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* Benaroya Research Institute at Virginia Mason, Seattle, WA 98101; and
Children’s Hospital and Regional Medical Center, Seattle, WA 98105
Defects in immune regulation have been implicated in the pathogenesis of diabetes in mouse and in man. In vitro assays using autologous regulatory (Treg) and responder effector (Teff) T cells have shown that suppression is impaired in diabetic subjects. In this study, we addressed whether the source of this defect is intrinsic to the Treg or Teff compartment of diabetic subjects. We first established that in type 1 diabetes (T1D) individuals, similar levels of impaired suppression were seen, irrespective of whether natural (nTreg) or adaptive Treg (aTreg) were present. Then using aTreg, we examined the ability of T1D aTreg to suppress Teff of healthy controls, as compared with the ability of control aTreg to suppress Teff of diabetic subjects. Taking this approach, we found that the aTregs from T1D subjects function normally in the presence of control Teff, and that the T1D Teff were resistant to suppression in the presence of control aTreg. This escape from regulation was seen with nTreg as well and was not transferred to control Teff coincubated with T1D Teff. Thus, the "defective regulation" in T1D is predominantly due to the resistance of responding T cells to Treg and is a characteristic intrinsic to the T1D Teff. This has implications with respect to pathogenic mechanisms, which underlie the development of disease and the target of therapies for T1D.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by the Benaroya Research Institute, Juvenile Diabetes Research Foundation Center for Translational Research, Juvenile Diabetes Research Foundation Research Award (33-2008-398) (to J.H.B.), Dana Foundation Grant R01 DK072457 (to J.H.B.), and a Deutsche Forschungsgemeinschaft fellowship (1083/2-1) (to A.S.).
2 Address correspondence and reprint requests to Dr. Jane H. Buckner, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101. E-mail address: jbuckner{at}benaroyaresearch.org
3 Abbreviations used in this paper: Treg, regulatory T cell; T1D, type 1 diabetes; T2D, type 2 diabetes; aTreg, adaptive Treg; Teff, effector T cell; nTreg, natural Treg.
4 The online version of this article contains supplemental material.
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