LAIR1

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This entry is adapted from the peer-reviewed paper 10.3390/ijms232416136

Leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1, CD305) belongs to the family of immune-inhibitory receptors and is widely expressed on hematopoietic mature cells, particularly on immune cells. Four different types of ligands of LAIR1 have been described, including collagens, suggesting a potential immune-regulatory function on the extracellular matrix. By modulating cytokine secretion and cellular functions, LAIR1 displays distinct patterns of expression among NK cell and T/B lymphocyte subsets during their differentiation and cellular activation and plays a major negative immunoregulatory role. Beyond its implications in physiology, the activity of LAIR1 can be inappropriately involved in various autoimmune or inflammatory disorders and has been implicated in cancer physiopathology, including hematological neoplasms. Its action as an inhibitory receptor can result in the dysregulation of immune cellular responses and in immune escape within the tumor microenvironment.

LAIR1 autoimmunity inflammation inhibitory receptor collagen hematological neoplasms immunoregulatory

1. Introduction

Immune responses must be tightly regulated to prevent undesired events such as autoimmunity. A balance between cell activation and inhibition is required to modulate immune cellular events, relying on complex processes integrating signals generated from activating (AR) and inhibitory receptors (IR), these receptors being expressed by a large diversity of immune cells.

Leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1), also termed CD305, is a type I glycoprotein of 287 amino acids, belonging to the family of immune IR, and was first molecularly cloned in 1997 ^[1].

Its structure contains one extracellular C2-type-Ig-like domain and two Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) domains in its cytoplasmic tail. ITIMs are pivotal domains in the functionality of IR. They mediate negative control signals during the activation of immune cells, their effects being opposite to the action of Immunoreceptor Tyrosine-Based Activation Motifs (ITAMs), which are found in the intracellular domains of AR ^[2]. Phosphorylation of the tyrosine in the ITIM region is a central signaling event for the functionality of IR, including LAIR1, which require the phosphorylation of tyrosines of both ITIMs by Src family kinases in order to fully inhibit cellular responses ^[3]. ITIMs can then recruit and activate the Src homology 2 domain-containing tyrosine phosphatases SHP-1 and SHP-2, which in turn dephosphorylate cellular targets implicated in cell activation, to negatively regulate these processes ^[4].

Moreover, LAIR2, also known as CD306, is a soluble protein sharing 84% homology with LAIR1. LAIR2 can antagonize this homologous transmembrane receptor via competition for some ligands, regulating the inhibitory potential of LAIR1 ^[5]. Several splice variants of LAIR1 and LAIR2 have been identified, including LAIR1a, 1b, 1c, 1d, 2a, and 2b. Variations in structure have been described from one variant to another, but little is known about their functionality ^[6].

2. Expression Patterns of LAIR1

LAIR1 is widely expressed on almost all hematopoietic mature cells (Figure 1), including NK cells, T and B lymphocytes, monocytes ^[7], macrophages, basophils, mastocytes ^[8], eosinophils ^[9], dendritic cells ^[10], and a fraction of circulating plasmocytes ^[11].

Figure 1. Summary of LAIR1 expression and functions in normal leucocytes, plasmacytoid dendritic (pDCs) cells, and tumor cells.

LAIR1 is a collagen receptor expressed by the majority of immune cells, including T cells, B cells, NK cells, monocytes, neutrophils, macrophages, and pDCs, as well as tumor cells. Generally, LAIR1 acts as an immune-inhibitory receptor, which, upon ligand binding, blocks the activation and/or differentiation of these cells. The major effects of LAIR1 on each immune cell type are depicted.

In T lymphocytes, LAIR1 is heterogeneously expressed (Figure 2), the highest levels being described in CD8⁺ T cells compared to CD4⁺ T cells, and in naive populations in comparison with central or effector memory T cells in the CD4 and the CD8 compartments. These observations contrast with other IRs, known to be classically expressed after T cell activation. Moreover, in T cells, ligation of LAIR1 can inhibit T cell receptor (TCR)-mediated functions, suggesting that LAIR1 could contribute to the inhibition of the initiation of the immune response. On the contrary, TCR stimulation can upregulate LAIR1 expression on T cells, inhibiting effector functions ^[12].

In B lymphocytes, LAIR1 is expressed at high levels in naïve B cells, but only in 50% of memory B cells. Moreover, LAIR1 expression has been shown to be decreased upon cell activation ^[13].

In mature neutrophils, cell surface expression of LAIR1 is low or negative, as illustrated by Figure 2, this expression being progressively lost during granular differentiation. In addition, LAIR1 can be re-expressed at the surfaces of granulocytes after stimulation by tumor necrosis factor α, suggesting a regulatory role of this IR in the functionality of neutrophils ^[9].

Figure 2. LAIR1 expression in normal white blood cells. LAIR1 expression was evaluated by flow cytometry (FCM) in a total of 10 samples obtained from healthy adult subjects (n = 10 blood samples, median age: 31 (range: 21–63); gender (male/female): 3/7) after red blood cell lysis by Versalyse© Beckman Coulter. For technical procedures, see ^[14]. Age (median): 31 (range: 21–63); gender (male/female): 3/7. Monocytes and granulocytes were selected based on their well-known CD45/side scatter (SSC) profile. In the “lymphocyte gate” determined on the graph CD45/SSC, T lymphocytes, NK cells, and B lymphocytes were selected according to the respective criteria of expression of CD3, absence of expression of CD3 and CD19 and expression of CD56, and expression of CD19 and CD20. The results obtained for the mean fluorescence intensity (MFI) of LAIR1 are presented. The dotted line represents the positivity threshold for this marker.

In macrophages, LAIR1 is highly expressed and can regulate their functions, including macrophage polarization ^[15]. In addition, LAIR1 can contribute to the inhibition of the differentiation of monocytes and dendritic cells from peripheral precursors ^[16].

Besides these mature cells, LAIR1 has been described as expressed by hematopoietic CD34⁺ progenitors ^[17] and by hematopoietic precursors as megakaryocytes, with a role as an early marker of differentiation and a negative regulator of thrombopoiesis, while not been detectable on platelets ^[18]. A murine model lacking LAIR1 was described as exhibiting peripheral thrombocytosis, increased proplatelet formation, a prolonged platelet half-life, enhanced Src kinase activity, and an increased risk of thrombus formation ^[19]. Thus, LAIR1 seems to be essential in the regulation of thrombopoiesis.

In non-hematopoietic cells, LAIR1 has been described to be expressed by osteoclasts, with a role in the inhibition of osteoclastogenesis ^[20].

3. LAIR1 in Autoimmunity and Inflammatory Diseases

Protection against self-damage due to the loss of self-tolerance, hyperimmune activation, or autoimmunity relies on immune-inhibitory receptors expressed by both innate and adaptive immune cells. It is therefore not surprising that LAIR1 has a critical role in autoimmunity, given its widespread pattern of expression and its ability to suppress cell activation in a number of hematopoietic cells. It is thought that the inhibitory signals created through LAIR1 provide a threshold for immune activation, especially in collagen-rich tissues, thereby preventing uncontrolled immune responses and allowing the maintenance of immune cell homeostasis. In this section, researchers will discuss some instances in which LAIR1 has been shown to be involved in autoimmunity and inflammatory diseases.

4. LAIR1 and Allergy

To address its role in allergic responses, Omiya and colleagues generated a transgenic mouse system expressing a chimeric version of LAIR1. This chimeric protein contained its extracellular domain fused with an immunoglobulin tag and acted as a decoy by competing with endogenous LAIR1 ^[21]. Using a murine experimental model of allergic dermatitis, the authors showed that the decoy LAIR1 transgenic mice had an increased susceptibility to contact hypersensibility (CHS). This increased susceptibility to CHS happened both at the sensitization and elicitation phases and implicated the repression of cytokine production (IL-6 and IL-12) by dendritic cells and the inhibition of proliferation and cytokine of both naïve and memory T cells.

Similarly, the role of LAIR1 in airway hyper-reactivity and type 2 asthma was recently addressed by Helou and colleagues ^[22]. They were able to demonstrate that LAIR1 can be induced on activated pulmonary ILC2, leading to decreased cytokine secretion and effector functions. Airway hyper-reactivity was indeed exacerbated in the absence of LAIR1 in both mouse and human models, highlighting its normal protective anti-inflammatory role. Interestingly, circulating human ILC2 shows surface LAIR1 expression, which can be further increased upon IL-33 stimulation. This contrasts with mouse ILC2, which only expresses LAIR1 upon cytokine stimulation ^[22]. It still remains to be seen how LAIR1 can be targeted clinically for therapeutic purposes in the case of asthma.

5. LAIR1 and Lupus

The complement system is involved in both innate and adaptive immune systems and has been shown to be important in the pathogenesis of systemic lupus erythematosus (SLE). Deficiencies in some members of the classical pathway, such as C1q, C4, and C2, can predispose individuals to the development of autoimmune diseases, explained in part by their important roles in promoting the clearance of immune complexes and apoptotic cells ^[23]. Furthermore, C1q has been shown to regulate, via LAIR1, myeloid cell activity and prevent the unwarranted activation of circulating monocytes and the development of mono-derived dendritic cells ^[24]^[25]. At the protein level, the collagen tail of C1q interacts with LAIR1, whereas C1q’s globular head interacts with the transmembrane receptor CD33 (Siglec-3), inducing the phosphorylation of the ITIM motifs in the tail of CD33, and altogether forms a C1q/CD33/LAIR1 inhibitory ternary complex ^[26]. Disruption of this inhibitory complex is frequently found in SLE, consistent with abnormalities related to C1q or a lack of LAIR1 and CD33 expression on circulating SLE myelomonocytes observed in SLE patients ^[26]^[27]. Aberrant C1q function may be linked to impaired LAIR1 expression and may be CD33-independent, since LAIR1 has been shown to be abnormally expressed on B cells and plasmacytoid DCs (pDCs) in SLE patients ^[28]. Defective LAIR1 expression in both B cells and pDCs, as well as the subsequent decreased inhibitory signals, lead to abnormal cell activation and may contribute to SLE development, highlighting the critical role of complement-mediated inhibition through LAIR1 in controlling immune homeostasis in normal and anomalous physiology.

6. LAIR1 and Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease associated with progressive disability and systemic complications, characterized by events such as synovial inflammation, autoantibody production, and cartilage and bone destruction ^[29]. Patients with RA have lower surface expression of LAIR1 on their fibroblast-like synoviocytes (FLS) but significantly higher levels of soluble LAIR1 and its secreted homolog LAIR2 in the serum and synovial fluid ^[30]. Its expression is used as a biomarker when analyzing synovial fluid for evidence of RA ^[31].

Although FLS expressed low levels of surface LAIR1, treatment of these cells with TNF-alpha induced LAIR1′s shedding. A reduction in FLS invasion could be achieved by LAIR1 overexpression, as well as a decrease in inflammatory cytokines such as IL-6 and IL-8. All these data suggest that LAIR1 serves as an anti-inflammatory molecule in RA. LAIR1 expression is also affected on T cells from RA patients. As similarly observed with FLC cells, reduced surface LAIR1 expression on CD4+ T cells was seen in RA patients, leading to the decreased inhibition of T cell activation and hyperactivation. Mice rendered deficient for LAIR1 show more severe arthritis than their wildtype counterparts ^[32]. The mechanisms responsible for the inhibition of TCR signaling by LAIR1 engagement have recently been addressed by Park and colleagues. They were able to show that LAIR1 stimulation by collagen inhibits TCR signaling by decreasing the phosphorylation of key components of the TCR signaling pathway, such as Lck, ZAP-70, c-Jun, and p38 ^[33]. The kinase Csk, known to bind the intracellular tail of LAIR1 after phosphorylation of the ITIM motifs ^[1]^[34], was shown to be essential for the LAIR1-dependent inhibition of the TCR signaling cascade ^[33]. In conclusion, LAIR1 engagement by collagen-like domains could be an interesting therapeutic strategy to control inflammation in autoimmune diseases such as RA, SLE, and many other inflammatory states. Interestingly, it was recently observed that the effect of the vitamin D could be at least partially mediated by the upregulation of LAIR1 in a model of arthritis ^[35].

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