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

Abstract

Interleukin (IL)-27, a newly discovered IL-12 family cytokine, is composed of p28 and EBI3. In this study, CD11c-p28 f/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-γ (IFN-γ) in sera. Neutralizing IFN-γ prevented ConA-induced liver damage in these mice, indicating a critical role of IFN-γ in this pathological process. Interestingly, the main source of the increased IFN-γ in CD11c-p28 f/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-p28 f/f mice, but not from wild-type mice or CD11c-p28 f/f - IFN -γ−/− double knockout mice to CD4−/− mice, restored the increased liver damage. Further studies defined higher levels of IFN-γ and T-bet messenger RNA in naïve CD4+ T cells from CD11c-p28 f/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 cell–mediated liver injury and reveal a novel function of DC-derived p28 on ConA-induced fulminant hepatitis through regulation of the intrinsic ability for IFN-γ production by CD4+ T cells.

Critical Role of Dendritic Cell–Derived IL-27 in Antitumor Immunity through Regulating the Recruitment and Activation of NK and NKT Cells

“…*p , 0.05, **p , 0.01, ***p , 0.001. munity in both a chemical carcinogenesis model and a transplanted melanoma model. Given the fact that IL-27 is the only well-defined functional cytokine that is composed of IL-27p28 in vivo, we used IL-27p28 flox/flox conditional KO mouse generated in our laboratory (28). Studies in Itgax-p28 f/f mice proved that DCs were the cellular source of IL-27 in antitumor immunity.…”

“…IL-27p28 flox/flox mice in the 129/Sv genetic background were generated in our laboratory with the help of X. Gao (Model Animal Research Center, Nanjing University) and backcrossed to the C57BL/6 strain for 10 generations (28). IL-27p28…”

“…To study the biological function of IL-27, we used IL-27p28 flox/flox mice (hereafter referred to as WT mice) generated in our laboratory (28), which have been crossed with EIIa-Cre mice (30) and CD11c/ Itgax-Cre mice (31) to delete IL-27p28 alleles in nearly all tissues (hereafter referred to as EIIa-p28 f/f mice) and especially in DCs (hereafter referred to as Itgax-p28 f/f mice), respectively. To directly evaluate the importance of host-derived IL-27 in tumor development, we tested WT, EIIa-p28…”

“…In this study, we used IL-27p28 flox/flox conditional knockout (KO) mice (28) to examine the physiological function of endogenous IL-27 in tumor immunity using methyl-cholanthrene (MCA)-induced fibrosarcoma and transplanted B16 melanoma models. We identified a novel role of dendritic cell (DC)-derived IL-27 in antitumor immunity through shaping tumor microenvironment to regulate the recruitment and activation of NK and NKT cells.…”

MiR-29a and miR-652 Attenuate Liver Fibrosis by Inhibiting the Differentiation of CD4+ T Cells

“…Tel: +86-025-85816332 E-mail: wenweiabc@yeah.net CD4+ T cells were a set of cells that involved in the host immune system through liberating the cytokines such as T helper17 (Th17) (Schenten et al, 2014). Recently study has proved that the percent of CD4+ T cells were affecting the liver inflammation and fibrosis (Zhang et al, 2013). ) is a pro-inflammatory cell that plays vital role on host defenses and several autoimmune disorders through releasing of cytokines such as , and both IL-17A and IL-22 functioned to control of extracellular bacterial infection (Shigematsu et al, 2013).…”