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Review
. 2023 Nov 13:14:1282874.
doi: 10.3389/fimmu.2023.1282874. eCollection 2023.

Human leukocyte immunoglobulin-like receptors in health and disease

Silvia Redondo-García #  1 , Christopher Barritt #  1   2   3 , Charys Papagregoriou #  1 , Muchaala Yeboah  1 , Björn Frendeus  1   4 , Mark S Cragg  1   5 , Ali Roghanian  1   5
Affiliations
Review

Human leukocyte immunoglobulin-like receptors in health and disease

Silvia Redondo-García et al. Front Immunol. .

Abstract

Human leukocyte immunoglobulin (Ig)-like receptors (LILR) are a family of 11 innate immunomodulatory receptors, primarily expressed on lymphoid and myeloid cells. LILRs are either activating (LILRA) or inhibitory (LILRB) depending on their associated signalling domains (D). With the exception of the soluble LILRA3, LILRAs mediate immune activation, while LILRB1-5 primarily inhibit immune responses and mediate tolerance. Abnormal expression and function of LILRs is associated with a range of pathologies, including immune insufficiency (infection and malignancy) and overt immune responses (autoimmunity and alloresponses), suggesting LILRs may be excellent candidates for targeted immunotherapies. This review will discuss the biology and clinical relevance of this extensive family of immune receptors and will summarise the recent developments in targeting LILRs in disease settings, such as cancer, with an update on the clinical trials investigating the therapeutic targeting of these receptors.

Keywords: LILR; autoimmunity; cancer; immune tolerance; immunomodulation; immunotherapy; infection.

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Conflict of interest statement

BF is an employee of BioInvent International. AR and MSC receive institutional support from BioInvent International. AR acts as a consultant for Epsilogen. MSC has consulted for BioInvent International, Boehringer Ingelheim, GSK, Radiant, iteos, Surrozen, Hanall and Mestag and received research funding from BioInvent International, GSK, UCB and iTeos. He is a member of the GSK Immunology Network. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Leukocyte expression and ligand profiles of LILRAs. LILRAs have 2 to 4 extracellular lg-like domains, a transmembrane domain with a positively charged arginine residue and a truncated intracellular tail.
Figure 2
Figure 2
Leukocyte expression and ligand profiles of LILRBs. LILRBs have 2 to 4 extracellular lg-like domains and their cytoplasmic regions are composed of long ITIM-containing motifs exhibiting their inhibitory nature.
Figure 3
Figure 3
LILR signalling pathways. LILRA intracellular domain interacts with the dimeric FcεRIγ-chain comprised of cytoplasmic ITAM motifs. Phosphorylation of ITAM-bearing tyrosine residues by Src family kinases recruits Syk that mediates activating signalling cascades. Upon LILRB ligation, activated Lyn phosphorylates their ITIM domains, engaging phosphatases, which in turn abrogate activating signalling cascades essential for effector cell maturation and function.
Figure 4
Figure 4
Representative functions of LILRs in innate and adaptive immunity. (A) Innate immunity: LILRB1 is expressed on NK cells, and therefore may be involved in missing self, whereby the receptor recognises HLA I molecules on target cells, and those that do not express HLA I are destroyed. In neutrophils, LILRAs, such as LILRA2 and LILRA5, stimulate degranulation and pro-inflammatory cytokines release, while LILRBs, such as LILRB3, have the opposite effect and block their phagocytic activity. Moreover, the paired-receptors LILRA6 and LILRB3 recognise bacterially-infected cells. Interaction between LILRBs, such as LILRB1, with HLA I abrogates FcγR-mediated phagocytic function of macrophages. In addition, LILRAs, such as LILRA3, LILRA5 and LILRA6 promote the secretion of pro-inflammatory cytokines. However, this secretion is suppressed by LILRBs. (B) Humoral immunity: LILRB1 inhibits B cell responses in a T cell-independent manner. TGF-β1 and IL-10 induce follicular dendritic cells (DC) and follicular helper T cells (TFH) to secrete HLA-G. HLA-G binds to LILRB1 on the surface of germinal centre B cells resulting in a down-regulation of chemokine receptors CXCR4 and CXCR5 and inhibiting B cell trafficking. This interaction also inhibits differentiation into antibody-secreting plasma cells and memory B cells. Moreover, LILRB1 regulates B cell responses in a T cell-dependent manner. B cells can present antigen to T cells. LILRB1-HLA-G interaction can prevent antigen presentation and inhibits B cell proliferation by causing cell cycle arrest in the G0/G1 phase by disrupting the mTOR pathway mediated by SHP-2. (C) Cellular immunity: Ligation of LILRBs during DC development renders DCs tolerogenic by increasing the threshold of activation. Normal DCs have low levels of LILRBs. In contrast, tolerogenic DCs that express increased levels of LILRBs, promote anti-inflammatory cytokines release, CD4+ helper T cells activation and their conversion into Tregs. Conversely, LILRAs activate DCs towards a cytotoxic phenotype, inducing the secretion of pro-inflammatory cytokines that induce NK and CD8+ T cells activation.
Figure 5
Figure 5
Proposed mechanism of LILRB-mediated immune-evasion and tumour progression via myeloid cells. Engagement of LILRB1 and LILRB2 with HLA-G on myeloid-derived suppressor cells (MDSC) activates STAT6 and STAT3-mediated cascades, which in turn induces ARG1 and IDO production responsible for T cell suppression. LILRB4 ligation by APOE on monocytic AML cells mediates SHP-2 inhibitory signalling, which in turn positively regulate the NF-κB pathway. This leads to ARG1 production and urokinase-type plasminogen activator receptor (uPAR), responsible for T cell suppression and support of leukaemia migration. Although further studies are needed, LILRB3 ligation can mediate similar processes, such as induction of amphiregulin.
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