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The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses

Marczynska J1, Ozga A1, Wlodarczyk A1, Majchrzak-Gorecka M1, Kulig P1, Banas M1, Michalczyk-Wetula D2, Majewski P1, Hutloff A3, Schwarz J4, Chalaris A4,Scheller J5, Rose-John S4, Cichy J6.

J Immunol. 2014;193(6):2753-63.

1Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;

2Department of Biophysics, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.

3Robert Koch Institute, 13353 Berlin, Germany; German Rheumatism Research Center, 10117 Berlin, Germany;

4Department of Biochemistry, Medical Faculty, Christian Albrechts University, 24118 Kiel, Germany;

5Department of Biochemistry, Medical Faculty, Christian Albrechts University, 24118 Kiel, Germany; and Institute of Biochemistry and Molecular Biology, Heinrich Heine University, 40225 Düsseldorf, Germany.

6Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; [email protected]

 

Abstract 

About one fifth of the known proteases are membrane‑bound proteins, suggesting that proteolytic processing on the cell surface is important to cell function. Protease‑mediated refashioning of the cell surfaces is of particular relevance in host defense effector cells where rapid signaling events are often required for immune cell activation or differentiation. However, the role of cell surface proteolysis  in  adaptive immune responses remains purely defined. In this work we focused on the role of metalloproteinase ADAM17 also known as TACE (TNF-α converting enzyme) in shaping humoral (antibody-dependent) immunity. B-cell mediated humoral response is crucial for development of effective vaccination strategies which are seminal to the prevention and treatment of prevalent infectious diseases and tumors.  Moreover, abnormality in B cell compartment often leads to life-threatening diseases such as autoimmune disorders.  Therefore, better knowledge of  mechanisms controlling B cell function is of great interest to immunology and medicine. In this work we demonstated that ADAM17  inhibits humoral immune responses through down-regulating surface levels of ICOSL on B cells. Continuous high-level expression of ICOSL on surface of B cells due to the insufficient ADAM17 activity leads to exaggerated humoral responses. Thus our work resulted in uncovering novel ADAM17-mediated control point in regulating antibody responses.

 

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Additional information

Although ICOS is exclusively expressed on activated T cells, ICOSL is produced by other cells beside B cells, such as dendritic cells and non-immune cells. Our data suggest that other yet-to-be identified population of cells in lymph nodes may also contribute to ADAM17‑mediated regulation of antibody responses through ICOSL. Together, our data offer a conceptual basis for testing the potential efficacy of targeting ADAM17 for better vaccination strategies and treatment of antibody-dependent disorders.

Figure Legend

ICOSL on surface of B cells interacts with its partner ICOS on antigen-activated T cells and this interaction is critical to generation of effective humoral immune responses. ADAM17 controls the magnitude of this response by regulating surface levels of ICOSL.

In the absence of functional ADAM17, stronger/more prolonged interactions between ICOSL on B cells and ICOS on activated T cells lead to the increased antibody responses.

The Role of Metalloproteinase ADAM17 in Regulating ICOS Ligand-Mediated Humoral Immune Responses