An IL-21-expressing effector CD8+ T cell subset provides superior control of infection and cancer

CD8+ T cells are critical in immune responses against pathogens and malignancies. After activation, antigen-specific CD8+ T cells differentiate into cytotoxic effector cells, which are regarded to be phenotypically similar and unlike CD4+ T cells, do not contain different functional subsets. Interleukin 21 (IL-21), well known to be primarily produced by CD4+ T cells, exerts multifaceted effects on the regulation and function of CD8+ T cells. In this study, utilizing IL-21 reporter and fate-mapping mice, we have uncovered a new population of IL-21-expressing CD8+ T cells in the context of infection and cancer. These T cells, coined as Tc21 cells, exhibited remarkable proliferative and cytotoxic capacities, with elevated expression levels of IFNγ and GZMB, than IL-21- T cells. Tc21 cells efficiently developed into memory cells during acute infections and maintained a less dysfunctional state in chronic infection. Importantly, Tc21 cells played a pivotal role in mounting effective protection to virus and cancer. Collectively, these findings highlight an effector subset of IL-21-expressing CD8+ T cells pivotal in host protection, and may suggest new approaches of cancer immunotherapy.