Search

Helicobacter pylori is the major etiological agent for most gastric cancer. CagA has been reported to be an important virulence factor of H. pylori, but its effect on the immune response is not yet clear. In this study, wild-type C57BL/6 mice and Ptpn6me-v/me-v mice were randomly assigned for infection with H. pylori. We demonstrated that CagA suppressed H. pylori–stimulated expression of proinflammatory cytokines in vivo. Besides, we infected mouse peritoneal macrophages RAW264.7 and AGS with H. pylori. Our results showed that CagA suppressed expression of proinflammatory cytokines through inhibiting the MAPKs and NF-κB pathways activation in vitro. Mechanistically, we found that CagA interacted with the host cellular tyrosine phosphatase SHP-1, which facilitated the recruitment of SHP-1 to TRAF6 and inhibited the K63-linked ubiquitination of TRAF6, which obstructed the transmission of signal downstream. Taken together, these findings reveal a previously unknown mechanism by which CagA negatively regulates the posttranslational modification of TRAF6 in innate antibacterial immune response and provide molecular basis for new therapeutics to treat microbial infection.

Inducible regulatory T cells (iTregs) are an important subset of Tregs and play a role in the maintenance of peripheral tolerance, and the occurrence of a number of diseases, including tumors and autoimmune diseases. However, the instability of iTregs is a major obstacle for their potential application in clinical trials. The underlying mechanism of iTreg instability remains largely unknown. In the present study, the expression level of microRNA (miRNA/miR)‑30a in murine iTregs was evaluated using reverse transcription‑quantitative PCR. miR‑30a mimics and a miR‑negative control (NC) were transiently transfected into iTregs using Nucleofector technology. The effects of miR‑30a on the suppressive function of murine iTregs in vitro and in vivo were investigated using MTT, adoptive cell transfer (ACT) and flow cytometry assays, as well as a murine model of lung cancer. In the present study, it was identified that the expression level of miR‑30a was lower in murine iTregs in vitro compared with natural (n)Tregs. Furthermore, compared with miR‑NC, miR‑30a mimics impaired the suppressive function of murine iTregs on murine CD4+ T cell proliferation in vitro, which was accompanied by the altered expression of cytotoxic T lymphocyte‑associated antigen 4 and glucocorticoid induced tumor necrosis factor receptor, as well as transforming growth factor‑β and interleukin‑10. It was also observed that, compared with miR‑NC, miR‑30a mimics abrogated the suppressive effects of murine iTregs on murine CD8+ T cell function in vivo, producing an effective antitumor effect in mice bearing 3LL lung cancer cells in the ACT assay. From a mechanistic point, the expression level of suppressor of cytokine signaling 1, a putative target of miR‑30a, was elevated, altering the activation of the Akt and STAT1 pathway in the miR‑30a mimic transfected group compared with the miR‑NC group, reducing the suppressive function of murine iTregs. The present study identified a role for miR‑30a in the instability of iTregs and provided a novel insight into the development of therapeutic strategies for promoting T‑cell immunity via the regulation of iTreg instability by targeting specific miRNAs.

BACKGROUND Fractalkine (FKN) was recently shown to play an important role in atherosclerotic plaque rupture and cardiac remodeling and dysfunction. We evaluated the changes in serum FKN (sFKN) in patients with acute ST-elevation myocardial infarction (STEMI) and the influence of a percutaneous coronary intervention (PCI) on the levels of sFKN. METHODS The study population included 40 patients with acute STEMI [acute myocardial infarction (AMI)+PCI: 20 underwent primary PCI; AMI: 20 without PCI] and 40 patients with symptomatic stable angina pectoris (SAP+PCI: 20 underwent PCI; SAP: 20 without PCI). sFKN were measured at different time points by ELIZA. The gene expression of heart FKN was assessed by real-time reverse transcription-PCR in a model of myocardial infarction mice. RESULTS We found that the baseline level of sFKN in patients with acute STEMI was significantly higher than that of patients with SAP. Primary PCI in STEMI resulted in a rapid decrease within 24 h and to a similar level after 48 h as in the SAP and SAP+PCI patients, whereas in the AMI group, the sFKN level showed a slight decrease from 6 to 24 h (from 1307.6±368.9 to 1092.7±258.1 pg/ml, P=0.036) and remained significantly higher at all later time points (P

Exosomes are small extracellular vesicles (EVs), released by a wide variety of cell types, carry donor origin-proteins, cytokines, and nucleic acids, transport these cargos to adjacent or distant specific recipient cells, and thereby regulate gene expression and activation of target cells. In this study, we isolated and identified exosomes in rhesus macaques, and investigated their effects on cell tropism and activation, especially their potential to reactivate HIV latency. The results indicated that plasma-derived exosomes preferentially fuse to TCR-activated T cells and autologous parent cells. Importantly, the uptake of exosomes, derived from IL-2 stimulated CD4+ T cells, effectively promoted reactivation of resting CD4+ T-cell, as indicated by an increased viral transcription rate in these cells. These findings provide premise for the potential application of exosome in the reactivation of HIV latency, in combination its use as functional delivery vehicles with antiretroviral therapy (ART).

Pregnancy loss occurs in about 15% of clinically recognized pregnancies, and defective maternal-fetal immune tolerance contributes to more than 50% of these events. We found that signaling by the type I membrane protein T cell immunoglobulin and mucin-containing protein 3 (Tim-3) in natural killer (NK) cells had an essential protective role during early pregnancy. Tim-3 on peripheral NK (pNK) cells was transiently increased in abundance during the first trimester of pregnancy, which depended on interleukin-4 (IL-4)-signal transducer and activator of transcription 6 (STAT6) and progesterone signaling. Tim-3+ pNK cells displayed immunosuppressive activities, including the production of anti-inflammatory cytokines and the induction of regulatory T cells (Tregs) in a transforming growth factor-β1 (TGF-β1)-dependent manner. Tim-3 on pNK cells was stimulated by its ligand galectin-9 (Gal-9), leading to signaling by the kinases c-Jun N-terminal kinase (JNK) and AKT. In recurrent miscarriage (RM) patients, Tim-3 abundance on pNK cells was reduced and the immunosuppressive activity of Tim-3+ pNK cells was impaired. Compared to Tim-3+ pNK cells from donors with normal pregnancies, RM patient Tim-3+ pNK cells exhibited changes in DNA accessibility in certain genetic loci, which were reversed by inhibiting accessible chromatin reader proteins. Furthermore, Tim-3+ pNK cells, but not Tim-3- pNK cells, reduced fetal loss in abortion-prone and NK cell-deficient mice. Together, our findings reveal a critical role for Tim-3-Gal-9 signaling-mediated immunoregulation by pNK cells in maternal-fetal immune tolerance and suggest that Tim-3 abundance on pNK cells is a potential biomarker for RM diagnosis.

Background It has been shown that dendritic cells (DCs) and fractalkine play a role in accelerating progression of the inflamed atherosclerotic lesions and plaque rupture. We evaluated the numbers and functional changes of DCs and its subsets in human type 2 diabetes with or without unstable angina pectoris (UAP). Methods The study population consisted of 39 diabetic patients (DM:18 without CAD; DM + UAP: 21 with UAP), 18 non-diabetic UAP patients (UAP), and 15 healthy control (Normal). Peripheral blood DCs and its subsets were measured by three color flow cytometry. Serum levels of fractalkine, IL-12, and IFN-α were also measured. The functional status of the monocyte-derived DCs was analyzed by flow cytometry and allogeneic mixed T lymphocytes reaction. Results The percent and absolute numbers of DCs and mDC within the total leukocyte population was similar for Normal and DM, while significantly lower in DM + UAP. pDC numbers were not significantly altered. Serum fractalkine in DM + UAP was highest among the four groups (p = 0.04 vs. UAP, p = 0.0003 vs. DM, p < 0.0001 vs. Normal). Circulating mDC inversely correlated with serum fractalkine (r = -0.268, p = 0.01) level. Compared with DM and UAP, the costimulatory molecules CD86 and proliferation of T cells stimulated by DCs were significantly increased in DM + UAP group. Conclusions Our study suggested that increases in the fractalkine level and the number and functional changes of blood DCs might contribute to diabetic coronary atherosclerosis and plaque destabilization.