IL-21 Is Required to Control Chronic Viral Infection

CD4⁺ and CD8⁺ T cell functions are rapidly aborted during chronic infection, preventing viral clearance. CD4⁺ T cell help is required throughout chronic infection so as to sustain CD8⁺ T cell responses; however, the necessary factor(s) provided by CD4⁺ T cells are currently unknown. Using a mouse model of chronic viral infection, we demonstrated that interleukin-21 (IL-21) is an essential component of CD4⁺ T cell help. In the absence of IL-21 signaling, despite elevated CD4⁺ T cell responses, CD8⁺ T cell responses are severely impaired. CD8⁺ T cells directly require IL-21 to avoid deletion, maintain immunity, and resolve persistent infection. Thus, IL-21 specifically sustains CD8⁺ T cell effector activity and provides a mechanism of CD4⁺ T cell help during chronic viral infection.