Despite its initially defined role as a T-helper type 1 cell (Th1)-inducing cytokine, interleukin-27 (IL-27) has complex roles in vivo. The role of IL-27 receptor (IL-27R) was defined in experimental crescentic glomerulonephritis induced by a foreign antigen, sheep globulin, which is planted in glomeruli. This lesion is dependent on a Th1 effector cellular response. Twenty-one days after the administration of sheep anti-mouse glomerular basement membrane antibody, wild-type mice developed histologic and functional inflammatory renal injury. Injury was attenuated in the absence of IL-27R I? chain (IL-27RI?), the unique component of the IL-27R complex. In contrast to the attenuated renal injury on day 21, Il27ra(-/-) mice exhibited enhanced systemic immune responses, including Th1 responses, with increased IL-2-dependent interferon-I? (IFN-I?) production. However, earlier in the development of the nephritogenic immune response, IFN-I? production was decreased, with reduced early immune responses translating into attenuated renal injury. Having demonstrated decreased early Th1 systemic immune responses, followed by enhanced nephritogenic Th1 immune responses, renal injury was studied at later time points. On days 28 and 35 after injection of the nephritogenic antigen, renal injury was enhanced in Il27ra(-/-) mice compared with wild-type mice in an at least partially IFN-I?-dependent manner. In Th1-dependent autoinflammatory lesions, IL-27RI? has a biphasic role in vivo, initially pathogenic, but ultimately playing a protective role by regulating immune responses and attenuating disease.