High susceptibility to liver injury in IL-27 p28 conditional knockout mice involves intrinsic interferon-γ dysregulation of CD4+ T cells.

Interleukin (IL)-27, a newly discovered IL-12 family cytokine, is composed of p28 and EBI3. In this study, CD11c-p28f/f conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC-derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon- (IFN-) in sera. Neutralizing IFN- prevented ConA-induced liver damage in these mice, indicating a critical role of IFN- in this pathological process. Interestingly, the main source of the increased IFN- in CD11c-p28f/f mice was CD4+ T cells, but not natural killer T (NKT) cells. Depletion of CD4+, but not NK1.1+, cells completely abolished liver damage, whereas transferring CD4+ T cells from CD11c-p28f/f mice, but not from wild-type mice or CD11c-p28f/f-IFN-/ double knockout mice to CD4/ mice, restored the increased liver damage. Further studies defined higher levels of IFN- and T-bet messenger RNA in naive CD4+ T cells from CD11c-p28f/f mice, and these CD4+ T cells were highly responsive to both low and higher concentrations of anti-CD3, indicating a programmed functional alternation of CD4+ T cells. Conclusion: We provide a unique model for studying the pathology of CD4+ T cellmediated liver injury and reveal a novel function of DC-derived p28 on ConA-induced fulminant hepatitis through regulation of the intrinsic ability for IFN- production by CD4+ T cells. (HEPATOLOGY 2013)