The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants

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CD8+ T cells induced by adenovirus-vectored vaccine are capable of preventing establishment of latent murine γ-herpesvirus 68 infection

CD8+ T cells are known to control infections, but their role in preventing latent infection from establishing has not been thoroughly investigated.We hypothesized that a potent CD8+ T cell response patrolling the mucosal viral entry points could kill the first infected cells and thereby abrogate the infection before latency is established.To investigate this, replication deficient adenovirus serotype 5 vectors encoding murine γ-herpesvirus-68 CD8+ T cell epitopes linked to the T cell adjuvant Invariant chain, were developed. We show that intranasal vaccination of mice reduces the risk of establishment of latent infection from multiple intranasal ID50 challenges with murine γ-herpesvirus-68 by 81% per exposure at 14 days post vaccination. Protection waned over time, but immune responses were extended by heterologous prime-boost vaccination applied simultaneously intramuscularly and intranasally, and animals vaccinated 66 days prior to challenge showed a strong trend of long-term protection.Our data provides evidence that CD8+ T cells are able to protect against establishment of latent infection. Although the protective efficacy is difficult to maintain over time, this proof-of-concept study suggests a role for a CD8+ T cell arm in future vaccine strategies against latent human viral infections caused by pathogens such as HIV and multiple herpes virus.     

Interleukin-34 drives macrophage polarization to the M2 phenotype in autoimmune hepatitis

BackgroundAutoimmune hepatitis is a chronic inflammatory disease, the abnormal immunological function is the main pathogenesis. Interleukin-34 is a newly identified cytokine that shares the same receptor as colony stimulating factor-1.MethodsWe used interleukin-34 knockout and wild-type mice in a Con A-induced hepatitis model and cocultured RAW264.7 macrophage cells with interleukin-34. We then detected associated inflammatory cytokine and chemokine levels to elucidate the role of interleukin-34.ResultsIn this study, we found that the loss of interleukin-34 resulted in higher sensitivity to Con A-induced hepatitis. RAW264.7 macrophage cells were able to differentiate to the M2 phenotype upon interleukin-34 stimulation.ConclusionsWe conclude that interleukin-34 may protect the liver from Con A-mediated hepatitis by driving M2 macrophage polarization and suppressing inflammation.     

淫羊藿苷对骨微血管内皮细胞自噬及外泌体产生的影响

目的评估淫羊藿苷对低浓度糖皮质激素诱导的骨微血管内皮细胞（bone microvascular endothelial cells，BMECs）自噬和外泌体分泌的影响。方法从行全髋关节置换术切取的股骨头中分离 BMECs，用一系列低浓度梯度氢化可的松（0、0.03、0.06、0.10 mg/mL）干预（设为 A、B、C、D 组），在此基础上再用 5×10⁻⁵ mol/L 淫羊藿苷干预（设为 A1、B1、C1、D1 组），24 h 后采用 Western blot 检测自噬相关蛋白微管相关蛋白轻链 3B（microtubule-associated protein 1 light chain 3B，LC3B）及死骨片 1（p62）的表达。从经淫羊藿苷处理（干预组）和未经淫羊藿苷处理（未干预组）的 BMECs 中提取外泌体，纳米颗粒跟踪分析技术检测其直径和浓度，BCA 法检测外泌体总蛋白质含量，Western blot 检测外泌体 CD9、CD81、TGF-β₁ 和 VEGFA 蛋白的表达。进一步将 BMECs 分为 3 组，实验组和对照组分别分离经或未经淫羊藿苷处理的 BMECs 分泌的外泌体，与 BMECs 共培养；空白对照组为单纯 BMECs。氢化可的松处理后，采用 Western blot 检测 LC3B 和 p62 表达，划痕实验检测细胞迁移能力，并观察血管生成能力。 结果随氢化可的松浓度升高，各组 LC3B-Ⅱ蛋白相对表达量逐渐增加，p62 蛋白相对表达量减少，各组间差异均有统计学意义（P<0.01）；相同激素浓度下，淫羊藿苷干预后，LC3B-Ⅱ蛋白相对表达量减少，p62 蛋白相对表达量增加（P<0.01）。干预组外泌体浓度显著高于未干预组（t=−10.191，P=0.001）；两组外泌体直径和总蛋白质含量比较差异均无统计学意义（P>0.05）。未干预组和干预组 CD9 和 CD81 蛋白均高度表达；干预组 VEGFA/CD9 和 TGF-β₁/CD9 蛋白相对表达量比值均显著高于未干预组（P<0.01）。外泌体共培养后，空白对照组、对照组和实验组中 p62 蛋白相对表达量呈递增趋势，LC3B-Ⅱ蛋白相对表达量呈递减趋势，各组间比较差异均有统计学意义（P<0.05）。氢化可的松处理 12、24 h 时，对照组和实验组划痕闭合率明显高于空白对照组（P<0.05），实验组明显高于对照组（P<0.05）；氢化可的松处理 4、8 h 时，实验组和对照组管腔数、出芽数和小管分支长度均显著大于空白对照组（P<0.05）；实验组小管分支长度和管腔数显著大于对照组（P<0.05）。 结论淫羊藿苷及 BMECs 产生的外泌体能改善低浓度激素诱导的 BMECs 自噬，对内皮细胞起到保护作用。     

CD10蛋白在结直肠癌组织中的表达及其临床意义

目的：研究CD10蛋白在结直肠癌组织中的表达及其与结直肠癌的各临床病理指标之间的关系，探讨其在结直肠癌发生、发展中的作用。方法：收集78例结直肠癌组织标本及22例癌旁正常组织样本，运用免疫组化EliVision法检测CD10蛋白的表达，并采用卡方检验分析其表达强度及分布比例与结直肠癌临床病理指标的关系。结果：CD10蛋白在结直肠癌组织和正常结肠黏膜组织中的阳性表达率分别为46.2%（36/78）和0，差异有统计学意义（P < 0.01）。结直肠癌组织中CD10蛋白表达比例与各临床病理指标均无明显相关（P > 0.05）。结直肠癌组织中CD10蛋白表达强度与患者性别、年龄、肿瘤部位、分化程度、浸润深度无明显相关（P > 0.05），而与肿瘤的临床分期、有无脉管侵犯及淋巴结转移有关（P < 0.05），中晚期结直肠癌CD10蛋白表达强度高于早期肿瘤（P=0.033），周围淋巴结转移阳性的结直肠癌CD10蛋白表达强度高于淋巴结阴性病例（P=0.023），存在脉管受侵犯的结直肠癌CD10蛋白表达强度高于无脉管受侵病例（P=0.004）。结论：CD10蛋白在结直肠癌组织中呈高表达，且表达强度与肿瘤的临床分期、有无脉管侵犯及淋巴结转移有关，可能有促进结直肠癌发展和浸润转移的作用。     

Analysis of the role of palmitoleic acid in acute anterior uveitis

PurposeTo study the role of palmitoleic acid (PA) in the pathogenesis of acute anterior uveitis (AAU).MethodsPA levels in feces from AAU patients were measured by gas chromatography coupled with a mass spectrometer (GC-MS) and compared with samples obtained from healthy individuals. Enzyme linked immunosorbent assay (ELISA) and flow cytometry (FCM) were used to assess the effect of PA on dendritic cells (DCs) and CD4⁺T cells obtained from mice, AAU patients and healthy individuals. C57BL/6 mice were fed with PA or vehicle and experimental autoimmune uveitis (EAU) was induced with a human retinal IRBP651-670 peptide. Disease severity of EAU was evaluated by clinical manifestation and histology. Differentiation of splenic Type 1 helper T cells (Th1) and Th17 cells was evaluated by FCM. Tandem mass tag (TMT)-based proteomics analysis was used to identify differentially expressed proteins following incubation of DCs with PA.ResultsThe fecal concentration of PA was increased in AAU patients as compared with healthy individuals. In vitro, PA promoted apoptosis of DCs and inhibited the secretion of TNF-α from mouse bone-marrow-derived dendritic cells (BMDCs) as well as in DCs from AAU patients and healthy individuals. It only decreased DCs surface marker expression and IL-12p70 secretion in BMDCs and healthy individuals DCs but not in AAU patient DCs. PA-treated BMDCs inhibited Th cell differentiation from mouse naïve CD4⁺T cells and IL-17 and IFN-γ secretion in co-culture supernatants. PA also inhibited the differentiation of Th cells and secretion of IFN-γ and IL-17 in CD4⁺T cells from mice, AAU patients and healthy individuals. In vivo, PA-treated EAU mice showed milder clinical and histopathological intraocular manifestations as compared with the control group. PA feeding inhibited differentiation of splenic Th17 cells, whereas Th1 cells were not affected. Up to 30 upregulated and 77 downregulated proteins were identified when comparing PA-treated DCs with controls.ConclusionAn increased expression of fecal PA was observed in AAU patients. PA was shown to have immunoregulatory effects on DCs and CD4⁺T cells and attenuated disease severity in EAU mice.