Emerging evidence indicates that NK cells play an important and complex role in autoimmune disease. Humans with autoimmune diseases often have reduced NK cell numbers and compromised NK cell functions. Mechanisms underlying this NK cell degeneration and its biological significance are not known. In this study we show that, in an experimental model of human autoimmune myasthenia gravis induced by a self-Ag, the acetylcholine receptor, NK cells undergo proliferation during the initiation of autoimmunity, followed by significant degeneration associated with the establishment of the autoreactive T cell response. We show that NK cell degeneration was mediated by IL-21 derived from autoreactive CD4(+) T cells, and that acetylcholine receptor-immunized IL-21R-deficient mice, with competent NK cells, developed exacerbated autoimmunity. Thus, NK cell degeneration may serve as a means evolved by the immune system to control excessive autoimmunity.