title: CD4⁺ CD45RA⁻ FoxP3high activated regulatory T cells are functionally impaired and related to residual insulin-secreting capacity in patients with type 1 diabetes.
abstract: Accumulating lines of evidence have suggested that regulatory T cells (T(regs)) play a central role in T cell-mediated immune response and the development of type 1A and fulminant type 1 diabetes. CD4(+) forkhead box protein 3 (FoxP3)(+) T cells are composed of three phenotypically and functionally distinct subpopulations; CD45RA(+) FoxP3(low) resting T(regs) (r-T(regs)), CD45RA(-) FoxP3(high) activated T(regs) (a-T(regs)) and CD45RA(-) FoxP3(low) non-suppressive T cells (non-T(regs)). We aimed to clarify the frequency of these three subpopulations in CD4(+) FoxP3(+) T cells and the function of a-T(regs) with reference to subtypes of type 1 diabetes. We examined 20 patients with type 1A diabetes, 15 patients with fulminant type 1 diabetes, 20 patients with type 2 diabetes and 30 healthy control subjects. A flow cytometric analysis in the peripheral blood was performed for the frequency analysis. The suppressive function of a-T(regs) was assessed by their ability to suppress the proliferation of responder cells in a 1/2:1 co-culture. A flow cytometric analysis in the peripheral blood demonstrated that the frequency of a-T(regs) was significantly higher in type 1A diabetes, but not in fulminant type 1 diabetes, than the controls. Further, the proportion of a-T(regs) among CD4(+) FoxP3(+) T cells was significantly higher in patients with type 1A diabetes with detectable C-peptide but not in patients with type 1A diabetes without it and with fulminant type 1 diabetes. A proliferation suppression assay showed that a-T(regs) were functionally impaired both in fulminant type 1 diabetes and in type 1A diabetes. In conclusion, a-T(regs) were functionally impaired, related to residual insulin-secreting capacity and may be associated with the development of type 1 diabetes.
authors.affiliation: Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Osaka, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Haseda
authors.forename: A
authors.initials: A
authors.lastname: Imagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Murase-Mishiba
authors.forename: J
authors.initials: J
authors.lastname: Terasaki
authors.forename: T
authors.initials: T
authors.lastname: Hanafusa
mesh_terms: D002096:C-Peptide / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D002096:C-Peptide; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007328:Insulin; D017493:Leukocyte Common Antigens
keywords: CD4+CD45RA−FoxP3high activated Treg; FoxP3; fulminant type 1 diabetes; sCTLA-4; type 1A diabetes