Cytotoxic CD4+ T cells in chronic viral infections and cancer

Abstract

CD4⁺ T cells play an important role in immune responses against pathogens and cancer cells. Although their main task is to provide help to other effector immune cells, a growing number of infections and cancer entities have been described in which CD4⁺ T cells exhibit direct effector functions against infected or transformed cells. The most important cell type in this context are cytotoxic CD4⁺ T cells (CD4⁺ CTL). In infectious diseases anti-viral CD4⁺ CTL are mainly found in chronic viral infections. Here, they often compensate for incomplete or exhausted CD8⁺ CTL responses. The induction of CD4⁺ CTL is counter-regulated by Tregs, most likely because they can be dangerous inducers of immunopathology. In viral infections, CD4⁺ CTL often kill via the Fas/FasL pathway, but they can also facilitate the exocytosis pathway of killing. Thus, they are very important effectors to keep persistent virus in check and guarantee host survival. In contrast to viral infections CD4⁺ CTL attracted attention as direct anti-tumor effectors in solid cancers only recently. Anti-tumor CD4⁺ CTL are defined by the expression of cytolytic markers and have been detected within the lymphocyte infiltrates of different human cancers. They kill tumor cells in an antigen-specific MHC class II-restricted manner not only by cytolysis but also by release of IFNγ. Thus, CD4⁺ CTL are interesting tools for cure approaches in chronic viral infections and cancer, but their potential to induce immunopathology has to be carefully taken into consideration.

Keywords: CD4 CTL; CD4 T cells; cancer; chronic viral infections; cytotoxicity.

Figure 1

Schematic representation of the cytotoxic pathways exerted by CD4⁺ CTL in different chronic virus infections. For every virus infection, the blue silhouette represents the model in which CD4⁺ CTL were described (i.e., human, primate and mouse model). Figure highlights the main effector molecules secreted by CD4⁺ CTL in response to each virus (IFNγ, perforin, granzymes, CD107a, or FasL). Created with BioRender.com.

Figure 2

Strategies to exploit virus-induced cytotoxic CD4⁺ T cells in therapy of solid cancers. (A) Proposed model for reactivation of virus-specific CD4⁺ CTL based on endogenous and exogenous loading of viral-antigen peptides onto tumor MHC Class II molecules to mimic local re-infection with a previously encountered pathogen. 1. Synthesis of immunogenic peptides from chosen virus; 2a. Intratumoral injection of viral-peptide vaccine; 2b. Conjugation of immunogenic viral peptides to an antibody targeting a specific integral tumor membrane protein for internalization upon engagement. 3. Binding of the immunoconjugate to its target; 4. Engagement-triggered internalization of the immunoconjugate complex into the endosomal compartment; 5. Release of antibody from the complex and dissociation of the peptide from the antibody; 6. Loading of released viral peptide onto MHC Class II molecules; 7. Transport of the peptide-MHC complex to the cell surface for presentation to CD4⁺ T cells. The proposed endogenous loading model (2b-7) is based on work by Sefrin et al. (212). (B) Cross-recognition of MHC Class II-presented tumor antigen peptides by virus-induced CD4⁺ CTL based on sequence similarity. Potential killing-modes of CD4⁺ CTL are depicted. Created with BioRender.com.