A20 Controls Macrophage to Elicit Potent Cytotoxic CD4⁺ T Cell Response

Emerging evidence indicates that CD4⁺ T cells possess cytotoxic potential for tumor eradication and perforin/granzyme-mediated cytotoxicity functions as one of the important mechanisms for CD4⁺ T cell-triggered cell killing. However, the critical issue is how the cytotoxic CD4⁺ T cells are developed. During the course of our work that aims at promoting immunostimulation of APCs by inhibition of negative regulators, we found that A20-silenced Mф drastically induced granzyme B expression in CD4⁺ T cells. As a consequence, the granzyme-highly expressing CD4⁺ T cells exhibited a strong cytotoxic activity that restricted tumor development. We found that A20-silenced Mф activated cytotoxic CD4⁺ T cells by MHC class-II restricted mechanism and the activation was largely dependent on enhanced production of IFN-γ.