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Li F.,Hefei National Laboratory for Physical science at Microscale | Tian Z.,Hefei National Laboratory for Physical science at Microscale | Tian Z.,Hefei University of Technology
Cellular and Molecular Immunology | Year: 2013

Because of its unique blood supply, the liver maintains a special local immune tolerogenic microenvironment. Moreover, the liver can impart this immune tolerogenic effect on other organs, thus inducing systemic immune tolerance. The network of hepatic regulatory cells is an important mechanism underlying liver tolerance. Many types of liver-resident antigen-presenting cells (APCs) have immune regulatory function, and more importantly, they can also induce the differentiation of circulating immune cells into regulatory cells to further extend systemic tolerance. Thus, the liver can be seen as a type of 'school', where liver APCs function as 'teachers' and circulating immune cells function as 'students.'. © 2013 CSI and USTC. All rights reserved.

Sojka D.K.,University of Washington | Tian Z.,Anhui University of Science and Technology | Tian Z.,Hefei National Laboratory for Physical science at Microscale | Yokoyama W.M.,University of Washington | Yokoyama W.M.,Howard Hughes Medical Institute
Seminars in Immunology | Year: 2014

Conventional NK cells are well characterized in the mouse spleen and circulate in the blood. Less well described are NK cells found in organs such as the liver, thymus, and uterus. Recently we identified a tissue-resident NK (trNK) cell population in the liver, suggesting a potential diversity of trNK cells in other organs. In this review we compare and contrast the similarities and differences among the subpopulations of NK and innate lymphoid cells to the trNK cells in the liver. © 2014 Elsevier Ltd.

Zheng M.,Hefei University of Technology | Yu J.,Hefei University of Technology | Yu J.,Hefei National Laboratory for Physical science at Microscale | Tian Z.,Hefei University of Technology | Tian Z.,Hefei National Laboratory for Physical science at Microscale
Cellular and Molecular Immunology | Year: 2013

The lymphatic system is important in mounting an immune response to foreign antigens and tumors in humans and animal models. The liver produces a large amount of lymph, and its lymphatic system is divided into three major components: the portal, sublobular and superficial lymphatic vessels. Despite the fact that mice are the most commonly used laboratory animals, detailed descriptions of the anatomical location and function of the lymph nodes (LNs) that drain the liver are surprisingly absent. In this study, we found that the portal and celiac LNs adjacent to mouse liver were stained with Evans blue within 5-8 min. Enhanced green fluorescence protein (EGFP)-positive cells from the liver also drained into the two aforementioned LNs. These data indicate that the portal and celiac LNs drain the mouse liver. Lymphadenectomy of the identified liver-draining LNs resulted in hepatitis B virus (HBV) persistence in immunocompetent mice compared with the sham group. In addition, the frequencies of CD8 + T cells and dendritic cells (DCs) increased significantly in the liver-draining LNs after hydrodynamic injection of HBV plasmid. Liver-draining LN cells in HBV plasmid-injected mice also showed significant antigen-specific proliferation in response to stimulation with recombinant hepatitis B core antigen in vitro. Adoptive transfer of these cells into Rag1-/-mice induced a reduction in the serum concentration of hepatitis B surface antigen (HBsAg) compared to liver-draining LN cells in uninjected mice. Altogether our data characterize the liver-draining LNs and provide evidence that the liver-draining LNs induce an anti-HBV-specific immune response responsible for HBV clearance. © 2013 CSI and USTC. All rights reserved.

Xu L.,Anhui University of Science and Technology | Yin W.,Anhui University of Science and Technology | Sun R.,Anhui University of Science and Technology | Sun R.,Hefei National Laboratory for Physical science at Microscale | And 4 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

The liver plays a critical role in inducing systemic immune tolerance, for example, during limiting hypersensitivity to food allergy and in rendering acceptance of allotransplant or even hepatotropic pathogens. We investigated the unknown mechanisms of liver tolerance by using an established hepatitis B virus (HBV)-carrier mouse model, and found that these mice exhibited an antigen-specific tolerance toward peripheral HBsAg vaccination, showing unenlarged draining lymph node (DLN), lower number of germinal centers (GC), and inactivation of GC B cells and follicular T helper (Tfh) cells. Both in vivo and in vitro immune responses toward HBsAg were suppressed by mononuclear cells from HBV-carrier mice, which were CD4+ Foxp3- type 1 regulatory T (Tr1)-like cells producing IL-10. Using recipient Rag1 -/- mice, hepatic Tr1-like cells from day 7 of HBV-persistent mice acquired the ability to inhibit anti-HBV immunity 3 d earlier than splenic Tr1-like cells, implying that hepatic Tr1-like cells were generated before those in spleen. Kupffer cell depletion or IL-10 deficiency led to impairment of Tr1-like cell generation, along with breaking HBV persistence. The purified EGFP+CD4+ T cells (containing Tr1-like cells) from HBV-carrier mice trafficked in higher numbers to DLN in recipient mice after HBsAg vaccination, and subsequently inactivated both Tfh cells and GC B cells via secreting IL-10, resulting in impaired GC formation and anti-HB antibody production. Thus, our results indicate Tr1-like cells migrate from the liver to the DLN and inhibit peripheral anti-HBV immunity by negatively regulating GC B cells and Tfh cells.

Wei H.,Hefei National Laboratory for Physical science at Microscale | Wei H.,Hefei University of Technology | Li F.,Hefei National Laboratory for Physical science at Microscale | Li F.,Hefei University of Technology | And 6 more authors.
Gastroenterology | Year: 2013

BACKGROUND & AIMS: We studied the functions of natural killer (NK) cells and the role of the NK cell inhibitory receptor (NKG2A) during hepatitis B virus (HBV) infection in patients and mice. METHODS: We analyzed levels of NKG2A on peripheral blood NK cells from 42 patients with active chronic hepatitis B (CHB), 31 patients with inactive CHB, and 35 healthy volunteers (controls). Five patients with CHB treated with antiviral therapy were also included to evaluate changes in NK cells after HBV titers decreased. We examined the effects of blocking antibodies against NKG2A or its ligand Qa-1 (equivalent to HLA-E in humans) in immunocompetent mice that express HBV from a plasmid and are positive for serum hepatitis B surface antigen (a mouse model of HBV infection). RESULTS: A higher percentage of NK cells from patients with active CHB were positive for NKG2A (38.47%) than from patients with inactive CHB (19.33%; P<.01) or controls (27.96%; P<.05). The percentage of NKG2A + cells correlated with serum viral load (r=0.5457; P<.001). The percentage of NKG2A+ cells decreased along with HBV load in patients that received antiviral therapy (P<.05). Blocking NKG2A interaction with HLA-E in peripheral NK cells from patients with active CHB increased their cytotoxicity in vitro.NKcells of HBV carrier mice also had higher percentages of NK cells that expressed NKG2A compared with control mice; NKG2A was likely to be up-regulated by production of interleukin-10 by hepatic regulatory CD4 +CD25+ T cells. Blocking Qa-1 in these mice promoted viral clearance in an NK cell=dependent manner. CONCLUSIONS: Infection with HBV increases levels of the inhibitory receptor NKG2A on NK cells in mice and humans, and reduces their ability to clear HBV. Reagents designed to block the interaction between NKG2A and HLA-E might be developed to treat CHB infection. © 2013 by the AGA Institute.

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