Park Mijeong, Liu Robert W, An Hongyan, Geczy Carolyn L, Thomas Paul S, Tedla Nicodemus
1 Mechanisms of Diseases Translational Research, University of New South Wales, School of Medical Sciences, Department of Pathology, Sydney, Australia.
2 Stanford University School of Medicine, Department of Medicine, Stanford, CA, USA.
Innate Immun. 2017 May;23(4):381-391. doi: 10.1177/1753425917699465. Epub 2017 Mar 16.
The leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory cell surface receptor, primarily expressed on mono-myeloid cells. It contains 2 C-type Ig-like extracellular domains and a long cytoplasmic domain that contains three intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Data suggest that LILRB4 suppresses Fc receptor-dependent monocyte functions via its ITIMs, but relative contributions of the three ITIMs are not characterised. To address this, tyrosine (Tyr) residues at positions 337, 389 and 419 were single, double or triple mutated to phenylalanine and stably transfected into a human monocytic cell line, THP-1. Intact Tyr was sufficient to maximally inhibit FcγRI-mediated TNF-α production in THP-1 cells, but, paradoxically, Tyr significantly enhanced TNF-α production. In contrast, bactericidal activity was significantly enhanced in mutants containing Tyr, while Tyr markedly inhibited bacteria killing. Taken together, these results indicate that LILRB4 might have dual inhibitory and activating functions, depending on the position of the functional tyrosine residues in its ITIMs and/or the nature of the stimuli.
白细胞免疫球蛋白样受体B4（LILRB4）是一种抑制性细胞表面受体，主要表达于单核-髓系细胞。它包含2个C型免疫球蛋白样细胞外结构域和一个长的细胞质结构域，该细胞质结构域包含三个基于免疫受体酪氨酸的细胞内抑制基序（ITIM）。数据表明，LILRB4通过其ITIM抑制Fc受体依赖性单核细胞功能，但三个ITIM的相对作用尚未明确。为了解决这个问题，将第337、389和419位的酪氨酸（Tyr）残基分别单突变、双突变或三突变为苯丙氨酸，并稳定转染到人单核细胞系THP-1中。完整的Tyr足以最大程度地抑制THP-1细胞中FcγRI介导的TNF-α产生，但矛盾的是，Tyr显著增强了TNF-α的产生。相反，含有Tyr的突变体的杀菌活性显著增强，而Tyr显著抑制细菌杀伤。综上所述，这些结果表明，LILRB4可能具有双重抑制和激活功能，这取决于其ITIM中功能性酪氨酸残基的位置和/或刺激的性质。
