IL-21 is a central component of CD4 T cell help required to purge a persistent viral infection (44.27)

Abstract

Abstract Therapies to cure persistent viral infections have largely been unsuccessful because it is unclear what is required of the immune system to purge virus once it proceeds past acute infection. T cell immunity is crucial to eliminate viral infection. However, CD4 and CD8 T cell functions are rapidly aborted during persistent infection, preventing viral clearance. To date the majority of work examining T cell function during viral persistence has focused on CD8 T cells. Yet, many aspects of immune exhaustion are associated with functions performed by CD4 T helper cells (which are also rapidly exhausted after persistent infection), suggesting that loss of CD4 T cell function is a key mechanism permitting viral persistence. CD4 T cell help is required throughout persistence to sustain CD8 T cell responses and resolve persistent viral infection, suggesting that CD4 T cells maintain some yet undefined, but essential, helper functions. We demonstrate that IL-21 as an essential component of CD4 T cell help during viral persistence. In the absence of IL-21 signaling, despite elevated CD4 T cell responses, help to CD8 T cells is not provided. CD4 T cells utilize IL-21 to prevent CD8 T cell deletion, sustain immunity and resolve persistent infection. Thus, we identify a novel mechanism of CD4 T cell help during viral persistence and propose that CD4 help is not lost during viral persistence, but instead is altered from promoting memory development toward the production of factors that ultimately sustain effector responses to control viral replication.