IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis

•IL-21 optimizes CNS CD4 and CD8 T cell responses during viral encephalomyelitis.•IL-21 promotes peripheral and CNS humoral immunity.•IL-21 promotes CNS viral control and prevents mortality.

Acute coronavirus encephalomyelitis is controlled by T cells while humoral responses suppress virus persistence. This study defines the contribution of interleukin (IL)-21, a regulator of T and B cell function, to central nervous system (CNS) immunity. IL-21 receptor deficiency did not affect peripheral T cell activation or trafficking, but dampened granzyme B, gamma interferon and IL-10 expression by CNS T cells and reduced serum and intrathecal humoral responses. Viral control was already lost prior to humoral CNS responses, but demyelination remained comparable. These data demonstrate a critical role of IL-21 in regulating CNS immunity, sustaining viral persistence and preventing mortality.