Programmed cell death-1 (PD-1) is a co-stimulatory molecule that inhibits T-cell proliferation. Recently, we have reported that the prevalence of 7785 T/T genotype of the gene encoding PD-1, PDCD-1 was significantly lower in type 1A diabetes (T1AD) (Metabolism 2007, IDS meeting 2012). We aimed to clarify the expression level of CD4+PD-1+T-cells and analyzed the association between the expression level of PD-1 and 7785C/T polymorphism of PDCD-1 in T1AD and fulminant type 1 diabetes (FT1D) in Japanese population.
We examined 22 patients with T1AD, 14 with FT1D, 19 with type 2 diabetes (T2D) and 29 healthy control subjects (HC). Flow cytometric analysis (FACS) and RT-PCR were performed for the quantitative analysis of PD-1. Genotyping of 7785 C/T polymorphisms in a total of 50 subjects (21 T1AD, 15 FT1D and 14 HC) was performed by the TaqMan method.
FACS analysis showed a significant reduction in the frequency of CD4+PD-1+ T-cells in patients with T1AD (median: 4.0% vs 6.4% in FT1D, p=0.045; vs 6.4% in T2D, p=0.014; vs 5.4% in HC, p=1.7x10-3). PD-1 mRNA expression in CD4+ T-cells was also significantly lower in patients with T1AD than that in HC (median: 0.548 vs 1.877, p=0.002), but not so in patients with FT1D (0.548 vs 0.610, ns). 27(54%), 17(34%) and 6(12%) subjects had the C/C, C/T and T/T genotypes, respectively. The expression level of PD-1 on CD4+PD-1+T-cells in subjects with C/C genotype was significantly lower than that in those with the C/T or T/T genotypes (median 4.1% vs 6.8%, p=0.009).
In conclusion, the expression level of PD-1 on peripheral CD4+PD-1+T-cells was decreased in Japanese patients with type 1A diabetes. Low expression of PD-1 in subjects with C/C genotype might contribute to the development of type 1A diabetes through excessive T-cell activation.