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Inhibitory pattern recognition receptors: lessons from LAIR1

Abstract

Many inhibitory receptors that regulate immune cell function recognize a limited number of specific ligands. However, a subgroup of so-called inhibitory pattern recognition receptors (iPRRs) can bind a much larger array of ligands of structural similarity. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is one such iPRR that is expressed by most immune cells and recognizes a common structural pattern present in collagens and collagen domain-containing proteins. LAIR1 signalling regulates diverse immune cell populations and is currently the focus of multiple clinical trials for the treatment of cancer. We here review the current literature on LAIR1, as a prototypic example of how inhibitory PRRs contribute to immune balance and of how these receptors are regulated. We discuss the function of LAIR1 in homeostasis, infection, inflammation and cancer, and consider the advantages and potential pitfalls of targeting this receptor in human disease.

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Fig. 1: Flexibility of LAIR1 signalling.
Fig. 2: Regulation of the LAIR1 inhibitory axis.
Fig. 3: LAIR1 in the tumour microenvironment.

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Acknowledgements

The authors thank all members of the Inhibitory Receptor Lab for their critical review and discussion of the manuscript.

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The authors contributed equally to all aspects of the article.

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Correspondence to Linde Meyaard.

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The research laboratory at University Medical Center Utrecht has received research funding from NextCure, NGM Biopharmaceuticals, Boehringer Ingelheim and argenx. L.M. has received consultancy fees from Eli Lilly, Third Rock Ventures and Abbvie, all paid to the institute. M.I.P.R., L.M. and M.v.d.V. have not received personal fees or other personal benefits.

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Glossary

C2-type immunoglobulin-like domain

A protein domain that shows evolutionary similarity, in both linear sequence and folded structure, to the immunoglobulin constant region type 2 (C2) domains. This structural motif is found in various proteins involved in cell adhesion, immune responses and signalling. As part of the immunoglobulin superfamily (IgSF), this domain has a characteristic β-sandwich fold, typically comprising two β-sheets that form a stable, compact structure.

Carboxy-terminal Src-family kinase

(CSK). A non-receptor tyrosine kinase critical for regulating Src-family kinases (SFKs), a group of proteins that have key roles in cellular processes such as growth, differentiation and survival. By phosphorylating a conserved tyrosine residue in the C-terminal tail of SFKs, CSK inactivates these kinases. This inhibitory mechanism is vital for maintaining cellular homeostasis, as unchecked SFK activity is linked to cancer, immune disorders and other diseases. CSK is broadly expressed in mammalian cells and functions as a negative regulator, ensuring controlled activation of pathways related to cell motility, proliferation and adhesion.

Damage-associated molecular patterns

(DAMPs). Endogenous molecules released by stressed, damaged or dying cells that alert the immune system to non-infectious tissue injury. Unlike pathogen-associated molecular patterns (PAMPs), which originate from microbial sources, DAMPs are host-derived signals. They are recognized by pattern recognition receptors (PRRs) on immune cells, such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), leading to an inflammatory response aimed at containing tissue damage and promoting repair. Common examples of DAMPs include high-mobility group box 1 (HMGB1), ATP, heat shock proteins (HSPs) and extracellular DNA. DAMPs play an essential role in conditions such as trauma, autoimmune diseases and cancer by modulating inflammation and immune responses.

Extracellular matrix

(ECM). The structural network of secreted proteins and glycosaminoglycans that provides structure to tissue.

Immune-related adverse events

Toxic side effects that occur when therapies that block immune inhibitory receptors, such as anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4) and anti-PD1, are used to activate an anticancer immune response. Overactivation of the immune system with these therapies can cause harmful autoimmune attacks in other organs and tissues.

Immunoreceptor tyrosine-based activation motif

(ITAM). A short peptide motif containing tyrosine residues that is found in the cytoplasmic tails of several activating receptors and in adaptors such as DAP12. The consensus sequence is (Asp/Glu)-X-X-Tyr-X-X-(Leu/Ile)-X6–8-Tyr-X-X-(Leu/Ile), with X denoting any amino acid. Tyrosine phosphorylation of this motif triggers a cascade of intracellular events that usually results in cellular activation.

Immunoreceptor tyrosine-based inhibitory motifs

(ITIMs). Short peptide motifs containing tyrosine residues that are found in the cytoplasmic regions of many inhibitory receptors. The consensus sequence is (Ile/Val/Leu/Ser)-X-Tyr-X-X-(Leu/Val), with X denoting any amino acid. Tyrosine phosphorylation produces a binding site for cytoplasmic phosphatases and other signalling molecules, resulting in the dephosphorylation of activation complexes and inhibition of signalling cascades.

Pathogen-associated molecular patterns

(PAMPs). Molecular components of pathogens that are not normally found in mammals and are often common to whole classes of microorganisms. PAMPs are sensed by host pattern recognition receptors (PRRs). Examples include β-glucan, which binds dectin-1, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind Toll-like receptors (TLRs).

Pattern recognition receptor

(PRR). A receptor (such as Toll-like receptor (TLR)) that can sense pathogen-associated molecular pattern (PAMPs) or damage-associated molecular patterns (DAMPs) and initiate signalling cascades that lead to immune responses.

Pre-metastatic niche

A microenvironment at a distant site that supports the survival and growth of disseminated tumour cells, preparing the site for their establishment even before their arrival.

SHP1 and SHP2

SH2 domain-containing phosphatases that bind phosphorylated immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The recruitment of SRC-homology region 2 domain-containing phosphatase 1 (SHP1) and SHP2 by ITIM-bearing receptors represents a general mechanism for modulation of immune cell signalling.

Sialic acid-binding immunoglobulin-like lectins

(SIGLECs). A family of cell surface receptors that primarily recognize sialic acid-containing glycans, which are commonly found on the surface of cells. These receptors are involved in regulating immune cell signalling and interactions, particularly in controlling immune responses and maintaining self-tolerance.

Single-nucleotide polymorphisms

(SNPs). Variations in a single nucleotide (the building blocks of DNA) in the genome that occur at a specific position in the DNA sequence among individuals of a species. These variations are common in the human population and can have implications for genetic diversity, disease susceptibility and drug responses.

Tumour microenvironment

(TME). A complex and dynamic ecosystem surrounding a tumour, comprising a diverse network of cells, molecules and structures that interact with the tumour to shape its growth, progression and response to therapies.

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Pascoal Ramos, M.I., van der Vlist, M. & Meyaard, L. Inhibitory pattern recognition receptors: lessons from LAIR1. Nat Rev Immunol 25, 711–724 (2025). https://doi.org/10.1038/s41577-025-01181-2

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