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The biliary epithelium presents antigens to and activates natural killer T cells.

ABSTRACT: Cholangiocytes express antigen-presenting molecules, but it has been unclear whether they can present antigens. Natural killer T (NKT) cells respond to lipid antigens presented by the major histocompatibility complex class I-like molecule CD1d and are abundant in the liver. We investigated whether cholangiocytes express CD1d and present lipid antigens to NKT cells and how CD1d expression varies in healthy and diseased bile ducts. Murine and human cholangiocyte cell lines as well as human primary cholangiocytes expressed CD1d as determined by flow cytometry and western blotting. Murine cholangiocyte cell lines were able to present both exogenous and endogenous lipid antigens to invariant and noninvariant NKT cell hybridomas and primary NKT cells in a CD1d-dependent manner. A human cholangiocyte cell line, cholangiocarcinoma cell lines, and human primary cholangiocytes also presented exogenous CD1d-restricted antigens to invariant NKT cell clones. CD1d expression was down-regulated in the biliary epithelium of patients with late primary sclerosing cholangitis, primary biliary cirrhosis, and alcoholic cirrhosis compared to healthy controls.Cholangiocytes express CD1d and present antigens to NKT cells and CD1d expression is down-regulated in diseased biliary epithelium, findings which show that the biliary epithelium can activate an important lymphocyte subset of the liver. This is a potentially important immune pathway in the biliary system, which may be capable of regulating inflammation in the context of biliary disease.

SUBMITTER: Schrumpf E

PROVIDER: S-EPMC4589438 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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The biliary epithelium presents antigens to and activates natural killer T cells.

Schrumpf Elisabeth E Tan Corey C Karlsen Tom H TH Sponheim Jon J Björkström Niklas K NK Sundnes Olav O Alfsnes Kristian K Kaser Arthur A Jefferson Douglas M DM Ueno Yoshiyuki Y Eide Tor J TJ Haraldsen Guttorm G Zeissig Sebastian S Exley Mark A MA Blumberg Richard S RS Melum Espen E

Hepatology (Baltimore, Md.) 20150520 4

<h4>Unlabelled</h4>Cholangiocytes express antigen-presenting molecules, but it has been unclear whether they can present antigens. Natural killer T (NKT) cells respond to lipid antigens presented by the major histocompatibility complex class I-like molecule CD1d and are abundant in the liver. We investigated whether cholangiocytes express CD1d and present lipid antigens to NKT cells and how CD1d expression varies in healthy and diseased bile ducts. Murine and human cholangiocyte cell lines as we ...[more]

PMID: 25855031

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Project description:Natural killer (NK) cells participate in immunity against several pathogens by exerting cytotoxic and cytokine-production activities. Some NK cell subsets also mediate recall responses that resemble memory of adaptive lymphocytes against antigenic and non-antigenic stimuli. The C-X-C motif chemokine receptor 6 (CXCR6) is crucial for the development and maintenance of memory-like responses in murine NK cells. In humans, several subsets of tissue-resident and circulating NK cells with different functional properties express CXCR6. However, the role of CXCR6+ NK cells in immunity against relevant human pathogens is unknown. Here, we addressed whether murine and human CXCR6+ NK cells respond to antigens of Mycobacterium tuberculosis (Mtb). For this purpose, we evaluated the immunophenotype of hepatic and splenic CXCR6+ NK cells in mice exposed to a cell-wall (CW) extract of Mtb strain H37Rv. Also, we characterized the expression of CXCR6 in peripheral NK cells from active pulmonary tuberculosis (ATB) patients, individuals with latent TB infection (LTBI), and healthy volunteer donors (HD). Furthermore, we evaluated the responses of CXCR6+ NK cells from HD, LTBI, and ATB subjects to the in vitro exposure to CW preparations of Mtb H37Rv and Mtb HN878. Our results showed that murine hepatic CXCR6+ NK cells expand in vivo after consecutive administrations of Mtb H37Rv CW to mice. Remarkably, pooled hepatic and splenic, but not isolated splenic NK cells from treated mice, enhance their cytokine production capacity after an in vitro re-challenge with H37Rv CW. In humans, CXCR6+ NK cells were barely detected in the peripheral blood, although slightly significative increments in the percentage of CXCR6+, CXCR6+CD49a-, CXCR6+CD49a+, and CXCR6+CD69+ NK cells were observed in ATB patients as compared to HD and LTBI individuals. In contrast, the expansion of CXCR6+CD49a- and CXCR6+CD69+ NK cells in response to the in vitro stimulation with Mtb H37Rv was higher in LTBI individuals than in ATB patients. Finally, we found that Mtb HN878 CW generates IFN-γ-producing CXCR6+CD49a+ NK cells. Our results demonstrate that antigens of both laboratory-adapted and clinical Mtb strains are stimulating factors for murine and human CXCR6+ NK cells. Future studies evaluating the role of CXCR6+ NK cells during TB are warranted.

Project description:The most challenging complication associated with Factor VIII (FVIII) replacement therapy is the development of neutralizing anti-drug antibodies, or inhibitors, which occur in 23-35% of severe (FVIII level <1%) hemophilia A (HA) patients and are a serious hindrance to effective management of HA. Consequently, strategies that can either prevent anti-FVIII inhibitors from developing or "tolerize" individuals who develop such antibodies represent a clinically important unmet need. One intervention for patients with high-titer inhibitors is immune tolerance induction (ITI) therapy. Although ITI therapy is the only clinically proven strategy to eradicate anti-FVIII inhibitors, mechanisms of inhibitor reduction remain unknown. Factor VIII Fc-fusion (rFVIIIFc) is an enhanced half-life antihemophilic factor used in replacement therapy for HA. Fc-fusion is a successful protein bio-engineering platform technology. In addition to enhancement of plasma half-life via neonatal Fc receptor (FcRn) binding, other Fc-mediated interactions, including engagement with Fc gamma receptors (FcγR), may have immunological consequences. Several case reports and retrospective analyses suggest that rFVIIIFc offers superior outcomes with respect to ITI compared to other FVIII products. Previously we and others demonstrated rFVIIIFc interactions with activating FcγRIIIA/CD16. Here, we investigated if rFVIIIFc activates natural killer (NK) cells via CD16. We demonstrated rFVIIIFc signaling via CD16 independent of Von Willebrand Factor (VWF):FVIII complex formation. We established that rFVIIIFc potently activated NK cells in a CD16-dependent fashion resulting in IFNγ secretion and cytolytic perforin and granzyme B release. We also demonstrated an association between rFVIIIFc-mediated NK cell IFNγ secretion levels and the high-affinity (158V) CD16 genotype. Furthermore, we show that rFVIIIFc-activated CD16+ NK cells were able to lyse a B-cell clone (BO2C11) bearing an anti-FVIII B-cell receptor in an antibody-dependent cellular cytotoxicity (ADCC) assay. These in vitro findings provide an underlying molecular mechanism that may help explain clinical case reports and retrospective studies suggesting rFVIIIFc may be more effective in tolerizing HA patients with anti-FVIII inhibitors compared to FVIII not linked to Fc. Our in vitro findings suggest a potential use of Fc-fusion proteins acting via NK cells to target antigen-specific B-cells, in the management of unwanted immune responses directed against immunogenic self-antigens or therapeutic protein products.

Dataset Information

The biliary epithelium presents antigens to and activates natural killer T cells.

Publications

The biliary epithelium presents antigens to and activates natural killer T cells.

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