Alternative splicing of CD244 restrains natural killer cells at the maternal-fetal interface.

Abstract

Decidual natural killer (dNK) cells are the predominant lymphocyte population at the maternal-fetal interface during early pregnancy, where they support placentation, vascular remodelling and immune tolerance. Despite their abundance, the mechanisms governing their proliferative state remain poorly understood. Here, we show that first-trimester dNK cells reside in a stable non-cycling state characterized by G0/G1 arrest, suppression of proliferation-associated transcriptional programmes and attenuated kinase signalling. Unlike peripheral blood NK (pNK) cells, dNK cells did not proliferate in response to IL-15 stimulation or exposure to human cytomegalovirus-infected autologous decidual stromal cells, indicating entry into cell-cycle is actively restrained within the decidual compartment. Mechanistically, dNK cells exhibited altered CD244 splice-variant usage together with markedly reduced expression of the adaptor protein SAP (SH2D1A), accompanied by broad attenuation of Src, MAPK, and mTOR signalling. Blockade of the CD244-CD48 axis promoted dNK-cell cycle entry and modulated ERK and p38 activation, identifying this signalling axis as a regulator of proliferative quiescence. Furthermore, decidua-associated cytokines remodelled CD244 splice-variant usage and receptor expression in pNK cells, demonstrating that soluble microenvironmental cues are sufficient to reprogramme NK-cell signalling. Together, these findings reveal a mechanism by which the decidual microenvironment restrains NK-cell proliferation, promoting immune homeostasis at the maternal-fetal interface.