期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 210, 期 6, 页码 1153-1165出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20122248
关键词
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资金
- National Institutes of Health [R01AI051530, R01AI51321]
- Howard Hughes Medical Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
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-gamma. 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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