Leukocyte immunoglobulin-like receptors (LILRs) are a diverse family of cell surface proteins predominantly expressed on various immune cells such as monocytes, macrophages, dendritic cells, and subsets of B and T lymphocytes. These receptors play crucial roles in regulating immune responses through both activating and inhibitory mechanisms. LILRs are integral to maintaining immune homeostasis, preventing autoimmunity, and responding to infections and tumors.
Structurally, LILRs are characterized by extracellular immunoglobulin (Ig)-like domains and cytoplasmic tails that either contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or associate with activating adaptor proteins. The balance of LILR signaling helps tune the immune threshold and contributes to various immune processes ranging from tolerance to inflammation and pathogen clearance.
LILRs are encoded in the leukocyte receptor complex (LRC) located on chromosome 19q13.4, a region that also contains other immunoregulatory receptors. Their classification includes activating receptors (LILRA subfamily) and inhibitory receptors (LILRB subfamily), each recognizing a variety of ligands including classical and non-classical major histocompatibility complex (MHC) class I molecules.
The LILR family is divided into two main subgroups:
LILRA (Activating Receptors): These receptors have short cytoplasmic tails and lack ITIMs. Instead, they associate with Fc receptor common gamma chains (FcRγ) or other activating adaptors via a charged residue in the transmembrane region. Members include LILRA1 through LILRA6.
LILRB (Inhibitory Receptors): These receptors possess long cytoplasmic tails with multiple ITIM motifs. Upon ligand binding, they recruit phosphatases like SHP-1 and SHP-2, which dephosphorylate signaling intermediates to dampen cellular activation. LILRB1 through LILRB5 belong to this subgroup.
Most LILRs contain two or four Ig-like extracellular domains and a transmembrane region. Some can bind both classical (HLA-A, -B, -C) and non-classical (HLA-E, -F, -G) MHC class I molecules, while others show specificity for free heavy chains of MHC molecules.
Genetic Organization
LILRs are encoded in a tightly clustered region known as the leukocyte receptor complex (LRC) on chromosome 19q13.4. This locus contains genes with high sequence similarity and evidence of duplication events, supporting the idea that these receptors have evolved rapidly in response to pathogenic pressures.
The close linkage of LILRs with killer-cell immunoglobulin-like receptors (KIRs) and other immune regulatory genes suggests coordinated regulation and functional interplay in innate immunity.
Ligands and Binding Specificity
A defining feature of LILRs is their ligand diversity:
LILRB1 and LILRB2 bind to a broad range of classical and non-classical MHC class I molecules in complex with β₂-microglobulin.
LILRA1 and LILRA3, in contrast, recognize MHC class I heavy chains devoid of β₂-microglobulin, enabling detection of stress or pathological conditions that disrupt MHC stability.
Beyond MHC molecules, certain LILRs bind to viral proteins, self-lipids, or damage-associated molecular patterns (DAMPs), implying a broader role in sensing both self and non-self entities.
Expression and Cellular Distribution
LILRs are expressed variably across immune cell types:
Monocytes and macrophages: Express both activating and inhibitory LILRs, modulating responses to infection and inflammation.
Dendritic cells: Use LILRs to regulate maturation, antigen presentation, and cytokine production.
B cells and T cells: Express select LILRs (e.g., LILRB1), influencing adaptive immune responses.
NK cells: Some subsets express LILRB1 and LIL
Biological Functions and Immune Modulation
Leukocyte immunoglobulin-like receptors (LILRs) calibrate immune responses across both innate and adaptive systems through two complementary mechanisms:
Inhibitory LILRBs (e.g., LILRB1–B5) contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon ligand binding, these receptors recruit SHP-1/2 phosphatases, which attenuate cell activation, reduce phagocytosis, and suppress inflammatory signaling pathways such as PI3K/AKT cascades
Activating LILRAs (e.g., LILRA1–A6) lack ITIMs but pair with ITAM-bearing adaptor proteins, like FcRγ, via a charged transmembrane residue, thus triggering phosphorylation cascades that potentiate cytokine release, cell maturation, and cytotoxic responses.
Key Roles:
Monocytes/macrophages: Express LILRB1 and LILRB2 to sense “self” via MHC I, inhibiting phagocytosis when engaging self-structures, thereby preventing auto-aggression. During infection, activating LILRAs help override this inhibition to enable pathogen clearance.
Dendritic cells: Balance between activation and tolerance is mediated by LILR expression; outcome determines whether immune responses are immunogenic or tolerogenic.
NK, B, and T lymphocytes: Particularly express inhibitory LILRBs (e.g., LILRB1/B2), which dampen cytotoxicity and antibody production, thus avoiding collateral tissue damage.
These regulatory mechanisms ensure immune responses remain specific yet nonpathogenic.
A subset of LILR recognise MHC class I (also known as HLA class I in humans). The LILR family is a cluster of paired receptors with both activating and inhibitory functions.[1] Of these, the inhibitory receptors LILRB1 and LILRB2 show a broad specificity for classical and non-classical MHC alleles with preferential binding to b2m-associated complexes. In contrast, the activating receptors LILRA1 and LILRA3 prefer b2m-independent free heavy chains of MHC class I, and in particular HLA-C alleles.[2]
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