title: α1-Antitrypsin modifies general NK cell interactions with dendritic cells and specific interactions with islet β-cells in favor of protection from autoimmune diabetes.
abstract: The autoimmune destruction of pancreatic β-cells is the hallmark of type 1 diabetes (T1D). Failure of anti-CD3 antibodies to provide long-lasting reversal of T1D and the expression of an NK cell ligand on β-cells suggest that NK cells play a role in disease pathogenesis. Indeed, killing of β-cells by NK cells has been shown to occur, mediated by activation of the NK cell activating receptor, NKp46. α1-antitrypsin (AAT), an anti-inflammatory and immunomodulatory glycoprotein, protects β-cells from injurious immune responses and is currently evaluated as a therapeutic for recent onset T1D. While isolated T lymphocytes are not inhibited by AAT, dendritic cells (DCs) become tolerogenic in its presence and other innate immune cells become less inflammatory. Yet a comprehensive profile of NK cell responses in the presence of AAT has yet to be described. In the present study, we demonstrate that AAT significantly reduces NK cell degranulation against β-cells, albeit in the whole animal and not in isolated NK cell cultures. AAT-treated mice, and not isolated cultured β-cells, exhibited a marked reduction in NKp46 ligand levels on β-cells. In related experiments, AAT-treated DCs exhibited reduced inducible DC-expressed IL-15 levels and evoked a weaker NK cell response. NK cell depletion in a T1D mouse model resulted in improved β-cell function and survival, similar to the effects observed by AAT treatment alone; nonetheless, the two approaches were non-synergistic. Our data suggest that AAT is a selective immunomodulator that retains pivotal NK cell responses, while diverting their activities away from islet β-cells. This article is protected by copyright. All rights reserved.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Guttman
authors.forename: Rami
authors.initials: R
authors.lastname: Yossef
authors.forename: Gabriella
authors.initials: G
authors.lastname: Freixo-Lima
authors.forename: Peleg
authors.initials: P
authors.lastname: Rider
authors.forename: Angel
authors.initials: A
authors.lastname: Porgador
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
keywords: crosstalk; interleukin-15; islets; pancreatic β-cells; type 1 diabetes