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 CX(3)CR1-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.