FOXP3+ regulatory T cells and T helper 1, T helper 2, and T helper 17 cells in human early pregnancy decidua

Abstract

In pregnancy, the decidua is infiltrated by leukocytes promoting fetal development without causing immunological rejection. Murine regulatory T (Treg) cells are known to be important immune regulators at this site. The aim of the study was to characterize the phenotype and origin of Treg cells and determine the quantitative relationship between Treg, T-helper type 1 (T(H)1), T(H)2, and T(H)17 cells in first-trimester human decidua. Blood and decidual CD4(+) T cells from 18 healthy first-trimester pregnant women were analyzed for expression of Treg-cell markers (CD25, FOXP3, CD127, CTLA4, and human leukocyte antigen-DR [HLA-DR]), chemokine receptors (CCR4, CCR6, and CXCR3), and the proliferation antigen MKI67 by six-color flow cytometry. Treg cells were significantly enriched in decidua and displayed a more homogenous suppressive phenotype with more frequent expression of FOXP3, HLA-DR, and CTLA4 than in blood. More decidual Treg cells expressed MKI67, possibly explaining their enrichment at the fetal-maternal interface. Using chemokine receptor expression profiles of CCR4, CCR6, and CXCR3 as markers for T(H)1, T(H)2, and T(H)17 cells, we showed that T(H)17 cells were nearly absent in decidua, whereas T(H)2-cell frequencies were similar in blood and decidua. CCR6(+) T(H)1 cells, reported to secrete high levels of interferon gamma (IFNG), were fewer, whereas the moderately IFNG-secreting CCR6(-) T(H)1 cells were more frequent in decidua compared with blood. Our results point toward local expansion of Treg cells and low occurrence of T(H)17 cells. Furthermore, local, moderate T(H)1 activity seems to be a part of normal early pregnancy, consistent with a mild inflammatory environment controlled by Treg cells.