Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2

Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Journal of Experimental Medicine (Impact Factor: 12.52). 05/2013; 210(6). DOI: 10.1084/jem.20122248
Source: PubMed


Regulatory T (T reg) cells control progression to autoimmune diabetes in the BDC2.5/NOD mouse model by reining in natural killer (NK) cells that infiltrate the pancreatic islets, inhibiting both their proliferation and production of diabetogenic interferon-γ. In this study, we have explored the molecular mechanisms underlying this NK-T reg cell axis, following leads from a kinetic exploration of gene expression changes early after punctual perturbation of T reg cells in BDC2.5/NOD mice. Results from gene signature analyses, quantification of STAT5 phosphorylation levels, cytokine neutralization experiments, cytokine supplementation studies, and evaluations of intracellular cytokine levels collectively argue for a scenario in which T reg cells regulate NK cell functions by controlling the bioavailability of limiting amounts of IL-2 in the islets, generated mainly by infiltrating CD4(+) T cells. This scenario represents a previously unappreciated intertwining of the innate and adaptive immune systems: CD4(+) T cells priming NK cells to provoke a destructive T effector cell response. Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets.

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Available from: Aaron M Ring, May 23, 2014
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    • "Interest for the IL-2 dependent control of NK cells has recently been renewed by a series of studies proposing that NK cell activity was kept in check by Treg cells buffering excess IL-2 produced by activated T cells (77, 78). In these studies, the authors show that systemic Treg cell depletion leads to an increase in CD4 T cell derived IL-2. "
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    ABSTRACT: The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non-self-ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2-dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2.
    Journal of Experimental Medicine 05/2013; 210(6). DOI:10.1084/jem.20122462 · 12.52 Impact Factor
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