Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition

Abstract

Basophils, recruited from the blood to tissues, have been implicated by their presence in diverse allergic disorders including bronchial asthma, allergic rhinitis, and cutaneous contact hypersensitivity. We hypothesized that like other leukocytes involved in inflammatory responses, basophils would express members of the leukocyte immunoglobulin-like receptor (LIR) family of immunoregulatory molecules on their cell surface. We identified LIR7, an activating member coupled to the common Fc receptor gamma chain, and LIR3, an inhibitory member containing cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, on these cells from human peripheral blood. Cross-linking of LIR7 resulted in the concentration-dependent net release of histamine (29.8 ؎ 10.8%) and cysteinyl leukotrienes (cysLTs) (31.4 ؎ 8.7 ng/10 6 basophils) that were maximal at 30 minutes, and of interleukin-4 (IL-4) (410.2 ؎ 61.6 pg/10 6 basophils) that was maximal at 4 hours and comparable with the response initiated by cross-linking of the high-affinity receptor for immunoglobulin E (Fc⑀RI). Coligation of LIR3 to LIR7 or to Fc⑀RI by means of a second monoclonal antibody significantly inhibited net histamine release, cysLT production, and IL-4 generation. That LIR3 is profoundly counterregulatory for both adaptive and innate receptors suggests a broad role in containment of the inflammatory response. IntroductionBecause they resemble mast cells in their panel of mediators and cell surface expression of the high-affinity receptor for the Fc portion of immunoglobulin E (Fc⑀RI), peripheral blood basophils have in the past often been studied as mast cell surrogates due to the relative ease with which they can be isolated. However, basophils differ importantly from mast cells in their developmental pathway and limited supply of effector molecules. Developmentally, basophils originate and mature in the bone marrow, circulating as terminally differentiated cells, while mast cells circulate as precursors and complete their development after transendothelial migration to specific tissues. [1][2][3] Indeed, basophils bear a closer developmental relationship to eosinophils than to mast cells. 4,5 A case report documents the absence of both eosinophils and basophils in a single patient, 6 possibly secondary to destruction or dysfunction of a shared progenitor cell. Infection of Ws/Ws rats, which are deficient in mast cells due to a mutation in c-kit, with the parasite Nippostrongylus brasiliensis led to a more than 50-fold increase in peripheral blood basophils, equal to that observed in wild-type rats. 7 Basophils also appear to have a limited capacity to provide inflammatory mediators in comparison with mast cells. 8 Those currently recognized include histamine stored in preformed granules, leukotriene (LT) C 4 generated from arachidonic acid with cell activation, and interleukin (IL) 4 induced also by activation. 9 That basophils can provide IL-4 has led to the suggestion that these cells may reinforce T helper 2 (Th2) cell polarization. [10][11][12] Basop...

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

“…ILT1 (LIR7) is a receptor expressed on myeloid and lymphoid cells, but that lacks ITIMs (31). It has been reported that ILT1/LIR7 activates human eosinophils and basophils (32,33). ILT7 is a similar activating receptor that has been proposed as a marker for plasmacytoid dendritic cells (34,35).…”

Association of LILRA2 (ILT1, LIR7) splice site polymorphism with systemic lupus erythematosus and microscopic polyangiitis

“…29 Several lines of evidence demonstrated the role of LILRA2 in the activation of myeloid cells and macrophages. 14,[19][20][21] Thus, stronger signals via D419-421 isoform might explain its association with MPA.…”

“…LILRA2 is implicated in the activation of eosinophils, 19 basophils 20 and macrophages. 21 On the other hand, it is reported that activation of LILRA2 suppresses innate host defense mechanisms by shifting monocyte production from IL-12 toward IL-10 and blocking toll-like receptor (TLR)-mediated antimicrobial activity.…”

Structural immunology and crystallography help immunologists see the immune system in action: How T and NK cells touch their ligands

“…Some LILR activating receptors with short cytoplasmic tail were proved to recruit the c-chain of FceRI with charged Arg residue in transmembrane region to activate the immune system via ITAM motifs of FceRIc (75)(76)(77). Shiroishi et al demonstrated the crystal structure of LILRA5 (ILT11/LIR-9/CD85f) in 2006 and found its nonbinding with several classical and non-classical pMHCI molecules (66).…”