Immunoglobulin-like Transcript 4 Expression Research Articles

The expression and function of immunoglobulin-like transcript 4 in dendritic cells from patients with hepatocellular carcinoma

Due to their easy availability and expansion in vitro, monocyte-derived dendritic cells (moDCs) are most frequently used for tumor vaccination. Immunoglobulin-like transcript 4 (ILT4), as inhibitory receptor, has been reported to be related to DC tolerance. However, the influence of ILT4 for DC tolerance in hepatocellular carcinoma (HCC) patients has not been illustrated. In this research, we explored the expression of ILT4 on moDCs from HCC patients and its effect on moDC function. We demonstrated that the expression of ILT4 on mature DCs (mDCs) was higher in the peripheral blood from HCC patients than in that from healthy donors. The levels of cytokines IL-1β and IL-6 secreted by mDCs from both HCC patients and healthy controls, stimulated by anti-ILT4 agonistic mAb, were decreased. In contrast, the levels of IL-10 and IL-23 were upregulated. In addition, ILT4, triggered by anti-ILT4 agonistic mAb, could reduce allogeneic T cell proliferation stimulated by the mDCs. Moreover, ILT4 triggered by anti-ILT4 agonistic mAb could also reduce the ability of the mDCs to stimulate tumor cell antigen-specific autologous CD4+ T cells (production of IFN-γ) and CD8+ T cells (production of IFN-γ and IL-2). Furthermore, ILT4 expression impaired the cytotoxicity of autologous T cells induced by the mDCs against the HCC tumor cell line SMMC-7721. Our data revealed that the high expression of ILT4 promoted the immune tolerance of DCs, resulting in an inefficiency of the T cell response, a process that is exacerbated in HCC patients.

Co-expression of ILT4/HLA-G in human non-small cell lung cancer correlates with poor prognosis and ILT4-HLA-G interaction activates ERK signaling.

Non-small cell lung cancer (NSCLC) is the most common malignant tumor in the world, of which prognosis is generally poor due to insufficient mechanistic understanding. To explore the molecular pathogenesis of NSCLC, the co-expression of immunoglobulin-like transcript 4 (ILT4) and its ligand human leukocyte antigen G (HLA-G) in NSCLC tissues and cells were investigated. Here, we detected the expression of ILT4 and HLA-G in 81 tumor specimens from primary NSCLC patients, and we found that co-expression of ILT4/HLA-G was significantly associated with regional lymph node involvement, advanced stages, and the overall survival of patients. In NSCLC cell lines, HLA-G expression increased/decreased accordingly when ILT4 was up-/down-regulated, and ILT4 expression increased in a concentration-dependent manner via the stimulation of HLA-G fusion protein. Interestingly, HLA-G fusion protein could also up-regulate the phospho-ERK1/2 expression, which means the activation of extracellular signal-regulated kinase (ERK) signaling. All in all, our results indicate that the ILT4-HLA-G interaction might play an important role in NSCLC progression. Identification of ILT4 and HLA-G expression may provide an indicator to predict prognosis and guide prevention and treatment of NSCLC.

Co-expression of immunoglobulin-like transcript 4 and angiopoietin-like proteins in human non-small cell lung cancer.

The development of strategies for the inhibition of non‑small cell lung cancer (NSCLC) progression and metastasis have been mainly unsuccessful, in part due to insufficient mechanistic understanding of the disease. In the current study, the critical role of the co‑expression of immunoglobulin‑like transcript 4 (ILT4) and its ligands, angiopoietin‑like proteins (ANGPTLs), in the development of NSCLC was demonstrated. ILT4 and ANGPTL2 or ANGPTL5 were found to be co‑expressed in the five NSCLC cell lines that were investigated at the mRNA and protein level. Upon up‑ or downregulation of ILT4, the expression of ANGPTL2 was increased or reduced, respectively, while the expression of ANGPTL5 was unaffected. The co‑expression of ILT4 and ANGPTL2/ANGPTL5 was detected in human primary NSCLC tissues using immunohistochemical analysis. In total, 114 lung cancer specimens were included in the study; high expression of ILT4, ANGPTL2 and ANGPTL5 was observed in 58.8, 45.6 and 55.3%, respectively. The expression of ILT4 was found to be significantly correlated with a high expression level of ANGPTL2 (R=0.466, P=0.004); however, it was not correlated with the expression of ANGPTL5 (R=0.142, P=0.131). In ILT4‑positive samples, cases with ANGPTL2‑positive expression levels presented greater levels of lymph node metastasis (P=0.011) and shorter overall survival times (P=0.045). In addition, cases with ANGPTL5‑positive expression presented poor overall survival rates (P=0.040). By contrast, in the ILT4‑negative cases, no statistically significant differences were identified in the overall survival rates between samples with high and low expression of ANGPTL2 or ANGPTL5. In conclusion, the present study demonstrated the presence of interaction among ILT4 and ANGPTLs, which may be important in NSCLC progression. Therefore, the blockade of ANGPTLs or ILT4 may be an effective therapeutic approach for NSCLC treatment.

THU0514 Evidences of A Nontolerogenic-Proinflammatory Surface and Cytokine Phenotype in Monocytes from Patients with Psoriatric Arthritis

BackgroundThe immunoglobulin-like transcript-4 (ILT4) is an inhibitory receptor that modulates the activity of innate immune agents. Furthermore, acquisition of an nontolerogenic-proinflammatory phenotype by monocytes may contribute to enhance inflammation and...

Downregulation of Immunoglobulin-Like Transcript-4 (ILT4) in Patients with Psoriatic Arthritis

ObjectiveThe immunoglobulin-like transcript-4 (ILT4) is an inhibitory receptor that modulates the activity of innate immune agents. We determined the expression of ILT4 and analysed the relationship with the expression of costimulatory proteins and tumor necrosis factor-α (TNF-α) production in monocytes from patients with psoriatic arthritis (PsA) starting anti-TNF treatment.MethodsPeripheral blood monocytes from 15 healthy controls and from 16 patients with PsA were activated in vitro by CD40 ligand (CD40L) and analyzed for ILT4, CD40, CD80 and CD86 expression, and spontaneous lipopolysaccharide (LPS)-induced TNF-α production by flow cytometry, before and after treatment with adalimumab.ResultsThe percentage of ILT4-negative monocytes was greater in PsA patients compared to controls and negatively correlated with DAS44. Normal monocytes treated with sera of PsA patients showed a reduced expression of ILT4 compared with monocytes exposed to sera from controls. CD40, CD80 and CD86 expression was higher in patients compared to controls. Both spontaneous and LPS-induced TNF-α production was restricted to ILT4-negative monocytes and was greater in PsA patients compared to controls. Finally, twelve weeks-treatment with adalimumab resulted in a significant increase of ILT4 expression and a decrease of costimulatory molecules expression in PsA patients, compared to pre-therapy levels.ConclusionsThese data support the possibility that changes in the immunophenotype of monocytes play a role in the pathogenesis of PSA. Thus, modulation of the expression of ILT4 may represent an enticing new therapeutic target.

Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions

Neutrophils play a major role in inflammatory responses and immune defense against pathogens. Even though expression of inhibitory receptors has been reported on neutrophils, their role remains poorly defined. Here we show that primary human neutrophils expressed immunoglobulin-like transcript 4 (ILT4) inhibitory receptor and that this expression was induced during differentiation of the myelomonoblast PLB-985 cell line into "neutrophil-like" cells. Functional assays indicated that human leukocyte antigen G, the preferred ligand of ILT4, inhibited the phagocytic function of neutrophils. ILT4 engagement also impaired reactive oxygen species production induced through CD32a and both receptors were found colocalized into neutrophil lipid rafts. Moreover, neutrophil degranulation induced through inflammatory stimuli increased ILT4 expression as a result of the rapid translocation of an intracellular pool to the cell surface. Consequently to this ILT4 up-regulation, the human leukocyte antigen G-mediated inhibition of neutrophil phagocytic function was enhanced. Finally, we found that ILT4 up-regulation induced on healthy donor neutrophils following stimulation was impaired in presence of plasma from patients with sepsis. Similarly, ILT4 up-regulation was inhibited in neutrophils from septic patients. Altogether, our results reveal a unique mechanism of regulation of neutrophil functions through ILT4 and its exocytosis that may have implications in inflammatory disorders.

Upregulation of the inhibitory receptor ILT4 in monocytes from septic patients

Sepsis-induced immune dysfunction is a complex phenomenon that involves both innate and adaptive responses. Upregulation of the inhibitor receptor named immunoglobulin like transcript 4 (ILT4) is crucial to the tolerogenic function of monocytes. Here, ILT4 expression, endotoxin-induced IL-12 and IL-10 production and CD86 expression were investigated in circulating monocytes from 16 patients with severe sepsis and 16 age and sex matched controls. We found that monocytes from patients with severe sepsis express significantly higher levels of ILT4 than monocytes from controls. Upregulation of ILT4 expression appeared to be induced by soluble factors present in the serum of septic patients and directly correlated with the degree of organ dysfunction. ILT4(+) monocytes from septic patients also displayed an alteration in the cytokine response to endotoxin stimulation characterized by reduced IL-12 production and increased IL-10 production, and a reduced expression of the costimulatory molecule CD86. In conclusion, the increased ILT4 expression and IL-10 production and the decreased CD86 expression and IL-12 production indicate that during sepsis monocytes undergo substantial modulation of the surface and cytokine phenotype. These phenotypic changes may interfere with the antigen presenting cell activity of monocytes, which may contribute to the impairment of adaptive immune responses that takes place during sepsis.

AB0092 Downregulation of immunoglobulinlike transcript 4 (ilt4) in patients with rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is characterized by destruction of juxtaarticular cartilage and bone due to excessive activation of inflammatory cells of which the underlying mechanisms are not fully elucidated. Macrophages may...