Abstract

A previously successful pregnancy promotes the fitness of subsequent pregnancies, of which the pregnancy-induced memory is ascribed exclusively to adaptive lymphocytes. However, whether macrophages at maternal-fetal interface acquire pregnancy-specific immune memory remains unclear. Using human decidual samples and complementary mouse models, we identify human leukocyte immunoglobulin-like receptor subfamily B3 + (LILRB3 + ) and murine paired immunoglobulin-like receptor B + (PIR-B + ) macrophages as a uterine memory subset, which expands progressively with gravidity and gestational age, and exhibits paternal specific immune memory. In both species, these cells exhibited hallmarks of pregnancy-induced trained tolerance, including elevated IL-10, TGF-β, and CD206, together with reduced CD80/CD86 expression and suppression of pro-inflammatory cytokines. Mechanistically, PIR-B-SHP signaling drives macrophage metabolic reprogramming to oxidative phosphorylation/fatty acid oxidation for the formation of memory. Moreover, adoptive transfer of PIR-B + uterine macrophages into abortion-prone mouse models significantly improves pregnancy outcomes, highlighting their therapeutic potential. Together, our findings uncover a previously unrecognized form of decidual macrophage trained memory in an antigen-specific manner, which opens avenues for therapeutic strategies aimed at preventing or reducing recurrent pregnancy loss.