Editorial: Membrane lipids in T cell functions

Plasma membrane lipids play essential roles in regulating T cell signaling, differentiation, and effector functions. The major lipid species in the plasma membrane are glycerophospholipids, sphingolipids, and sterol lipids. TCR and costimulatory molecules lead to profound changes in the composition, distribution, and dynamic of plasma membrane lipids. For instance, cholesterol, sphingomyelin, and saturated phosphocholine are enriched at the contact zone between T cells and antigen-presenting cells during peptide/MHC complexes recognition, where they constitute a platform of lipid domains essential for optimal T cell signaling. Glycerophospholipid provide docking sites for binding pivotal signaling proteins as well as for their conformation, portioning, and mobility. Finally, plasma membrane lipids also act as second messengers with important immune-regulatory functions. This Research Topic contains seven articles that review the current understanding of the mechanisms and molecules involved in the metabolism and function of membrane lipids and how differences in their content may affect T cell functional properties

Soluble interleukin-2 receptor combined with interleukin-8 is a powerful predictor of future adverse cardiovascular events in patients with acute myocardial infarction

BackgroundLittle is known about the role of interleukin (IL) in patients with acute myocardial infarction (MI), especially soluble IL-2 receptor (sIL-2R) and IL-8. We aim to evaluate, in MI patients, the predictive value of serum sIL-2R and IL-8 for future major adverse cardiovascular events (MACEs), and compare them with current biomarkers reflecting myocardial inflammation and injury.MethodsThis was a prospective, single-center cohort study. We measured serum concentrations of IL-1β, sIL-2R, IL-6, IL-8 and IL-10. Levels of current biomarkers for predicting MACEs were measured, including high-sensitivity C reactive protein, cardiac troponin T and N-terminal pro-brain natriuretic peptide. Clinical events were collected during 1-year and a median of 2.2 years (long-term) follow-up.ResultsTwenty-four patients (13.8%, 24/173) experienced MACEs during 1-year follow-up and 40 patients (23.1%, 40/173) during long-term follow-up. Of the five interleukins studied, only sIL-2R and IL-8 were independently associated with endpoints during 1-year or long-term follow-up. Patients with high sIL-2R or IL-8 levels (higher than the cutoff value) had a significantly higher risk of MACEs during 1-year (sIL-2R: HR 7.7, 3.3–18.0, p < 0.001; IL-8: HR 4.8, 2.1–10.7, p < 0.001) and long-term (sIL-2R: HR 7.7, 3.3–18.0, p < 0.001; IL-8: HR 4.8, 2.1–10.7, p < 0.001) follow-up. Receiver operator characteristic curve analysis regarding predictive accuracy for MACEs during 1-year follow-up showed that the area under the curve for sIL-2R, IL-8, sIL-2R combined with IL-8 was 0.66 (0.54–0.79, p = 0.011), 0.69 (0.56–0.82, p < 0.001) and 0.720 (0.59–0.85, p < 0.001), whose predictive value were superior to that of current biomarkers. The addition of sIL-2R combined with IL-8 to the existing prediction model resulted in a significant improvement in predictive power (p = 0.029), prompting a 20.8% increase in the proportion of correct classifications.ConclusionsHigh serum sIL-2R combined with IL-8 levels was significantly associated with MACEs during follow-up in patients with MI, suggesting that sIL-2R combined with IL-8 may be a helpful biomarker for identifying the increased risk of new cardiovascular events. IL-2 and IL-8 would be promising therapeutic targets for anti-inflammatory therapy

Vancomycin associated acute kidney injury in patients with infectious endocarditis: a large retrospective cohort study

Background: Vancomycin remains the cornerstone antibiotic for the treatment of infective endocarditis (IE). Vancomycin has been associated with significant nephrotoxicity. However, vancomycin associated acute kidney injury (AKI) has not been evaluated in patients with IE. We conducted this large retrospective cohort study to reveal the incidence, risk factors, and prognosis of vancomycin-associated acute kidney injury (VA-AKI) in patients with IE.Methods: Adult patients diagnosed with IE and receiving vancomycin were included. The primary outcome was VA-AKI.Results: In total, 435 of the 600 patients were enrolled. Of these, 73.6% were male, and the median age was 52 years. The incidence of VA-AKI was 17.01% (74). Only 37.2% (162) of the patients received therapeutic monitoring of vancomycin, and 30 (18.5%) patients had reached the target vancomycin trough concentration. Multiple logistic regression analysis revealed that body mass index [odds ratio (OR) 1.088, 95% CI 1.004, 1.179], duration of vancomycin therapy (OR 1.030, 95% CI 1.003, 1.058), preexisting chronic kidney disease (OR 2.291, 95% CI 1.018, 5.516), admission to the intensive care unit (OR 2.291, 95% CI 1.289, 3.963) and concomitant radiocontrast agents (OR 2.085, 95% CI 1.093, 3.978) were independent risk factors for VA-AKI. Vancomycin variety (Lai Kexin vs. Wen Kexin, OR 0.498, 95% CI 0.281, 0.885) were determined to be an independent protective factor for VI-AKI. Receiver operator characteristic curve analysis revealed that duration of therapy longer than 10.75 days was associated with a significantly increased risk of VA-AKI (HR 1.927). Kidney function was fully or partially recovered in 73.0% (54) of patients with VA-AKI.Conclusion: The incidence of VA-AKI in patients with IE was slightly higher than in general adult patients. Concomitant contrast agents were the most alarmingly nephrotoxic in patients with IE, adding a 2-fold risk of VA-AKI. In patients with IE, a course of vancomycin therapy longer than 10.75 days was associated with a significantly increased risk of AKI. Thus, closer monitoring of kidney function and vancomycin trough concentrations was recommended in patients with concurrent contrast or courses of vancomycin longer than 10.75 days

Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors

Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis

Regulation of T Cell Receptor Activation by Dynamic Membrane Binding of the CD3ɛ Cytoplasmic Tyrosine-Based Motif

SummaryMany immune system receptors signal through cytoplasmic tyrosine-based motifs (ITAMs), but how receptor ligation results in ITAM phosphorylation remains unknown. Live-cell imaging studies showed a close interaction of the CD3ɛ cytoplasmic domain of the T cell receptor (TCR) with the plasma membrane through fluorescence resonance energy transfer between a C-terminal fluorescent protein and a membrane fluorophore. Electrostatic interactions between basic CD3ɛ residues and acidic phospholipids enriched in the inner leaflet of the plasma membrane were required for binding. The nuclear magnetic resonance structure of the lipid-bound state of this cytoplasmic domain revealed deep insertion of the two key tyrosines into the hydrophobic core of the lipid bilayer. Receptor ligation thus needs to result in unbinding of the CD3ɛ ITAM from the membrane to render these tyrosines accessible to Src kinases. Sequestration of key tyrosines into the lipid bilayer represents a previously unrecognized mechanism for control of receptor activation

ORM 1 as a biomarker of increased vascular invasion and decreased sorafenib sensitivity in hepatocellular carcinoma

This study aimed to clarify the role of Orosomucoid 1 (ORM1) in the development and therapy resistance in hepatocellular carcinoma (HCC). The mRNA expression level of ORM1 was analyzed via integrative analysis of Gene Express Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The protein expression level of ORM1 in our cohort was determined using immunohistochemistry. Correlation analysis was used to investigate the relationship between ORM1 expression and clinical parameters. The Cell Counting Kit-8 assay was used to clarify the role of ORM1 in HCC malignant behaviors, including cell growth and sorafenib sensitivity, in vitro. The results indicated that ORM1 was significantly downregulated in the hepatic cancer cells compared to that in the non-cancerous cells. However, it was upregulated in microvascular invasion samples, especially in the cancer embolus compared to that in the surrounding tumor cells. Though Kaplan-Meier analysis did not show an association of ORM1 expression with the overall survival rates of HCC patients, univariate analysis indicated that ORM1 expression was highly correlated with tumor grade and stage. An in vitro assay also revealed that downregulation of ORM1 led to the suppression of tumor growth and enhancement of sorafenib sensitivity without epithelial-to-mesenchymal transition (EMT) alteration, which was consistent with our bioinformatic analysis. Hence, ORM1 played a key role in HCC tumorigenesis and may serve as a potential target for the development of therapeutics against HCC in the future

Ectopic tissue engineered ligament with silk collagen scaffold for ACL regeneration: A preliminary study

Anterior cruciate ligament (ACL) reconstruction remains a formidable clinical challenge because of the lack of vascularization and adequate cell numbers in the joint cavity. In this study, we developed a novel strategy to mimic the early stage of repair in vivo, which recapitulated extra-articular inflammatory response to facilitate the early ingrowth of blood vessels and cells. A vascularized ectopic tissue engineered ligament (ETEL) with silk collagen scaffold was developed and then transferred to reconstruct the ACL in rabbits without interruption of perfusion. At 2 weeks after ACL reconstruction, more well-perfused cells and vessels were found in the regenerated ACL with ETEL, which decreased dramatically at the 4 and 12 week time points with collagen deposition and maturation. ACL treated with ETEL exhibited more mature ligament structure and enhanced ligament-bone healing post-reconstructive surgery at 4 and 12 weeks, as compared with the control group. In addition, the ETEL group was demonstrated to have higher modulus and stiffness than the control group significantly at 12 weeks post-reconstructive surgery. In conclusion, our results demonstrated that the ETEL can provide sufficient vascularity and cellularity during the early stages of healing, and subsequently promote ACL regeneration and ligament-bone healing, suggesting its clinic use as a promising therapeutic modality. Statement of Significance Early inflammatory cell infiltration, tissue and vessels ingrowth were significantly higher in the extra articular implanted scaffolds than theses in the joint cavity. By mimicking the early stages of wound repair, which provided extra-articular inflammatory stimulation to facilitate the early ingrowth of blood vessels and cells, a vascularized ectopic tissue engineered ligament (ETEL) with silk collagen scaffold was constructed by subcutaneous implantation for 2 weeks. The fully vascularized TE ligament was then transferred to rebuild ACL without blood perfusion interruption, and was demonstrated to exhibit improved ACL regeneration, bone tunnel healing and mechanical properties. (C) 2017 Published by Elsevier Ltd on behalf of Acta Materialia Inc