Immune checkpoint blockade therapy has been successful in treating some types of cancers but has not shown clinical benefits for treating leukemia 1 . This result suggests that leukemia exploits unique escape mechanisms. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukemia cells. It remains unknown whether these receptors can initiate immune-related primary signaling in tumor cells. Here we show that LILRB4, an ITIM-containing receptor and a monocytic leukemia marker, supports tumor cell infiltration into tissues and suppresses T cell activity via ApoE/LILRB4/SHP-2/uPAR/Arginase-1 signaling axis in acute myeloid leukemia (AML) cells. Blocking LILRB4 signaling using knockout and antagonistic antibody approaches impeded AML development. Thus, LILRB4 orchestrates tumor invasion pathways in monocytic leukemia cells by creating an immune-suppressive microenvironment. LILRB4 represents a compelling target for treatment of monocytic AML.
Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths annually1. Plasmodium falciparum is the causative agent of most life-threatening malaria cases. Acquired immunity to malaria is inefficient, even after repeated exposures to P. falciparum2; immune regulatory mechanisms employed by P. falciparum remain largely unclear. Here, we show that P. falciparum uses immune inhibitory receptors for immune evasion. RIFINs, products of a polymorphic multigene family comprising approximately 150–200 genes per parasite genome3, are expressed on the surface of infected erythrocytes. We found that a subset of RIFINs binds to either leucocyte immunoglobulin-like receptor B1 (LILRB1) or leucocyte-associated immunoglobulin-like receptor 1 (LAIR1). LILRB1-binding RIFINs inhibited activation of LILRB1-expressing B cells and NK cells. Furthermore, interactions between LILRB1 and P. falciparum-infected erythrocytes isolated from malaria patients were associated with severe malaria, although an extended study with larger sample sizes is required to confirm the findings. These results suggest that P. falciparum has acquired multiple RIFINs to evade the host immune system by targeting immune inhibitory receptors.
Key Points• b2GPI complexed with HLA class II molecules was found to be a target for autoantibodies in APS.• More than 80% of patients with APS possess autoantibodies against b2GPI/HLA class II complexes.Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. b2-glycoprotein I (b2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact b2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize b2GPI/HLA class II complexes in the absence of phospholipids. In situ association between b2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against b2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that b2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis. (Blood. 2015;125(18):2835-2844 IntroductionAntiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial or venous thrombosis and pregnancy complications, including recurrent spontaneous abortion.1,2 APS is associated with antiphospholipid (aPL) antibodies that bind to anionic phospholipid and serum protein complexes. [3][4][5] Interactions between aPL antibodies and vascular endothelial cells are thought to be involved in the pathogenesis of APS.6-9 b2-glycoprotein I (b2GPI) is the main phospholipid-binding molecule recognized by aPL antibodies 5,10,11 and is produced predominantly by hepatocytes, although some endothelial cells of blood vessels and placental villous tissue also express it.12,13 Plasma b2GPI circulates in a circular conformation with the aPL antibody epitopes being cryptic.14 When b2GPIassociates with anionic phospholipids such as cardiolipin (CL), the circular structure of plasma b2GPI is converted to a linear form, leading to exposure of the major epitope for aPL antibodies. [14][15][16][17][18][19] Therefore, b2GPI bound to negatively charged phospholipids or negatively charged plates is used clinically to detect antibodies. 20However, autoantibodies against the b2GPI associated with phospholipids are detected in less than half the patients with clinical manifestations of APS, [21][22][23] suggesting the existence of additional ta...
Human leukocyte immunoglobulin-like receptors (LILR) are a family of 11 functional genes encoding five activating (LILRA1, 2, 4-6), five inhibitory (LILRB1-5) and one soluble (LILRA3) form. The number of LILR genes is conserved among individuals, except for LILRA3 and LILRA6, which exhibit copy-number variations. The LILR genes are rapidly evolving and showing large interspecies differences, making it difficult to analyze the functions of LILR using an animal model. LILRs are expressed on various cells such as lymphoid and myeloid cells and the expression patterns are different from gene to gene. The LILR gene expression and polymorphisms have been reported to be associated with autoimmune and infectious diseases such as rheumatoid arthritis and cytomegalovirus infection. Although human leukocyte antigen (HLA) class I is a well-characterized ligand for some LILRs, non-HLA ligands have been increasingly identified in recent years. LILRs have diverse functions, including the regulation of inflammation, immune tolerance, cell differentiation and nervous system plasticity. This review focuses on the genetic and functional diversity of the LILR family.
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