CXCL12/CXCR4 signal involved in the regulation of trophoblasts on peripheral NK cells leading to Th2 bias at the maternal-fetal interface

Abstract

Objective: In the early pregnancy, large number of decidual natural killer (dNK) cells are present in decidua, which exhibit distinctive phenotype and functions from peripheral blood NK cells (pNK)1. Unlike the cytotoxic pNK cells, dNK cells display more pronounced characteristics of immune tolerance, which contribute the Th2 bias at the maternal-fetal interface and ensure successful pregnancy2. However, the origin and the differentiation program of dNK still remain unknown.

Materials and methods: Our previous study has demonstrated that the CXCL12/CXCR4 signal axis is involved in the shaping of Th2 bias at the maternal-fetal interface3,4.

Results: In this study, we demonstrated the first-trimester human trophoblast cells secrete chemokine CXCL12 that can recruit pNK cells to the decidua. We've also found that the pNK cells differentiate locally under the influence of trophablast cells. After co-culture with trophoblast cells, pNK cells could acquire dNK characteristics phenotypically while compared to the dNK cells; however, the blocking of CXCL12/CXCR4 signal of pNK cells has abrogated the modulation of trophoblast cells on the pNK cells. We've also found that JNK1/2/MAPK and ERK/MAPK signal pathways were required for the modulation of trophoblast cells on the pNK cells. MAPK signal pathway is involved in the functional modulation of human first-trimester trophoblast cells and decidual stromal cells on pNK and dNK cells.

Conclusions: Our study has elucidated that CXCL12/CXCR4 can recruit pNK cells to the decidua, then positively modulate pNK cells differentiation into the dNK cells, which thus results in Th2 bias and maternal-fetal immune tolerance.