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Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV.

ABSTRACT: 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.

SUBMITTER: Zheng M

PROVIDER: S-EPMC4003044 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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Project description:Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

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Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV.

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