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

Two different subsets of naturally occurring regulatory T cells (nT(regs)), 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- Treg pools with CD45RA(+) CD31(+) RTE T-regs, CD45RA(+) CD31(-) mature naive (MN) T-regs, CD45RA(-) CD31(+) and CD45RA(-) CD31(-) memory T-regs. 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 T-regs 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.