The role of regulatory T cell (Treg) subsets in gestational diabetes mellitus

Abstract

Physiological changes during normal pregnancy are characterized by an inflammatory immune response and insulin resistance. Therefore, we hypothesize that gestational diabetes mellitus (GDM) may be caused by an inappropriate adaption of the maternal immune system to pregnancy. In this study we examined the role of regulatory T cell (Treg) differentiation for the development of GDM during pregnancy. We used six-colour flow cytometric analysis to demonstrate that the total CD4(+) CD127(low+/-) CD25(+) forkhead box protein 3 (FoxP3(+)) T(reg) pool consists of four different T(reg) subsets: naive CD45RA(+) T(regs), HLA-DR(-) CD45RA(-) memory T(regs) (DR(-) T(regs)) and the highly differentiated and activated HLA-DR(low+) CD45RA(-) and HLA-DR(high+) CD45RA(-) memory T(regs) (DR(low+) and DR(high+) T(regs)). Compared to healthy pregnancies, the percentage of CD4(+) CD127(low+/-) CD25(+) FoxP3(+) T(regs) within the total CD4(+) T helper cell pool was not different in patients affected by GDM. However, the suppressive activity of the total CD4(+) CD127(low+/-) CD25(+) T(reg) pool was significantly reduced in GDM patients. The composition of the total T(reg) pool changed in the way that its percentage of naive CD45RA(+) T(regs) was decreased significantly in both patients with dietary-adjusted GDM and patients with insulin-dependent GDM. In contrast, the percentage of DR(-) -memory T(regs) was increased significantly in patients with dietary-adjusted GDM, while the percentage of DR(low+) and DR(high+) memory T(regs) was increased significantly in patients with insulin-dependent GDM. Hence, our findings propose that alterations in homeostatic parameters related to the development and function of naive and memory T(regs) may cause the reduction of the suppressive capacity of the total T(reg) pool in GDM patients. However, as this is an exploratory analysis, the results are only suggestive and require further validation.

Keywords: gestational diabetes mellitus; immune suppression; inflammation; pregnancy; subsets of regulatory T cells.