title: Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2.
abstract: 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.
authors: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Jonathan
authors: J
authors: Sitrin
authors: Aaron
authors: A
authors: Ring
authors: K Christopher
authors: KC
authors: Garcia
authors: Christophe
authors: C
authors: Benoist
authors: Diane
authors: D
authors: Mathis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007376:Interleukin-2 / Q000172:deficiency* / Q000276:immunology* / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D050799:STAT5 Transcription Factor; D016212:Transforming Growth Factor beta
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