Key molecules and functional subsets of regulatory T cells in maternal-fetal immune tolerance: Recent advances

The establishment and maintenance of maternal-fetal immune tolerance constitutes a fundamental immunological adaptation essential for a successful pregnancy. Regulatory T cells (Tregs) are central orchestrators of this process, actively suppressing effector responses and fostering a tolerogenic microenvironment at the maternal-fetal interface. This review systematically synthesizes recent advances in deciphering the specialized molecular signature and functional heterogeneity of decidual Tregs. We first delineate the molecular profile of CD4⁺ Tregs, emphasizing critical inhibitory receptors-including PD-1, TIM-3, CTLA-4, and TIGIT-that endow decidual CD4⁺ Tregs with their potent suppressive capacity and stability. In parallel, we highlight the critical roles of chemokine receptors such as CCR8 and CXCR4 in orchestrating Treg recruitment, positioning, and functional specialization within decidua. Dysregulation of these molecular pathways is closely linked to clinical conditions like recurrent pregnancy loss and preeclampsia, underscoring their pathophysiological relevance. Beyond the well-characterized CD4⁺ lineage, we further examine the emerging role of CD8⁺ Tregs, which may exhibit potential functional complementarity with their CD4⁺ counterparts through distinct cytotoxic and immunomodulatory mechanisms. By integrating evidence from human studies and experimental models, we underscore how alterations in Treg-associated molecules and subset dynamics underpin pregnancy pathology. Finally, we discuss how this mechanistic understanding paves the way for novel immunotherapeutic strategies-including adoptive transfer of engineered, tissue-homing Tregs or the pharmacological modulation of specific checkpoint pathways-offering promising avenues to restore immune balance and improve outcomes in patients with reproductive immune disorders.