Abstract
Microsporidia, a latent opportunistic infection associated with mild inflammation, is characterized by a strong CD8 T cell response, which has been shown to be CD4 T cell dependent. In this manuscript, we demonstrate that CD4 help is provided via IL-21 production, a common γ-chain cytokine closely related to IL-2. The peak of IL-21 expression, observed during the acute infection, is associated with an elevated IL-21(+) CD4 T subset, and these cells bear a phenotypic resemblance to T follicular helper cells. We observed that, during per-oral microsporidial infection, IL-21 was critical for the generation of an optimal effector CD8 T cell immunity. Sharply decreased effector KLRG1(+) CD8 response was observed in IL-21R knockout mice, and although these cells exhibited reduced functional properties, they retained the ability to proliferate. The role of IL-21 in the generation of CD8 effectors was cell intrinsic, as stronger defects were observed in the IL-21-deficient compartment from the bone marrow chimeric mice (IL-21R knockout/wild-type). These findings are different from those reported for viral infections in which IL-21 has been primarily associated with the generation and maintenance of CD8 memory response. To the best of our knowledge, this report demonstrates a critical role for IL-21 in the generation of a primary effector CD8 T cell response to an infectious disease model.