Altered decidual DC-SIGN+ antigen-presenting cells and impaired regulatory T-cell induction in preeclampsia

Abstract

Regulatory T (Treg) cell expansion is required for tolerance of the semi-allogeneic fetus in healthy pregnancy and impaired in preeclampsia in humans. However, the reasons remain unknown. Herein, we show that expansion of CD4(+)Helios(-)Foxp3(+) adaptive Treg (iTreg) cells, rather than CD4(+)Helios(+)Foxp3(+) natural Treg cells, accounts for this expansion in healthy pregnancy. This expansion is even more pronounced in the decidua, where there is an overrepresentation of iTreg cells. In preeclampsia, however, there is impaired systemic iTreg cell expansion, associated with a lack of iTreg cell overrepresentation in the decidua. Because decidual antigen-presenting cells (APCs) may be important for iTreg cell induction, we studied decidual CD14(+) APCs using immunohistochemistry and flow cytometry. We show that decidual CD14(+)DC-SIGN(+) APCs are closely associated with Foxp3(+) Treg cells. Furthermore, CD14(+)DC-SIGN(+) cells display a distinct phenotype compared with their CD14(+)DC-SIGN(-) counterparts. In particular, they have increased expression of tolerogenic molecules, HLA-G, and immunoglobulin-like transcript 4. In vitro, CD14(+)DC-SIGN(+) APCs from healthy pregnant women induced iTreg cells significantly more efficiently than CD14(+)DC-SIGN(-) APCs. Conversely, in preeclampsia, both CD14(+)DC-SIGN(+) and CD14(+)DC-SIGN(-) APCs induced iTreg cells poorly. These results suggest that decidual CD14(+)DC-SIGN(+) APCs may play important roles in iTreg cell induction, a process that is defective in preeclampsia and likely contributes to its pathogenesis.