CD4~+T细胞与血吸虫感染的保护性免疫

血吸虫病仍是一个严重的世界性公共卫生问题,据WHO最近估计,全世界仍有6亿人口处于感染血吸虫的危险环境中,其中约2亿人受感染,每年死于血吸虫病者超过10万人,造成巨大的社会经济损失.虽然全球范围内,血吸虫病防治已持续数十年,全面控制血吸虫病传播的前景仍不容乐观.血吸虫病疫苗的研制与发展已被置于防治研究的重要地位.近年来,许多研究均集中于抗血吸虫感染的获得性免疫应答机制和寻找可能诱导保护免疫的相关寄生虫抗原分子等基础研究.     

Teladorsagia circumcincta in the sheep abomasum: defining the role of dendritic cells in T cell regulation and protective immunity

Parasitic nematodes of the small-ruminant gastrointestinal tract pose a problem worldwide. The impact of these pathogens is worsened by the emergence of anthelmintic resistance to all three available classes of drugs. In addition to causing considerable economic loss, these parasites are detrimental to the health and welfare of sheep and goats. Vaccination offers an alternative approach to drug-based control and a great deal of investment has gone into the investigation of protective antigens for some of these nematode species. However, attempts at vaccination are hindered by a lack of understanding of how best to promote protective immunity to nematode species, such as Teladorsagia circumcincta , which inhabits the abomasum of sheep. This situation contrasts with that in murine models of gastrointestinal nematode infection, where the basis of protective immunity is increasingly well understood. In this review, we discuss the current knowledge of the immune effector mechanisms elicited by T. circumcincta and consider the probable role of dendritic cells in the initiation of both effector and regulatory responses in the abomasum.     

老年大鼠T细胞凋亡相关基因表达模式的研究

目的　探讨老年大鼠 T细胞凋亡的基因表达模式。方法　本研究利用 TUNEL标记的流式细胞检测和荧光实时定量 RT- PCR技术 ,研究了老年大鼠和年轻大鼠 T淋巴细胞凋亡情况及抗凋亡和促凋亡基因 (Fas,Fas L ,bcl- 2 ,bax,TNFR1 ,TNFR2 )的表达差异 ,以及 Caspase8、Caspase3活性的变化。结果　与年轻大鼠相比 ,老年大鼠激活诱导的细胞凋亡百分率增高 ,有显著性差异 (P<0 .0 1 ) ;老年大鼠促凋亡的 Fas,Fas L,TNFR1基因表达上调 ,抗凋亡的 bcl- 2 ,TNFR2基因表达下调 ,与年轻大鼠相比均有显著性差异 (P<0 .0 5或 P<0 .0 1 )。此外 ,老年大鼠激活诱导的T淋巴细胞 Caspase8、3活性增高 ,与年轻大鼠相比有显著性差异 (P<0 .0 1 )。结论　激活诱导的 T细胞过度凋亡与衰老密切相关 ;促凋亡基因表达上调及抗凋亡基因表达下调及 Caspase8、3活性增高是老年大鼠 T细胞凋亡易感性增高重要分子机制。     

T cell-mediated suppression of angiogenesis results in tumor protective immunity

Antiangiogenic intervention is known to inhibit tumor growth and dissemination by attacking the tumor's vascular supply. Here, we report that this was achieved for the first time using an oral DNA minigene vaccine against murine vascular endothelial growth factor receptor 2 (FLK-1), a self-antigen overexpressed on proliferating endothelial cells in the tumor vasculature. Moreover, we identified the first H-2Db-restricted epitope, FLK400 (VILT-NPISM), specifically recognized by cytotoxic T lymphocytes (CTLs). Such CTLs were capable of killing FLK-1+ endothelial cells, resulting in suppression of angiogenesis and long-lived tumor protection. The specificity of this immune response was indicated because the DNA vaccine encoding the entire FLK-1 gene also induced a FLK400-specific CTL response. This minigene vaccine strategy provides a more flexible alternative to whole-gene vaccination and facilitates in-depth mechanism studies to tailor DNA vaccines for optimal T-cell activation and tumor protection.     

T cells require tumor necrosis factor-alpha to provide protective immunity in mice infected with Histoplasma capsulatum

We examined whether neutralization of tumor necrosis factor (TNF)-alpha after intranasal exposure of mice to Histoplasma capsulatum was necessary for control of primary or secondary infection. All mice given monoclonal antibody to TNF-alpha on the day of infection or on day 3 after infection died. When antibody was administered on day 5 after infection, 60% of mice with primary infection died, whereas none with secondary infection did. Antibody treatment on day 7 after infection produced a transiently higher fungal burden. Because optimal clearance required TNF-alpha after the onset of infection, we hypothesized that it may regulate T cell function. Lung CD3+ cells were the dominant population of TNF-alpha-producing cells (approximately 40%-70%). Neutralization of this cytokine decreased the number of memory T cells but not the number of activated, proliferating, or interferon-gamma-producing cells. T cells from infected, TNF-alpha-neutralized mice failed to protect T cell-deficient mice. The absence of TNF-alpha induces a defect in T cell-mediated protection.     

Retrovirus infection and aging: Increase in UAG suppressor tRNA expression in aged mice

The effect of aging on expression of a natural glutamine suppressor tRNA (tRNA(Gln(UmUG))) was studied in different tissues of mice; this tRNA recognizes UAG and inserts glutamine at the site of the termination codon. The level of tRNA(Gln(UmUG)) was found to be strongly increased in aged mice, compared to newborn and mature animals. An elevated expression of tRNA(Gln(UmUG)) has also been found in retrovirus-infected cells; in Moloney virus-infected cells the suppressor tRNA allows to read-through the UAG codon within the retroviral protease gene. We suggest that the increase in the level of tRNA(Gln(UmUG)) may influence retroviral gene expression with age.     

SAP expression in T cells, not in B cells, is required for humoral immunity

SAP (also named SH2D1A) is an intracellular adaptor molecule expressed in T cells, natural killer (NK) cells, and some B cells. The SAP gene is mutated in X-linked lymphoproliferative (XLP) disease, a human immunodeficiency characterized by a faulty immune response to Epstein-Barr virus infection. Previous reports documented severe defects in antibody production and germinal center (GC) formation in SAP-deficient humans and mice genetically engineered to lack SAP expression. However, in vitro studies and adoptive transfer experiments provided conflicting data as to whether this phenotype is caused by a functional defect resulting from SAP deficiency in T cells, B cells, or both. Here, we ascertained which cell types are responsible for this humoral immunity defect by using a conditional gene targeting approach. We also thoroughly examined the expression pattern of SAP in normal immune cells by using intracellular flow cytometry. The results showed that expression of SAP in T cells, but not in B cells or NK cells, is required and sufficient for SAP-dependent antibody production and GC formation. These data provide a critical insight into the mechanism by which SAP regulates humoral immunity. They also help elucidate the basis of a severe human immunodeficiency.     

IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells

The conditions leading to the induction of adaptive Foxp3⁺ regulatory T cells (T-regs) from peripheral T cells in vivo are incompletely understood. Here, we show that unresponsiveness of T cells to IL-6 by T cell-selective deletion of gp130 or immunization of wild-type mice with antigen in incomplete Freund's adjuvant (IFA), which fails to induce IL-6, promotes the conversion of peripheral CD4⁺ T cells into adaptive Foxp3⁺ T-regs. Thus, both T cell-conditional gp130 knockout (KO) mice immunized with MOG35-55 in complete Freund's adjuvant (CFA) and wild-type mice immunized with MOG35-55 in IFA develop overwhelming antigen-specific T-reg responses and are protected from experimental autoimmune encephalomyelitis (EAE). Depletion of T-regs restores T helper (Th)17 responses and clinical EAE in MOG/CFA-immunized T cell-conditional gp130 KO mice, but not in MOG/IFA-immunized wild-type mice. We conclude that in the absence of T-regs, IL-6 signaling is dispensable for the induction of Th17 cells, and alternative pathways exist to induce Th17 cells and EAE in the absence of IL-6 signaling. However, IL-6 signaling is dominant in inhibiting the conversion of conventional T cells into Foxp3⁺ T-regs in vivo, and in the absence of IL-6 signaling, no other cytokine can substitute in inhibiting T-reg conversion. These data identify IL-6 as an important target to modulate autoimmune responses and chronic inflammation.     

Roles for both CD+ and CD8+ T cells in protective immunity against Onchocerca lienalis microfilariae in the mouse

Mice inoculated with microfilariae of the filarial nematode Onchocerca lienalis clear their parasites from the skin over a period of 3 to 4 months and are highly resistant to a challenge infection. The adoptive transfer of spleen cells at various time points following primary and secondary infections of mice shows that exposures of 50 days or greater are required for the generation of lymphocytes capable of transferring protection to naive recipients. This adoptive transfer of protection with spleen cells from infection-primed mice partitions with the T lymphocyte population. In contrast, the passive transfer of protection with spleen-derived B cells, or sera taken at various time points following infection was not achieved. Moreover, there was no detectable synergistic effect when B and T cells were co-administered to recipient animals. Depletion of CD4+ and CD8+ T cells with monoclonal antibodies shows that CD8 + T cells have some regulatory effect on parasite establishment early in primary infection, but this is later superseded by CD4+ T cell reactivity that is predominant both when primary infection microfilariae are cleared and also during resistance to reinfection. Measurement of cytokines in the sera of mice undergoing primary and secondary infections support a microfilariae-induced Th2 activity, with high levels of IL-5 that are sustained upon reinfection, and low levels oflFN-γ that are negligible at the time when mice are most strongly immune.     

补肾复方抗老年大鼠肝肾线粒体老化的实验研究

目的　观察补肾复方抗老年大鼠肝肾线粒体老化的作用 ,为“肝肾同源”提供实验依据。方法　实验大鼠分青年和老年组 ,其中老年组分空白对照组和补肾复方治疗组。采用荧光光度计测定肝肾线粒体内膜流动性 ,比色测磷法测定肝肾线粒体内膜 ATP酶活力 ,生物组织测氧仪测定肝肾线粒体氧化磷酸化效率 (ADP/ O)及呼吸控制率 (RCR) ,透射电镜观察肝肾线粒体形态及形态计量学分析。结果　老年大鼠肝肾线粒体内膜流动性、ATP酶活力、ADP/ O和 RCR均较青年组明显降低 ,而服用补肾复方 2个月后的老年大鼠上述指标均明显增高 (P<0 .0 5或 P<0 .0 1 ) ;透射电镜形态及形态计量学分析结果表明 ,老年组肝肾线粒体肿胀变性 ,补肾复方治疗后 ,肝肾线粒体超微结构变化得到明显改善 (P<0 .0 5或 P<0 .0 1 )。结论　补肾复方对老年大鼠肝肾线粒体老化的结构和功能均有一定的防护 ,线粒体可能是“肝肾同源”的重要物质基础之一。     

Nutrition and immunity in the elderly

Global malnutrition (reduced intake or increased requirements for protein and calories) is the most common nutritional deficit in the elderly population. Micronutrients (vitamins and trace minerals) deficiencies are also common in older adults. Malnutrition consequences on immunity are characterized by a decrease in cell mediation immunity with a reduction in naive T cells and in cytokine production. During infection, the treatment must be specific and after infection it has to associate nutritional supplementation and exercise. The lack of clear benefit in the use of specific micronutrient should discourage the use of high-dose supplementation for an immunologic indication.     

Active rosette-forming T cells in the elderly.

The numbers and percentages of active rosette-forming T cells were measured in two age groups, to assess the effects of aging. The study included 21 healthy persons in the 20--40 age group and 25 persons without major disease in the 60--85 age group. In the younger subjects the number of rosette-forming cells (RFC) averaged 1430 +/- 463/cu mm (mean and S.D.), a count not significantly different from that in the older subjects (1443 +/- 398/cu mm). Likewise, the active RFC count in the 20--40 age group (526 +/- 185/cu mm) and that in the 60--85 age group (558 +/- 197/cu mm) were not significantly different. There was no difference for the percentage total RFC (young 78 +/- 4%, elderly 78 +/- 6%) or the percentage active RFC (young 29 +/- 7%, elderly 30 +/- 6%). For the total lymphocyte count or the B lymphocyte count, there was no difference between the two groups of subjects. It is concluded that T lymphocytes, measured as total and active rosette-forming cells, are not decreased in healthy older persons.     

Diminished adrenal steroidogenic activity in aging rats: new evidence from adrenal cells cultured from young and aged normal and hypoxic animals

Adrenal cells from 2-6-month-old young rats (Y cells) and from 19-25-month-old aged male rats (O cells) were adapted to primary monolayer culture. The cultures of Y and O cells appeared to be primarily epithelial and rounded up in response to stimulation with adrenocorticotropic hormone (ACTH). The general morphology of O cells was comparable to that observed in Y cells except for the presence of lipofuscin-like granules, a cellular marker of aging, in O cells, but not in Y cells. ACTH-stimulated steroid production by O cells was 52% lower than that by Y cells. Exposure of intact young rats to hypoxia (0.5 atmosphere) for 21 days prior to sacrifice and culture resulted in a 122% increase of ACTH-stimulated adrenal steroidogenic activity in the cultured cells, but this effect was not observed in adrenal cells cultured from hypoxic aged rats. The results suggest that there is an age-related diminution in rat adrenal steroidogenic capacity in response to ACTH stimulation in culture derived from Y and O animals; hypoxic stress magnifies this difference.     

调节性T细胞在肝脏免疫及疾病中的作用

免疫抑制是控制免疫系统稳定的一种重要机制．调节性T细胞(regulatory T cells,Tregs)控制着免疫系统对自身抗原的免疫耐受,具有强大的抑制免疫反应能力,广泛参与了各种免疫抑制现象．随着对Tregs研究的不断深入,人们发现Tregs参与调节了肝脏免疫耐受、肝移植、慢性肝炎和肝癌等各种肝脏病理生理现象．Tregs的功能异常也会影响肝脏多种疾病的进程．我们总结了调节性T细胞的相关进展及其在肝脏免疫及疾病中的作用．     

Facilitating matched pairing and expression of TCR chains introduced into human T cells

Adoptive transfer of T lymphocytes is a promising treatment for a variety of malignancies but often not feasible due to difficulties generating T cells that are reactive with the targeted antigen from patients. To facilitate rapid generation of cells for therapy, T cells can be programmed with genes encoding the alpha and beta chains of an antigen-specific T-cell receptor (TCR). However, such exogenous alpha and beta chains can potentially assemble as pairs not only with each other but also with endogenous TCR alpha and beta chains, thereby generating alphabetaTCR pairs of unknown specificity as well as reducing the number of exogenous matched alphabetaTCR pairs at the cell surface. We demonstrate that introducing cysteines into the constant region of the alpha and beta chains can promote preferential pairing with each other, increase total surface expression of the introduced TCR chains, and reduce mismatching with endogenous TCR chains. This approach should improve both the efficacy and safety of ongoing efforts to use TCR transfer as a strategy to generate tumor-reactive T cells.