title: Proinflammatory cytokines contribute to development and function of regulatory T cells in type 1 diabetes.
abstract: Type 1 diabetes is caused by immune-mediated loss of pancreatic beta cells. It has been proposed that inflammatory cytokines play a role in killing beta cells. Expression of interleukin (IL)-1 and tumor necrosis factor (TNF-α) has been detected in islets from patients with type 1 diabetes, and these cytokines can induce beta cell death in vitro. We produced nonobese diabetic (NOD) mice lacking receptors for these cytokines. Islets from mice lacking IL-1RI or TNFR1 were killed when transplanted into wild-type NOD mice, suggesting that cytokine action on beta cells is not required for killing. Mice lacking TNFR1 did not develop diabetes, and mice lacking IL-1R had delayed onset of diabetes, indicating a role for these cytokines in disease development. TNFR1-deficient mice had an increased number of CD4(+) CD25(+) FoxP3(+) regulatory T cells with enhanced suppressive capacity. IL-1 was produced at higher levels in NOD mice and resulted in dilution of suppressor function of CD4(+) CD25(+) FoxP3(+) regulatory T cells. Our data suggest that blocking inflammatory cytokines may increase the capacity of the immune system to suppress type 1 diabetes through regulatory T cells.
authors.affiliation: Immunology and Diabetes Unit, St. Vincent's Institute, Fitzroy, Victoria, Australia. hthomas@svi.edu.au
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.forename: Kate L
authors.initials: KL
authors.lastname: Graham
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chee
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kay
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Krishnamurthy
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators