Dendritic cells (DCs) play critical roles in initiating and regulating innate immunity as well as adaptive immune responses. However, the role of conventional dendritic cells (cDCs) in concanavalin A (ConA)-induced fulminant hepatitis is unknown. In this study, we demonstrated that depletion of cDCs using either CD11c-diphtheria toxin receptor transgenic mice (DTR Tg) mice or anti-CD11c antibody reduced the severity of liver injury significantly, indicating a detrimental role of cDCs in ConA-induced hepatitis. We elucidated further the pathological role of cDCs as being the critical source of interleukin (IL)-12, which induced the secretion of interferon (IFN)-γ by natural killer (NK) T cells. Reconstitution of cDCs-depleted mice with IL-12 restored ConA-induced hepatitis significantly. Furthermore, we determined that NK T cells were the target of DC-derived IL-12, and NK T cells contributed to liver inflammation and injury through production of IFN-γ. In summary, our study demonstrated a novel function of cDCs in mediating ConA-induced hepatitis through regulating IFN-γ secretion of NK T cells in an IL-12-dependent fashion. Targeting cDCs might provide potentially therapeutic applications in treating autoimmune related liver diseases.

Liver fibrosis represents a severe stage of liver damage, with hallmarks of inflammation, hepatic stellate cell activation, and extracellular matrix accumulation. Although previous studies demonstrated γδ T cells are involved in liver fibrosis, the precise role and mechanisms of γδ T cells migrating to fibrotic liver have not been elucidated. Here, we aim to investigate the functional subsets of γδ T cells in hepatic fibrosis and to further explore the underlying causes and drivers of migration. In this study, we observed that γδ T cells accumulate in fibrotic liver. Adoptive transfer of γδ T, especially Vγ4 γδ T subset, can significantly alleviate liver fibrosis. In addition, CCl4 treatment also leads to activation of mTOR signaling in γδ T cells. Genetic deletion of the Rictor gene, but not Raptor, in γδ T cells markedly exacerbated liver fibrosis. Mechanistically, CCl4-induced liver injury causes macrophage accumulation in the liver, and IL-1β produced by macrophages promotes mTORC2 signaling activation in γδ T cells, which upregulates T-bet expression and eventually promotes CXCR3 transcription to drive γδ T cell migration. Moreover, hepatic γδ T cells ameliorated liver fibrosis by cytotoxicity against activated hepatic stellate cells in FasL-dependent manner, and secrete IFN-γ to inhibit the differentiation of pro-fibrotic Th17 cells. Thus, IL-1β-activated mTORC2 signaling in γδ T cells upregulates CXCR3 expression, which is critical for IFN-γ+ γδ T cells migration into the liver and amelioration of liver fibrosis. Our findings indicate that targeting the mTORC2 or CXCR3 in γδ T cells could be considered as a promising approach for γδ T cell immunotherapy against liver fibrosis.

Multiple myeloma (MM) is the second most common haematological malignancy. The use of novel drugs and treatment strategies has significantly improved the survival rate of patients with MM. 1 However, MM is still incurable and has frequent relapses. 2 Bispecific antibodies (BsAbs) represent the next generation of immunotherapies and are expected to become an integral part of the MM treatment paradigm. Bcell maturation antigen (BCMA) is widely expressed in MM and normal plasma cells, 3 making it an ideal target for Tcell redirecting therapies. 4 AMG 420, a BCMA/CD3 bispecific T-cell engager (BiTE®) construct, redirects T cells to BCMA-positive tumour cells, resulting in the activation of T-cell mediated lysis of tumour cells. Nevertheless, the short serum half-life of BiTE molecule necessitates administration via continuous intravenous infusion. AMG 420 has been discontinued, and AMG 701, the half-life extended (HLE) BiTE construct has been developed and demonstrated encouraging preliminary responses in patients with relapsed/ refractory MM. 5 Currently, six clinical trials are evaluating BCMA targeting BiTE molecules, and the most recent data in MM have shown promising results with good tolerability. 6 Nevertheless, the universal application of BsAbs is hampered by their complex manufacturing processes and high cost. Compared to treatment with antibodies, plasmid-based gene therapy has clear advantages in terms of production,