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

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.

Schober L ，Radnai D ，Spratte J ，Kisielewicz A ，Schmitt E ，Mahnke K ，Fluhr H ，Uhlmann L ，Sohn C ，Steinborn A ... -  《-》

Pregnancy-associated diseases are characterized by the composition of the systemic regulatory T cell (Treg) pool with distinct subsets of Tregs.

Dysregulations concerning the composition and function of regulatory T cells (T(regs)) are assumed to be involved in the pathophysiology of complicated pregnancies. We used six-colour flow cytometric analysis to demonstrate that the total CD4(+) CD127(low+/-) CD25(+) forkhead box protein 3 (FoxP3)(+) T(reg) cell pool contains four distinct T(reg) subsets: DR(high+) CD45RA(-), DR(low+) CD45RA(-), DR(-) CD45RA(-) T(regs) and naive DR(-) CD45RA(+) T(regs). During the normal course of pregnancy, the most prominent changes in the composition of the total T(reg) cell pool were observed between the 10th and 20th weeks of gestation, with a clear decrease in the percentage of DR(high+) CD45RA(-) and DR(low+) CD45RA(-) T(regs) and a clear increase in the percentage of naive DR(-) CD45RA(+) T(regs). After that time, the composition of the total T(reg) cell pool did not change significantly. Its suppressive activity remained stable during normally progressing pregnancy, but decreased significantly at term. Compared to healthy pregnancies the composition of the total T(reg) cell pool changed in the way that its percentage of naive DR(-) CD45RA(+) T(regs) was reduced significantly in the presence of pre-eclampsia and in the presence of preterm labour necessitating preterm delivery (PL). Interestingly, its percentage of DR(high+) CD45RA(-) and DR(low+) CD45RA(-) T(regs) was increased significantly in pregnancies affected by pre-eclampsia, while PL was accompanied by a significantly increased percentage of DR(-) CD45RA(-) and DR(low+) CD45RA(-) T(regs). The suppressive activity of the total T(reg) cell pool was diminished in both patient collectives. Hence, our findings propose that pre-eclampsia and PL are characterized by homeostatic changes in the composition of the total T(reg) pool with distinct T(reg) subsets that were accompanied by a significant decrease of its suppressive activity.

Steinborn A ，Schmitt E ，Kisielewicz A ，Rechenberg S ，Seissler N ，Mahnke K ，Schaier M ，Zeier M ，Sohn C ... -  《-》

The success of assisted reproduction technologies in relation to composition of the total regulatory T cell (Treg) pool and different Treg subsets.

Schlossberger V ，Schober L ，Rehnitz J ，Schaier M ，Zeier M ，Meuer S ，Schmitt E ，Toth B ，Strowitzki T ，Steinborn A ... -  《-》

CD4⁺ CD45RA⁻ FoxP3high activated regulatory T cells are functionally impaired and related to residual insulin-secreting capacity in patients with type 1 diabetes.

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.

Haseda F ，Imagawa A ，Murase-Mishiba Y ，Terasaki J ，Hanafusa T ... -  《-》

Differentiation of ICOS+ and ICOS- recent thymic emigrant regulatory T cells (RTE T regs) during normal pregnancy, pre-eclampsia and HELLP syndrome.

Two different subsets of naturally occurring regulatory T cells (nTregs), defined by their expression of the inducible co-stimulatory (ICOS) molecule, are produced by the human thymus. To examine the differentiation of ICOS(+) and ICOS(-) CD45RA(+) CD31(+) recent thymic emigrant (RTE) T regs during normal pregnancy and in the presence of pre-eclampsia or haemolysis elevated liver enzymes low platelet (HELLP)-syndrome, we used six-colour flow cytometric analysis to determine the changes in the composition of the ICOS(+) and ICOS(-) T reg pools with CD45RA(+) CD31(+) RTE T regs, CD45RA(+) CD31(-) mature naive (MN) T regs, CD45RA(-) CD31(+) and CD45RA(-) CD31(-) memory Tregs. With the beginning of pregnancy until term, we observed a strong differentiation of both ICOS(+) and ICOS(-) CD45RA(+) CD31(+) RTE, but not CD45RA(+) CD31(-) MN T regs, into CD45RA(-) CD31(-) memory T regs. At the end of pregnancy, the onset of spontaneous term labour was associated with a significant breakdown of ICOS(+) CD45RA(-) CD31(-) memory T regs. However, in the presence of pre-eclampsia, there was a significantly increased differentiation of ICOS(+) and ICOS(-) CD45RA(+) CD31(+) RTE T regs into CD45RA(-) CD31(+) memory T regs, wherein the lacking differentiation into CD45RA(-) CD31(-) memory T regs was partially replaced by the increased differentiation of ICOS(+) and ICOS(-) CD45RA(+) CD31(-) MN Tregs into CD45RA(-) CD31(-) memory T regs. In patients with HELLP syndrome, this alternatively increased differentiation of CD45RA(-) CD31(-) MN T regs seemed to be exaggerated, and presumably restored the suppressive activity of magnetically isolated ICOS(+) and ICOS(-) T regs, which were shown to be significantly less suppressive in pre-eclampsia patients, but not in HELLP syndrome patients. Hence, our findings propose that the regular differentiation of both ICOS(+) and ICOS(-) CD45RA(+) CD31(+) RTE T regs ensures a healthy pregnancy course, while their disturbed differentiation is associated with the occurrence of pre-eclampsia and HELLP syndrome.

Wagner MI ，Jöst M ，Spratte J ，Schaier M ，Mahnke K ，Meuer S ，Zeier M ，Steinborn A ... -  《-》