期刊
IMMUNOLOGY
卷 144, 期 3, 页码 530-539出版社
WILEY-BLACKWELL
DOI: 10.1111/imm.12403
关键词
cross-talk; interleukin-15; islets; pancreatic beta-cells; type 1 diabetes
类别
资金
- Juvenile Diabetes Research Foundation (JDRF)
- Israel Science Foundation (ISF) - JDRF Joint Program in Type I Diabetes Research
The autoimmune destruction of pancreatic beta-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 a natural killer (NK) cell ligand on beta-cells suggest that NK cells play a role in disease pathogenesis. Indeed, killing of beta-cells by NK cells has been shown to occur, mediated by activation of the NK cell activating receptor, NKp46. alpha 1-Antitrypsin (AAT), an anti-inflammatory and immunomodulatory glycoprotein, protects beta-cells from injurious immune responses and is currently evaluated as a therapeutic for recent onset T1D. Although isolated T lymphocytes are not inhibited by AAT, dendritic cells (DC) 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 beta-cells, albeit in the whole animal and not in isolated NK cell cultures. AAT-treated mice, and not isolated cultured beta-cells, exhibited a marked reduction in NKp46 ligand levels on beta-cells. In related experiments, AAT-treated DC exhibited reduced inducible DC-expressed interleukin-15 levels and evoked a weaker NK cell response. NK cell depletion in a T1D mouse model resulted in improved beta-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 beta-cells.
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