title: The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells.
abstract: 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.
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Anya
authors.initials: A
authors.lastname: Schneider
authors.forename: Mary
authors.initials: M
authors.lastname: Rieck
authors.forename: Srinath
authors.initials: S
authors.lastname: Sanda
authors.forename: Catherine
authors.initials: C
authors.lastname: Pihoker
authors.forename: Carla
authors.initials: C
authors.lastname: Greenbaum
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
mesh_terms: D049109:Cell Proliferation; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*