IL-21 is a pleiotropic type I cytokine that shares the common cytokine receptor ␥ chain and plays important roles for normal Ig production, terminal B cell differentiation to plasma cells, and Th17 differentiation. IL-21 is elevated in several autoimmune diseases, and blocking its action has attenuated disease in MRL/lpr mice and in collagen-induced arthritis. The diabetes-associated Idd3 locus is at the Il2/Il21 locus, and elevated IL-21 was observed in the nonobese diabetic (NOD) mouse and suggested to contribute to diabetes by augmenting T cell homeostatic proliferation. To determine the role of IL-21 in diabetes, Il21r-knockout (KO) mice were backcrossed to NOD mice. These mice were devoid of lymphocytic infiltration into the pancreas, and only 1 of 20 animals had an elevated glucose compared with 60% of NOD mice on a wild-type (WT) background. Although TCR and Treg-related responses were normal, these mice had reduced Th17 cells and significantly higher levels of mRNAs encoding members of the Reg (regenerating) gene family whose transgenic expression protects against diabetes. Our studies establish a critical role for IL-21 in the development of type I diabetes in the NOD mouse, with obvious potential implications for type I diabetes in humans. Reg genes ͉ Th17 cellsH uman type I diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic ␤ cells and subsequent loss of insulin production (1). Nonobese diabetic (NOD) mice develop a similar disease and serve as a model system for studying the mechanisms involved in the initiation and propagation of the autoimmune response (2). Although it has been established that ␤ islet cell destruction is initiated by proinflammatory CD4 ϩ and CD8 ϩ T cells infiltrating the pancreas, the molecular mechanisms and cytokine pathways that control this process are not fully understood.IL-21 is a type I cytokine (3) that is the most recently discovered member of the family of cytokines that share the common cytokine receptor ␥ chain, ␥ c (4) . ␥ c is also shared by IL-2, IL-4, IL-7, IL-9, and IL-15 and is mutated in humans with X-linked severe combined immunodeficiency (XSCID) (5). IL-21 is produced most abundantly by CD4 ϩ T cells, including Th17 lineage cells (6-8) and natural killer T (NKT) cells (9), and is known to act on both lymphoid and nonlymphoid target cells, thus controlling both innate and adaptive immune responses (4). IL-21 is critical for normal Ig production (10), can cooperatively drive expansion of CD8 ϩ T cells (11), can activate NK cells (12), and drives terminal B cell differentiation into plasma cells (13). IL-21 has been implicated as playing a role in the development of B cell-mediated lupus-like autoimmune disease based on studies in the BXSB-Yaa (13), Sanroque (14), and MRL/lpr mice (15), and treatment with a soluble IL-21R-Fc fusion protein was shown to lead to a partial decrease in disease severity in the MRL/lpr mice (15) and collagen-induced arthritis (16). In experimental allergic encephalitis (EAE), a model for ...

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