CD4⁺ T Cell Help Is Required for the Formation of a Cytolytic CD8⁺ T Cell Subset that Protects against Chronic Infection and Cancer

Although CD4⁺ T cell “help” is crucial to sustain antiviral immunity, the mechanisms by which CD4⁺ T cells regulate CD8⁺ T cell differentiation during chronic infection remain elusive. Here, using single-cell RNA sequencing, we show that CD8⁺ T cells responding to chronic infection were more heterogeneous than previously appreciated. Importantly, our findings uncovered the formation of a CX₃CR1-expressing CD8⁺ T cell subset that exhibited potent cytolytic function and was required for viral control. Notably, our data further demonstrate that formation of this cytotoxic subset was critically dependent on CD4⁺ T cell help via interleukin-21 (IL-21) and that exploitation of this developmental pathway could be used therapeutically to enhance the killer function of CD8⁺ T cells infiltrated into the tumor. These findings uncover additional molecular mechanisms of how “CD4⁺ T cell help” regulates CD8⁺ T cell differentiation during persistent infection and have implications toward optimizing the generation of protective CD8⁺ T cells in immunotherapy.