Dynamic expression of IL-21 in effector CD8 T cells helps control chronic infections

CD8 T cells are critical players in immune responses against pathogens. Interleukin-21 (IL-21) is predominantly produced by CD4 T cells and exerts multifaceted effects on CD8 T cell regulation and function. Using Il21-reporter and Il21-fate mapping mice, we report that a subpopulation of activated CD8 T cells also produces IL-21 in the context of lymphocytic choriomeningitis virus (LCMV) infection. During the early effector phase of both acute and chronic infections, IL-21-expressing CD8 T cells exhibit substantial proliferative and cytotoxic capacities, with higher levels of interferon-γ (IFN-γ) and granzyme B (GZMB) compared with IL-21^- counterparts. Moreover, CD8 T cell-derived IL-21 played a critical protective role in chronic, but not acute, infection. IL-21 expression in CD8 T cells appeared to be largely restricted to exhausted progenitor T cells during the exhaustion phase of chronic infection. These findings identify IL-21-expressing CD8 T cells as pivotal players in the control of chronic infection.