LILRA/B Immune Checkpoint Molecule for Drug Development

Introduction to LILRA/B

Molecules of the human leukocyte immunoglobulin-like receptor (LILR) family are expressed on leukocytes and are commonly dysregulated in a wide range of pathologies. There are 5 activating (LILRA1, 2, 4-6), 5 inhibitory (LILRB1-5), and 1 soluble (LILRA3) LILR that together regulate immune responses. They display 2, or 4, homologous C-2-type Ig-like extracellular domains but differ in their transmembrane and cytoplasmic regions.

Table.1 LILR family member.

Principle Name CD Name Alternative Names Expression
LILRA1 CD85i LIR-6, LIR6 Macrophages
LILRA2 CD85h ILT1, LIR-7, LIR7 Monocytes, macrophages, dendritic cells, NK cells, basophils, eosinophils
LILRA3 CD85e ILT6, LIR-4, LIR4, HM43, HM31 Monocytes
LILRA4 CD85g ILT7 Plasmacytoid dendritic cells
LILRA5 CD85f ILT11, LIR-9, LIR9, LILRB7 CD14+ monocytes
LILRA6 CD85b ILT8, LILRB6 Unknown
LILRB1 CD85j ILT2, LIR-1, LIR1, MIR7 Monocytes, macrophages, dendritic cells, osteoclasts, eosinophils, B cells, T cells, NK cells, placental stromal cells
LILRB2 CD85d ILT4, LIR-2, LIR2, MIR10, MIR-10 Monocytes, macrophages, dendritic cells, osteoclasts, basophils, eosinophils, placental vascular smooth muscle
LILRB3 CD85a ILT5, LIR-3, LIR3, HL9 Monocytes, macrophages, dendritic cells, osteoclasts, basophils, eosinophils
LILRB4 CD85k ILT3, LIR-5, LIR5, HM18 Monocytes, macrophages, dendritic cells, osteoclasts
LILRB5 CD85c LIR-8, LIR8 Unknown

Specifically, LILRA has short truncated cytoplasmic tails with charged arginine residues in their transmembrane domains, facilitating association with the immunoreceptor tyrosine-based activation motif-bearing Fcε receptor γ chain to propagate activating signaling cascades. Conversely, LILRB has long cytoplasmic tails containing multiple immunoreceptor tyrosine-based inhibition motifs (ITIMs), which recruit phosphatases such as SHP-1 and SHIP-1 to elicit inhibitory signaling.

Fig. 1 Schematic diagram of the LILR family. (Brown, 2004)Fig. 1 Schematic diagram of the LILR family.1

Hot Immune Checkpoints and Signal Pathway

The LILRB molecules are proposed to act as immune checkpoints serving to control and limit overt immune responses. LILRB expression is increased in suppressive macrophages and tolerogenic dendritic cells. On monocytes, colligation of LILRB1 and LILRB2 with the activatory Fcγ receptor I results in SHP-1 activation, decreasing downstream phosphorylation events and intracellular calcium mobilization. Engagement of LILRB1 on macrophages by the common HLA-I subunit, β2-microglobulin, on malignant cells limits their phagocytic potential. It has also been proved that ligation of LILRB1, 2, or 4 renders DCs tolerogenic, leading to inhibition of T cell responses. The engagement of LILRB1 and LILRB2 by their high-affinity ligand HLA-G is an important immunosuppressive pathway at the fetal-maternal interface during pregnancy and may be involved in tumor immune evasion.

HLA-G-induced pathways following interaction with its receptors. Fig.2 HLA-G-induced pathways following interaction with its receptors. (Carosella, 2021)

LILRB1 and LILRB2 are immune checkpoint receptors that regulate a wide range of physiological responses by binding to diverse ligands, exerting their functions in immunological, neurologic, developmental, and infectious responses. Fig.2 shows the interaction between HLA-G and LILRB1/LILRB2 receptors. Recent findings also reveal powerful immunosuppressive functions of LILRB3 and identify it as an important myeloid checkpoint receptor. Currently, many antibodies targeting human LILRBs are under clinical trials.

Many types of research and development programs target the LILRA/B of myeloid checkpoints to overcome immune resistance. Creative Biolabs brings significant drug discovery and development expertise to this challenge, complementary to over a decade of research by academic collaborators, to evaluate the role of this family of receptors in cancer. Our highlighted immune checkpoint-related services include immune checkpoint assays, immune checkpoint antibody development, and so on. For more services, please refer to our Services for more information. Please don't hesitate to contact us for more details.


  1. Carosella, E. D.; et al. HLA-G/LILRBs: A Cancer Immunotherapy Challenge. Trends in Cancer. 2021.
  2. Brown, D., John Trowsdale, and R. Allen. The LILR family: modulators of innate and adaptive immune pathways in health and disease. Tissue antigens. 64.3 (2004): 215-225

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