IL-21 signaling is critical for the development of type I diabetes in the NOD mouse

Abstract

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 ...

Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

“…IL-21 is necessary for the development of diabetes in the NOD mouse (23)(24)(25), but a number of important studies argue that decreased expression of IL-2 explains Idd3 (14,15,31). Our findings resonate with a critical role for IL-21 in T1D pathogenesis, but do not formally discount a role for IL-2.…”

“…IL-21 is produced by activated CD4 ϩ T cells and NK T cells, and can deliver a costimulatory signal to lymphocytes that affects their proliferation, differentiation, and survival in response to antigen (19)(20)(21). Consistent with its actions on lymphocyte populations, IL-21 has been shown to have an essential role in an array of conditions involving the destruction of self-tissues (20,(22)(23)(24). We have previously shown that NOD mice exhibited elevated levels of IL-21 (26), and a number of recent studies of NOD mice made genetically deficient in the IL-21R demonstrate that IL-21 is necessary for the development of T1D (23)(24)(25).…”

“…In contrast, they are also known to support the generation of lymphocyte subsets with opposing actions. This complexity is illustrated by the finding that a homozygous deficiency in Il21r prevents the onset of T1D in the NOD mouse, whereas a loss of one allele of Il2 increases disease incidence (15,(23)(24)(25). IL2 and Il21 are adjacent genes on chromosome 3 in mice, and the analogous locus exists on chromosome 4 in humans.…”

Key role for IL-21 in experimental autoimmune uveitis

“…It is also critical for B-cell differentiation into plasma cells and Ig production (9,10) and negatively regulates the function of dendritic cells (11). IL-21 plays a role in autoimmune diseases, including type I diabetes in nonobese diabetic mice (12,13), systemic lupus erythematosus in MRL/lpr and BXSB/Yaa mice (9,14,15), and collagen-induced arthritis (16). In experimental allergic encephalitis (EAE), divergent effects of IL-21 have been reported related to its role in the development and progression of the autoimmune response as well as whether it is required for disease development (1,17,18).…”

“…Coevolution of the IL-21 and IL-2 systems is further suggested not only by their sharing of γ c but also by the fact that IL-21R is most closely related to IL-2Rβ (20); nevertheless, IL-21 and IL-2 have distinct functions. For example, IL-21 is implicated in the development of autoimmunity (9,(12)(13)(14)16), but mice deficient in IL-2, IL-2Rα, and IL-2Rβ exhibit autoimmunity (21)(22)(23)(24), suggesting that IL-2 protects against development of autoimmune disease. IL-21 can promote the development of Th17 cells, whereas IL-2 inhibits the differentiation of Th17 cells (25), although it induces the expansion of Th17 cells that mediate uveitis and scleritis (26).…”