α 1‐Antitrypsin modifies general natural killer cell interactions with dendritic cells and specific interactions with islet β ‐cells in favour of protection from autoimmune diabetes

Summary The autoimmune destruction of pancreatic β ‐cells is the hallmark of type 1 diabetes (T1D). Failure of anti‐ CD 3 antibodies to provide long‐lasting reversal of T1D and the expression of a natural killer ( 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, NK p46. α 1‐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. 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 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 NK p46 ligand levels on β ‐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 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.