Previous thinking on EAE culprits has focused on Th1 CD4+ T cells and their distinctive product IFN-γ, both of which are found at EAE inflammation sites. But the details were confused by the biology of p40—a subunit shared by both IL-12 (an inducer of Th1 cells) and IL-23. This group showed recently that EAE is suppressed after p40 inactivation because of the loss of IL-23 not IL-12.
The authors now explain the pathogenic effect of IL-23 by showing that this cytokine induces a newly recognized subset of CD4+ T cells, which produces large amounts of IL-17 and IL-6 but very little IFN-γ. These T cells and IFN-γ–producing Th1 cells both invaded the CNS during EAE in wild-type mice, but only IFN-γ–producing Th1 cells were found in the CNS in mice lacking IL-23. Furthermore, T cells cultured in vitro with IL-23, but not those cultured with IL-12, could transfer the disease to naive mice.
How these cells induce disease is not completely understood. IL-17 appears to be a key player, as blocking IL-17 in wild-type mice partially reversed disease. IL-17 is known to drive the production of inflammatory cytokines from memory T cells, and IL-23 induces proliferation of these cells—both of which may amplify inflammation. Whatever the mechanism, this study appears to exonerate traditional Th1 cells as the main players in the pathogenesis of EAE.