Leukocyte immunoglobulin-like receptor subfamily B: A novel immune checkpoint molecule at the maternal-fetal interface

Pregnancy is a harmonious, complex physiological process. The reason for not rejecting a genetically different fetus by the maternal immune system is unclear. An increasing number of studies have confirmed that immunological tolerance exists throughout pregnancy, which accounts for protection against an aggressive maternal alloimmune response directed to the allogeneic fetus. Despite the huge progress made, the underlying mechanisms of immunological tolerance at the maternal-fetal interface are not fully elucidated still.

In recent years, the discovery of immune checkpoint molecules (ICMs) has provided some clues revealing the mystery of maternal-fetal tolerance (Miko et al., 2019). ICMs such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), T cell immunoglobulin mucin 3 (TIM-3), and programmed cell death-1 (PD-1) can bind to their ligands and transduce inhibitory signals into cells; thus, negatively regulating immune responses, which provides new insights into immunological research related to normal pregnancy and pregnancy complications. Although significant breakthroughs in ICMs have been made in the field of tumor immune evasion and transplantation tolerance, knowledge of ICMs at the maternal-fetal interface remains limited. The mining of new ICMs and the combined therapy of multiple ICMs not only offer fresh hope for treating tumors, organ transplantation, and autoimmune diseases but also act as a novel approach to explore the mechanism of maternal-fetal tolerance and the treatment of pregnancy-related diseases.

Leukocyte immunoglobulin-like receptor subfamily B (LILRB) is a group of inhibitory receptors widely expressed in a variety of immune cells, including monocytes, macrophages, NK cells, T cells, and B cells. It has attracted increasing interest due to its immunosuppressive effects on the tumor microenvironment. Recent studies have shown that both LILRB3 and LILRB4 are involved in the development of acute myeloid leukemia (AML) (Deng et al., 2018, Wu et al., 2021). LILRB3 in AML cells can lead to the recruitment of c-FLICE-like inhibitory protein and subsequent NF-κB upregulation, resulting in enhanced leukemic cell survival and inhibition of T cell-mediated anti-tumor activity (Wu et al., 2021). In addition, the LILRB4/SHP-2/NF-κB/uPAR/Arginase-1(Arg-1) signaling pathway in monocytic AML cells can suppress immune activity and support leukemic cell migration (Deng et al., 2018). This evidence suggests that LILRB is a potential negative regulator. Moreover, LILRB has a broader impact on immunomodulatory effects compared to CTLA-4 and PD-1. Recently, reports on the roles of LILRB at the maternal-fetal interface have emerged as new perspectives for understanding maternal-fetal dialogue. In this review, we summarize the latest advances in LILRB at the maternal-fetal interface.

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