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

J Sitrin, A Ring, KC Garcia, C Benoist… - Journal of Experimental …, 2013 - rupress.org
J Sitrin, A Ring, KC Garcia, C Benoist, D Mathis
Journal of Experimental Medicine, 2013rupress.org
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 …
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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