RESUMO
Programmed cell death-1 (PD-1) is a co-stimulatory molecule that inhibits T cell proliferation. We aimed to clarify PD-1 expression in CD4(+) T cells and the association between PD-1 expression and the 7785C/T polymorphism of PDCD1, with a focus on the two subtypes of type 1 diabetes, type 1A diabetes (T1AD) and fulminant type 1 diabetes (FT1D), in the Japanese population. We examined 22 patients with T1AD, 15 with FT1D, 19 with type 2 diabetes (T2D) and 29 healthy control (HC) subjects. Fluorescence-activated cell sorting (FACS) and real-time PCR were utilized to analyse PD-1 expression quantitatively. Genotyping of 7785C/T in PDCD1 was performed using the TaqMan method in a total of 63 subjects (21 with T1AD, 15 with FT1D and 27 HC). FACS revealed a significant reduction in PD-1 expression in CD4(+) T cells in patients with T1AD (mean: 4.2 vs. 6.0% in FT1D, P=0.0450; vs. 5.8% in T2D, P=0.0098; vs. 6.0% in HC, P=0.0018). PD-1 mRNA expression in CD4(+) T cells was also significantly lower in patients with T1AD than in the HC subjects. Of the 63 subjects, PD-1 expression was significantly lower in individuals with the 7785C/C genotype than in those with the C/T and T/T genotypes (mean: 4.1 vs. 5.9%, P=0.0016). Our results indicate that lower PD-1 expression in CD4(+) T-cells might contribute to the development of T1AD through T cell activation.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Expressão Gênica , Genótipo , Humanos , Japão , Leucócitos Mononucleares , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , RNA Mensageiro/genética , Adulto JovemRESUMO
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.