Interleukin (IL)-23 is a heterodimeric cytokine that promotes the expansion of a pathogenic CD4+ T cell population characterized by the production of IL-17, IL-17F, IL-6, and tumor necrosis factor (TNF). This IL-23-driven T cell subset is highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity. IL-23-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA), highlighting its role in autoimmune pathogenesis. In contrast to IL-12, which promotes the development of interferon-γ–producing Th1 cells, IL-23 does not promote Th1 cell development but is crucial for the expansion of IL-17–producing T cells. Gene expression analysis of IL-23-driven autoreactive T cells identified a unique pattern of proinflammatory cytokines and novel factors, distinguishing them from IL-12-driven T cells. In vitro studies confirmed that IL-23-dependent CD4+ T cells are highly pathogenic and essential for the development of organ-specific autoimmune inflammation.Interleukin (IL)-23 is a heterodimeric cytokine that promotes the expansion of a pathogenic CD4+ T cell population characterized by the production of IL-17, IL-17F, IL-6, and tumor necrosis factor (TNF). This IL-23-driven T cell subset is highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity. IL-23-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA), highlighting its role in autoimmune pathogenesis. In contrast to IL-12, which promotes the development of interferon-γ–producing Th1 cells, IL-23 does not promote Th1 cell development but is crucial for the expansion of IL-17–producing T cells. Gene expression analysis of IL-23-driven autoreactive T cells identified a unique pattern of proinflammatory cytokines and novel factors, distinguishing them from IL-12-driven T cells. In vitro studies confirmed that IL-23-dependent CD4+ T cells are highly pathogenic and essential for the development of organ-specific autoimmune inflammation.