Differential Effects of IL-21 during Initiation and Progression of Autoimmunity against Neuroantigen

The cytokine IL-21 is closely related to IL-2 and IL-15, a cytokine family that uses the common γ-chain for signaling. IL-21 is expressed by activated CD4+ T cells. We examined the role of IL-21 in the autoimmune disease experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. IL-21 administration before induction of EAE with a neuroantigen, myelin oligodendrocyte glycoprotein peptide 35-55, and adjuvant enhanced the inflammatory influx into the CNS, as well as the severity of EAE. Autoreactive T cells purified from IL-21-treated mice transferred more severe EAE than did the control encephalitogenic T cells. No such effects were observed when IL-21 was administered after EAE progressed. Additional studies demonstrated that IL-21 given before the induction of EAE boosted NK cell function, including secretion of IFN-γ. Depletion of NK cells abrogated the effect of IL-21. Therefore, IL-21, by affecting NK cells, has differential effects during the initiation and progression of autoimmune responses against neuroantigens.