Table 1.
Co-signaling molecules and their mechanism to induce the maternal-fetal immune tolerance.
| Cells | Co-signaling Molecules |
|---|---|
| Trophoblasts | Syncytiotrophoblasts: PD-L1, CD200, CD200R1, PD-L2 |
| Cytotrophoblasts: PD-L1, CD200, CD200R1 | |
| EVTs: ICOS-L, PD-L1, CD276, CEACAM1, Gal-9, CD200, CD200R1, CD155, CD112 | |
| Decidual stromal cells | TIM-3, Gal-9, PD-L1, PD-L2 |
| Decidual immune cells | dNK cells: CEACAM1, TIM-3, LAIR-1, CD226 |
| Decidual T cells: PD-1, CEACAM-1, TIM-3, LAIR-1 | |
| Decidual macrophages: LAIR-1 | |
| Main Molecules | Recent studies |
| PD-1/PD-L1 | Elevated PD-1 expression in decidual CD8+ T, CD4+ T, and NKT-like cells and PD-L1 expression in decidual CD4+ T, Treg, NKT-like and CD56+ NK cell compared to peripheral blood (30). |
| The soluble PD-L1 increased in pregnant women and suppress maternal immunity (31). | |
| Blockade of PD-1 resulted in decreased proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells (32). | |
| PD-1/PD-L1 signaling is critical for macrophage differentiation and function, which is the success of a pregnancy (33). | |
| PD-1 promote Th2 bias and pregnancy maintenance by regulating CD4+ T cell function at the maternal-fetal interface (34). | |
| TIM-3 | Decidual NKT cells exhibit a reduced TIM-3 expression with increased relative receptor expression and a slightly increased cytotoxicity when compared to the periphery (35). |
| TIM-3+CTLA-4+dCD8+ T cells produced more anti-inflammatory cytokines. Blocking TIM-3 pathways inhibited the anti-inflammatory cytokines and induced fetal loss (36). | |
| TIM-3 pathways maintain tolerance by regulating dCD4+T cells. Blockade of TIM-3 pathways induces fetal loss with altered cytokine profiles by dCD4+ T cells (37). | |
| TIM-3 is upregulated in NK cells and inhibits NK cytotoxicity toward trophoblast in Gal-9 dependent pathway (38). | |
| Activation of TLR signaling induced upregulated TIM-3 expression. TIM-3 inhibited TLR signaling-induced inflammatory cytokine production (39). | |
| TIM-3 are expressed on over 60% of dNK cells. TIM-3+ dNK cells display higher IL-4 and lower TNF-α and perforin production. | |
| Peripheral NK cells can be transformed into a dNK-like phenotype via Gal-9 and the interaction between Gal-9 and TIM-3. | |
| Trophoblasts inhibit LPS-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by TIM-3 neutralizing antibodies. | |
| Th2-type cytokines decreased and Th1-type cytokines increased in TIM-3+ dNK cells from human and mouse miscarriages (40). | |
| CTLA-4 | Blocking CTLA-4 pathways inhibited the anti-inflammatory cytokines and induced fetal loss (36). |
| CTLA-4 pathways maintain tolerance by regulating dCD4+T cells. Blockade of CTLA-4 pathways induces fetal loss with altered cytokine profiles by dCD4+ T cells (37). | |
| Antigen-stimulated T cells become activated ligated with CD28 and anergic ligated with CTLA-4 (41). | |
| ICOS/ICOS-L | ICOS-L blockade abrogates placental immune tolerance by enhancing CD8+ effector response and reducing local immunomodulation via CD8+ Treg cells (42). |
| CEACAM1 | CEACAM1 interactions inhibit the lysis, proliferation, and cytokine secretion of activated dNK, T, and NKT cells, respectively (43). |
| LAIR-1 | Co-culture of dNK with primary TROs/DSCs downregulated Th1 cytokine production, which were abrogated by LAIR-1 inhibitor (44). |
PD-L1, programmed death-ligand 1; CD200, cluster of differentiation-200; CD200R1, CD200 receptor 1; PD-L2, programmed death-ligand 2; ICOS-L, inducible co-stimulator ligand; CD276, cluster of differentiation-276; CEACAM1, carcinoembryonic Ag cell adhesion molecule 1; Gal-9, galectin-9; CD155, cluster of differentiation-155; CD112, cluster of differentiation-112; TIM-3, T cell immunoglobulin and mucin domain 3; LAIR-1, leukocyte-associated immunoglobulin-like receptor-1; CD226, cluster of differentiation-226.