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Although most [CD8.sup.+] T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self- peptides. Recognition and elimination of pathogenic target cells that express these Qa-1- self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression. Immunization with synthetic agonist peptides that mobilize CD8 Tregs in vivo efficiently inhibit antigraft antibody responses and markedly prolong heart and kidney organ graft survival. Definition of TCR-dependent differentiation and target recognition by this lineage of CD8 Tregs may open the way to new therapeutic approaches to inhibit pathogenic antibody responses., Introduction The immune system has evolved complex mechanisms that allow efficient destruction of microbial pathogens while sparing the host's own tissues. Maintenance of this balance depends, in part, on regulatory [...]

Grape skin serves as a reservoir for many bacteria and fungi, which can affect grape health, quality, and safety. However, grape skin microbiota and mycobiota of table grapes remain largely understudied. This study investigated bacterial and fungal communities residing on different table grapevine cultivars ('Summer Black' and 'Kyoho') as well as the impact of potential contributors thereby, via culture-dependent and culture-independent (analysis of 16S rRNA gene and internal transcribed spacer sequences) methods with different purposes. Microbiota of both grapevine cultivars were dominated by Cladosporium, Alternaria, Aspergillus, Thauera, and Pantoea. In addition, yeast strains belonging to Hanseniaspora opuntiae, Pichia terricola, Rhodotorula mucilaginosa, Candida stellimalicola, and Kodamaea ohmeri were enriched from the studied grapes, while some strains were considered as health-threatening pathogens. Differences in grapevine cultivars did not significantly affect their mycobiota and microbiota profiles. Nevertheless, their mycobiota exhibited significant variations across different grape-sampling sites in Shanghai, indicating the contribution of the grape-growing environment to grape skin mycobiota. Altogether, the current study demonstrated the contribution of the grape-growing environment to table grape skin mycobiota, and highlighted the importance of microbiota management in the production and consumption of table grapes. [ABSTRACT FROM AUTHOR]

The normal operation of various superconducting magnets is greatly influenced by the thermal stress of the insulating system, commonly made of epoxy resins with vacuum pressure impregnation (VPI) technology, throughout the curing and cooling processes. In this work, we developed a Fiber Bragg Grating (FBG) strain measurement method to monitor the real-time strain responses of an epoxy resin IR-3 and its glass fiber-reinforced composite during both curing and cooling processes. Then, we also monitored the same process of a Nb–Ti superconducting magnet coil prepared by VPI technology. With the help of FBG strain sensors, the residual strains of the coil at various positions and directions were investigated. The results show that the large residual strain occurred near the end of the coil in the axial direction. In addition, the interlaminar shear stress properties were measured at both room temperature and liquid nitrogen temperature. The strain characteristics of the epoxy resin IR-3 and the insulating system can provide useful guidance for the design and construction of high-field Nb–Ti superconducting magnets. [ABSTRACT FROM AUTHOR]

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single- cell RNA sequencing of the LNs showed that anti-CD40L promotes a [Madcam1.sup.+] FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node address in (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79-anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79-anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance., Introduction Lymph nodes (LNs) are integral sites at which the alloimmune response is mounted following transplantation. Our group has shown that LNs also function as sites of immune regulation by [...]

Chronic allograft dysfunction (CAD) is the major cause of late graft loss in long-term renal transplantation. In our previous study, we found that epithelial–mesenchymal transition (EMT) is a significant event in the progression of renal allograft tubulointerstitial fibrosis, and impaired autophagic flux plays a critical role in renal allograft fibrosis. Everolimus (EVR) has been reported to be widely used to prevent the progression of organ fibrosis and graft rejection. However, the pharmacological mechanism of EVR in kidney transplantation remains to be determined. We used CAD rat model and the human kidney 2 (HK2) cell line treated with tumor necrosis factor-α (TNF-α) and EVR to examine the role of EVR on TNF-α-induced EMT and transplanted renal interstitial fibrosis. Here, we found that EVR could attenuate the progression of EMT and renal allograft interstitial fibrosis, and also activate autophagy in vivo. To explore the mechanism behind it, we detected the relationship among EVR, autophagy level, and TNF-α-induced EMT in HK2 cells. Our results showed that autophagy was upregulated upon mTOR pathway inhibition by EVR, which could significantly reduce expression of TNF-α-induced EMT. However, the inhibition of EVR on TNF-α-induced EMT was partly reversed following the addition of autophagy inhibitor chloroquine. In addition, we found that TNF-α activated EMT through protein kinase B (Akt) as well as nuclear factor kappa B (NF-κB) pathway according to the RNA sequencing, and EVR's effect on the EMT was only associated with IκB-α stabilization instead of the Akt pathway. Together, our findings suggest that EVR may retard impaired autophagic flux and block NF-κB pathway activation, and thereby prevent progression of TNF-α-induced EMT and renal allograft interstitial fibrosis. [ABSTRACT FROM AUTHOR]

Background: Nowadays, renal allograft survival is confined by the development of allograft fibrosis. Previous studies have reported interleukin-33 (IL-33) upregulated significantly in patients with chronic renal allograft dysfunction, and it could induce renal tubular epithelial to mesenchymal transition (EMT), which eventually contributed to renal allograft fibrosis. Our study intended to detect the underlying association between single nucleotide polymorphisms (SNPs) of IL-33 gene and renal allograft fibrosis in kidney transplant recipients.Methods: We collected blood samples from 200 renal transplant recipients for the identification of SNPs and transplanted kidney tissue samples for identifying differentially expressed genes (DEGs). Intersection of SNP-related genes and DEGs was conducted for further analysis. Relationships between these SNPs and renal allograft fibrosis were evaluated by the inheritance models. Immunohistochemical (IHC) staining and western blotting (WB) were used to detect the expression of IL-33 and the markers of EMT in human kidney tissues obtained from control and chronic renal allograft dysfunction (CAD) patients. In vitro, we detected the progressions of EMT-related markers and the levels of MAPK signaling pathway mediators after transfecting IL-33 mutant plasmids in HK2 cells.Results: Three intersected genes including IL-33 genes were significantly expressed. IL-33 expression was validated in kidney tissues by IHC and WB. Thirty-nine IL-33-related SNPs were identified in targeted sequencing, in which 26 tagger SNPs were found by linkage disequilibrium analysis for further analysis. General linear models indicated sirolimus administration significantly influenced renal allograft fibrosis (P < 0.05), adjustment of which was conducted in the following analysis. By multiple inheritance model analyses, SNP rs10975519 of IL-33 gene was found closely related to renal allograft fibrosis (P < 0.005). Furthermore, HK2 cells transfected with mutated plasmid of rs10975519 showed stronger mobility and migration ability. Moreover, IL-33 mutant plasmids could promote the IL-33-induced EMT through the sustained activation of p38 MAPK signaling pathway in HK2 cells.Conclusion: In our study, rs10975519 on the IL-33 gene was found to be statistically associated with the development of renal allograft fibrosis in kidney transplant recipients. This process may be related to the IL-33-induced EMT and sustained activation of p38 MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Iguratimod (IGU) can mitigate the symptoms of rheumatoid arthritis through its anti-inflammatory effects. The objective of this study was to investigate the clinical efficacy and safety of IGU in highly HLA-mismatched renal transplant recipients, in combination with standard immunosuppressive regimen. This pilot study was designed as an open-label, blank-control, randomized clinical trial on patients recruited from a single transplant center in China. Patients who met the inclusion criteria were randomized to the IGU (n=27) and blank control (n=27) groups. IGU was administrated with the conventional triple immunosuppressive protocol for 52 weeks after kidney transplantation. The incidence of biopsy-proven acute rejection rate was 14.8% (4/27) in the IGU group and 29.6% (8/27) in the control group, P = 0.19. The clinical rejection rate was also substantially reduced in the IGU group (3.7% vs. 18.5%, P = 0.08). De novo donor-specific antibody also showed a decline trend in the IGU group after 52 weeks. The graft function and incidence of adverse events were similar between the two groups. In addition, IGU intervention significantly decreased the number of NK cells throughout the follow-up. In conclusion, our study has shown the possibility that IGU could reduce the allograft rejection rate and de novo DSA with appreciable safety in combination with conventional immunosuppressants. Formal clinical trials were warranted based on current findings. [ABSTRACT FROM AUTHOR]

To resist large electromagnetic loads, the ITER correction coils (CCs) are protected by a 20-mm thickness 316LN austenitic stainless steel case. Due to the strict tolerance requirement of the case manufacture, tungsten inert gas (TIG) welding technology was used for subcase assembly welding, whereas laser beam welding (LBW) technology was applied to enclosure welding of the cases. The case shall be operated at 4.2 K and shall undergo considerably cyclic stress due to magnet electromagnetization as well as interaction with the toroidal field (TF) and poloidal field (PF). This article focuses on the assessment of the mechanical properties of the welding joints at cryogenic temperature. Results indicated that the values of the ultimate tensile strength of the TIG welding joint and the LBW welding joint were 1555 and 1522 MPa, respectively, which reach to 99.7 and 97.6% of that of the base material (BM). The elongation at the fracture of both the TIG and LBW weldments was larger than 35%. The plane strain fracture toughness KIc(J) of the TIG and the LBW weldments was 210 and 241 MPa·m1/2, respectively. The fractographic analysis indicated that the fracture surface was composed of fine equiaxed dimples, which indicated that both welding joints fractured in a ductile manner. The welding joints survived the minimum of 30 000 cycles fatigue test at stress level and load ratio specified by the ITER document. In addition, the fatigue crack growth rates of both welding joints were lower than that of the BM. All mechanical properties of both the welding joints satisfied the ITER specifications. [ABSTRACT FROM AUTHOR]

In this work, the microstructure evolution and magnetic properties of the 316LN austenitic stainless steels under high-cycle-fatigue loading at liquid helium temperature (4.2 K) were assessed by using the X-ray diffractometer (XRD), electron microscopy and magnetic measurements. The microstructure was composed of a single face-centered cubic (FCC) phase, and the high local misorientation was found near the grain boundaries. Observations through the high-resolution transmission electron microscopy reveals that the deformation was dominated by the dislocation and stacking faults. The magnetic susceptibility varies slightly after cyclic loading test at 4.2 K. [Display omitted] [ABSTRACT FROM AUTHOR]

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 that 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 by 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 that 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. [Display omitted] • Tfh and Tfr cells are required for affinity maturation of GC B cells • Tfh and Tfr cells optimize antibody responses to SARS-CoV-2 vaccines • Aged mice have defective GC responses leading to bimodal antibody responses • Tfh/Tfr help balance affinity maturation with clonal diversity in germinal centers Cavazzoni et al. show that both Tfh and Tfr cells are essential for optimization of germinal center responses to SARS-CoV-2 vaccines. Limiting Tfh cells results in fewer SARS-CoV-2 GC responses and lower affinity maturation, whereas limiting Tfr cells promotes non-antigen-specific GC responses, leading to lower-affinity maturation. Altered Tfh/Tfr responses in aging result in unique bimodal antibody responses. [ABSTRACT FROM AUTHOR]

Follicular helper T (Tfh) cells have been implicated in controlling rejection after allogeneic kidney transplantation, but the precise subsets, origins, and functions of Tfh cells in this process have not been fully characterized. Here we show that a subset of effector Tfh cells marked by previous IL-21 production is potently induced during allogeneic kidney transplantation and is inhibited by immunosuppressive agents. Single-cell RNA-Seq revealed that these lymph node (LN) effector Tfh cells have transcriptional and clonal overlap with IL-21-producing kidney-infiltrating Tfh cells, implicating common origins and developmental trajectories. To investigate the precise functions of IL-21-producing effector Tfh cells in LNs and allografts, we used a mouse model to selectively eliminate these cells and assessed allogeneic B cell clonal dynamics using a single B cell culture system. We found that IL-21-producing effector Tfh cells were essential for transplant rejection by regulating donor-specific germinal center B cell clonal dynamics both systemically in the draining LN and locally within kidney grafts. Thus, IL-21-producing effector Tfh cells have multifaceted roles in Ab-mediated rejection after kidney transplantation by promoting B cell alloimmunity.

Background: Further research needs to be conducted on the role of genetic variables in kidney transplantation fibrosis. In this study, we used next-generation sequencing (NGS) to examine the relationship between matrix metalloproteinase (MMP) genes and single-nucleotide polymorphisms (SNPs) in renal allograft fibrosis., Methods: This study comprised 200 patients, whose complete DNA samples were taken. The SNPs in MMP genes were identified using targeted NGS. Hardy-Weinberg equilibrium (HWE) and minor allele frequency (MAF) tests were conducted, followed by a linkage disequilibrium (LD) analysis. Finally, the SNPs and severity of kidney allograft fibrosis were evaluated using different inheritance models., Results: In total, 41 MMP gene-related SNPs were identified using targeted sequencing, and 20 tagger SNPs were retained for further study. The general linear models (GLMs) revealed that sirolimus treatment had a substantial effect on kidney graft fibrosis. The multiple inheritance model analyses revealed that SNP rs9059 of the MMP9 gene was strongly associated with kidney graft fibrosis. The in-vitro experiments showed the MMP9 rs9509 mutation promotes the process of epithelial-mesenchymal transition (EMT) in the human kidney 2 (HK2) cells., Conclusions: The SNP rs9059 is associated with significant kidney allograft pathological changes by promoting EMT progression. Our findings provide insights into the etiology of renal allograft interstitial fibrosis and the MMP9 could be used as a potential treatment target in the future., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-22-506/coif). The authors have no conflicts of interest to declare., (2023 Translational Andrology and Urology. All rights reserved.)

Background: Following allogeneic kidney transplantation, a substantial proportion of graft loss is attributed to the formation of donor-specific antibodies and antibody-mediated rejection. B cells infiltrate kidney grafts during antibody-mediated rejection; however, the origins, repertoires, and functions of these intrarenal B cells remain elusive., Methods: Here, we use murine allogeneic kidney transplant models to study the origins, transcriptional programming and B cell receptor repertoire of intragraft B cells, and in vitro stimulation assays to evaluate the ability of intragraft B cells to promote CD4+ T cell expansion., Results: B cells infiltrate kidney grafts in settings of allogeneic, but not syngeneic, transplantation. Intragraft B cells have characteristics of activation but are transcriptionally distinct from germinal center B cells and resemble innate-like B cells. B cell receptor sequencing demonstrates that the majority of intragraft B cells do not originate from lymph node germinal center B cells and are largely germline. Class-switched intragraft B cells are rare but can be donor-specific and produce IgG capable of binding to the kidney allograft. Lastly, intrarenal B cells are capable of stimulating naive T cells but have an altered ability to promote T follicular helper cell expansion., Conclusions: Together, these data demonstrate that intrarenal B cells during transplant rejection are transcriptionally distinct from lymph node B cells., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)