Follicular helper T (Tfh) cells promote, whereas follicular regulatory T (Tfr) cells restrain, germinal center (GC) reactions. However, the precise roles of these cells in the complex GC reaction remain poorly understood. Here, we perturb Tfh or Tfr cells after SARS-CoV-2 spike protein vaccination in mice. We find Tfh cells promote the frequency and somatic hypermutation (SHM) of Spike-specific GC B cells and regulate clonal diversity. Tfr cells similarly control SHM and clonal diversity in the GC, but do so through limiting clonal competition. In addition, deletion of Tfh or Tfr cells during primary vaccination results in changes in SHM after vaccine boosting. Aged mice, which have altered Tfh and Tfr cells, have lower GC responses presenting a bimodal distribution of SHM. Together, these data demonstrate GC responses to SARS-CoV-2 spike protein vaccines require a fine balance of positive and negative follicular T cell help to optimize humoral immunity.
Allograft interstitial fibrosis was characterized by massive extracellular matrix deposition caused by activated fibroblasts and myofibroblasts. Epithelial‐mesenchymal transition (EMT) is recognized as an important source of myofibroblasts contributing to the pathogenesis of allograft interstitial fibrosis. Smad ubiquitination regulatory factor 1 (Smurf1) has been recently reported to be involved in the progression of EMT. Our study was to detect the effect of Bortezomib and Smurf1 in the EMT and allograft interstitial fibrosis. Biomarkers of EMT, as well as Smurf1, were examined in human proximal tubular epithelial cells (HK‐2) treated with tumour necrosis factor‐alpha (TNF‐α) in various doses or at various time points by Western Blotting or qRT‐PCR. We knockdown or overexpressed Smurf1 in HK‐2 cells. Furthermore, rat renal transplant model was established and intervened by Bortezomib. Allograft tissues from human and rats were also collected and prepared for HE, Masson's trichrome, immunohistochemical staining and western blotting assays. As a result, we found that TNF‐α significantly promoted the development of EMT in a time‐dependent and dose‐dependent manner through Smurf1/Akt/mTOR/P70S6K signalling pathway. More importantly, Bortezomib alleviated the progression of EMT and allograft interstitial fibrosis in vivo and in vitro by inhibiting the production of TNF‐α and expression of Smurf1. In conclusion, Smurf1 plays a critical role in the development of EMT induced by TNF‐α. Bortezomib can attenuate the Sumrf1‐mediated progression of EMT and renal allograft interstitial fibrosis, which could be suggested as a novel choice for the prevention and treatment of renal allograft interstitial fibrosis.
Over the past 20 years, the development of newer immunosuppressive drugs has improved short-term survival after kidney transplantation. 1 However, long-term survival has not substantially improved. Long-term graft loss has been attributed to chronic antibody-mediated rejection (AbMR) caused by donorspecific antibodies (DSAs). 1,2 DSA can be preexisting or can arise
Carbon-based aerogels have drawn substantial attention for a wide scope of applications. However, the high intrinsic electrical conductivity limits their potential thermal management application in electronic packaging materials. Herein, a highly compressible, thermally conductive, yet electrically insulating fluorinated graphene aerogel (FGA) is developed through a hydrofluoric acid-assisted hydrothermal process. The macroscopic-assembled FGA constituting of tailored interconnected graphene networks with tunable fluorine coverage shows excellent elasticity and fatigue resistance for compression, despite a low density of 10.6 mg cm–3. Moreover, the aerogel is proved to be highly insulating, with the observed lowest electrical conductivity reaching 4 × 10–7 S cm–1. Meanwhile, the aerogel exhibits prominent heat dissipation performance in a typical cooling procedure, which can be used to fabricate thermoconductive polymer composites for electronic packaging.
Acute lung injury (ALI) is an acute hypoxic respiratory insufficiency caused by various intra- and extrapulmonary injury factors. Presently, excessive inflammation in the lung and the apoptosis of alveolar epithelial cells are considered to be the key factors in the pathogenesis of ALI. Hypoxia-inducible factor-1 (HIF-1) is an oxygen-dependent conversion activator that is closely related to the activity of reactive oxygen species (ROS). HIF-1 has been shown to play an important role in ALI and can be used as a potential therapeutic target for ALI. This manuscript will introduce the progress of HIF-1 in ALI and explore the feasibility of applying inhibitors of HIF-1 to ALI, which brings hope for the treatment of ALI.
Acute rejection is a major risk for renal transplant failure. During this adverse process, activated T cells are considered the main effectors. Recently, B and T lymphocyte attenuator (BTLA), a member of the CD28 family receptor, was reported to be a novel inhibitory regulator of T cell activation in heart and pancreatic allograft rejection. Due to the similarity of acute rejection pathways among different organs, we hypothesized that BTLA might play a role in acute rejection of kidney transplant. In renal transplant patients, we observed that BTLA expression was significantly decreased in peripheral CD3+ T lymphocytes of biopsy-proven acute rejection (BPAR) recipients compared with control patients with stable transplanted kidney functions. Remarkably, overexpression of BTLA in the rat model was found to significantly inhibit the process of acute rejection, regulate the postoperative immune status, and prolong allograft survival. BTLA overexpression significantly suppressed IL-2 and IFN-γ production and increased IL-4 and IL-10 production both in vivo and in vitro . Moreover, vital factors in T-cell signaling pathways, including mitogen-associated protein kinases (MAPK), nuclear factor-kappa B (NF-κB) and nuclear factor of activated T cells (NFAT), were also significantly repressed by BTLA overexpression. Therefore, BTLA can suppress acute rejection and regulate allogeneic responses of kidney transplant by regulating TCR downstream signals and inflammatory cytokines production to improve allografts outcomes.
Background: The microRNA (miRNA) miR-200c-3p is involved in the tumorigenesis and progression of a variety of cancers. However, the underlying regulatory role of miR-200c-3p in prostate cancer (PCa) remains unclear. Methods: Online databases including Oncomine, Linkedomics and StarBase were used to investigate the clinical significance of miR-200c-3p, along with associated gene targets. PCa tissues and adjacent normal tissues were used for the detection of miR-200c-3p expression. A lentivirus overexpressing miR-200c-3p was constructed and transfected into PC3 and DU145 cells. Cell formation of proliferation, migration, and invasion were determined by cell viability and colony-formation assay, wound healing assay, and Matrigel invasion assay, respectively. Epithelial-mesenchymal transition (EMT)-associated markers were determined by qRT-PCR and Western blot. A luciferase reporter assay was performed to determine the direct relationship of miR-200c-3p and ZEB2. The tumor-suppressive role of miR-200c-3p was further confirmed by a xenograft tumor model and immunohistochemical (IHC) staining. Results: Online database analyses showed that miR-200c-3p was associated with pathologic T and N stage in PCa, and miR-200c-3p was downregulated in PCa tissues. Overexpression of miR-200c-3p was considered a tumor suppressor and was found to significantly suppress the formation of migration and invasion in PCa cells via repression of E-cadherin-induced EMT. The bioinformatic database indicated that ZEB2 has a significant correlation with miR-200c-3p and was upregulated in PCa tissues. Further, ZEB2 expression was suppressed by the upregulation of miR-200c-3p and was identified as a direct target of miR-200c-3p. In addition, repression of ZEB2 could restore the levels of miR-200c-3p in PCa cells in turn, suggesting a potential negative loop between miR-200c-3p and ZEB2. miR-200c-3p also had an antitumor effect by negatively regulating ZEB2 in a xenograft mouse model. Conclusions: Taken together, the results of our study demonstrated the novel regulatory loop of miR-200c-3/ZEB2 in PCa progression, providing effective therapeutic strategies for PCa in the future.
BackgroundCostimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation.Materials and MethodsThe rat kidney transplantation model was used to investigate graft rejection in single and combined therapy. Graft function was analyzed by detecting serum creatinine. Pathological staining was used to observe histological changes in grafts. The expression of T cells was observed by immunohistochemistry and flow cytometry. In vitro, we constructed an antigen-stimulated immune response by mixed lymphocyte culture, treated with or without Belatacept and BTLA-overexpression adenovirus, to observe the proliferation of receptor cells and the expression of cytokines. In addition, western blot and qRT-PCR analyses were performed to evaluate the expression of CTLA-4 and BTLA at various time points during the immune response.ResultsIn rat models, combined therapy reduced the serum creatinine levels and prolonged graft survival compared to single therapy and control groups. Mixed acute rejection was shown in the allogeneic group and inhibited by combination treatment. Belatacept reduced the production of DSA and the deposition of C4d in grafts. Belatacept combined with BTLA overexpression downregulated the secretion of IL-2 and IFN-γ, as well as increasing IL-4 and IL-10 expression. We also found that Belatacept combined with BTLA overexpression inhibited the proliferation of spleen lymphocytes. The duration of the elevated expression levels of CTLA-4 and BTLA differentially affected the immune response.ConclusionBelatacept combined with BTLA overexpression attenuated acute rejection after kidney transplantation and prolonged kidney graft survival, which suggests a new approach for the optimization of early immunosuppression after kidney transplantation.
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