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.
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
M I
MI
Wagner
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
M
M
Jöst
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
J
J
Spratte
Department of Medicine I (Nephrology), University of Heidelberg, Heidelberg, Germany.
M
M
Schaier
Department of Dermatology, University of Heidelberg, Heidelberg, Germany.
K
K
Mahnke
Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
S
S
Meuer
Department of Medicine I (Nephrology), University of Heidelberg, Heidelberg, Germany.
M
M
Zeier
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
A
A
Steinborn
D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation; D005260:Female; D017359:HELLP Syndrome / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011225:Pre-Eclampsia / Q000276:immunology*; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D011247:Pregnancy; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D055815:Young Adult
C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017493:Leukocyte Common Antigens
HELLP syndrome; ICOS+ and ICOS− Tregs; immune suppression; pre-eclampsia; pregnancy