cells to regulatory T cells, Th1 and CD8⁺ T cells, it is possible that FoxP3, Tbet, Eomes and Runx3 may play important roles in inducing this activity. Similarly, it possible that γ-chain cytokines such as IL-15 and IL-21 may participate in the generation of cytolytic CD4⁺ T-cell responses.

Figure 2. Hypothetical model for dual-pathway killing by cytolytic CD4⁺ and CD8⁺ T cells

Certain viruses like HIV-1 are able to establish infection within cells that express both MHC class I and class II molecules, such as antigen-presenting cells. Antigen presentation by these molecules is critical for recognition by circulating cytolytic CD4⁺ and CD8⁺ T cells. Even if the virus were to inhibit recognition through one pathway – for instance by downregulating MHC class I molecules or via the acquisition of escape mutations – effective recognition and lysis of the infected cell could still be achieved through the other pathway.