免疫老化与T淋巴细胞功能性分子的改变

免疫老化(senescence)是机体代谢过程中的一个必然阶段, 免疫系统参与机体正常的老化过程, 是机体衰老的主要调节系统之一.随着年龄的增长, 免疫细胞发生增龄性改变.T淋巴细胞是机体重要的介导细胞免疫的效应性细胞, 其在免疫老化过程中, 诸多功能性分子如免疫突触形成所涉及的分子、 T细胞活化所需的协同刺激分子及凋亡相关分子等均发生增龄性改变, 从而导致机体正常的免疫应答功能下降或出现异常, 致使老年人易罹患肿瘤、感染及自身免疫性疾病等.     

免疫衰老与固有免疫细胞的相关研究进展

免疫衰老是人类衰老进程中的一项重要生物学变化,主要特征是免疫功能下降导致的进行性免疫缺陷,对固有免疫和适应性免疫均有影响。其对人类固有免疫的影响机制尚不完全清晰。在衰老进程中,固有免疫细胞的功能、表面分子、细胞因子分泌及其信号传导等方面有改变。     

T细胞免疫衰老的研究进展

随着人口老龄化加剧,感染导致的发病率和病死率升高,老年人群肿瘤、自身免疫性疾病高发及疫苗接种效果变差,与适应性免疫系统功能受损密切相关。T细胞是适应性免疫系统的重要组成,介导细胞免疫并调控体液免疫。因此T细胞衰老的表型与机制及特异性针对衰老的免疫策略成为近年研究热点。本文将从T细胞“数量”和“质量”两个方面总结T细胞衰老的表型特征,进一步从细胞普遍衰老机制及T细胞独有衰老机制探讨T细胞衰老的机制,以期为免疫衰老机制深入研究与临床治疗提供新的思路。     

党参水煎剂对D-半乳糖致免疫衰老小鼠胸腺功能的影响

<正>衰老又称老化,通常是指在正常状态下生物发育成熟后,随着年龄增加,自身机能减退,组织环境稳定能力与应激能力下降,组织结构逐步退行性变,趋向死亡的不可逆转的现象[1]。近几年来,关于衰老机制的研究,中西医学分别建立了不同的衰老学说。中医脾虚衰老学说和现代衰老学说中的免疫学     

免疫系统衰老的研究进展

衰老是机体代谢过程中的一个必然阶段 ,伴随着机体免疫功能下降以及感染、恶性肿瘤等的发病率增高 ,对于衰老免疫学机制的研究有助于延缓衰老 ,改善老龄社会的生活质量。文章就衰老过程中机体的免疫细胞、细胞因子、细胞粘附分子以及细胞凋亡等方面作一简要综述。     

D-半乳糖致衰老小鼠胸腺T细胞重要膜型分子的改变及其意义

目的:建立D-半乳糖亚急性衰老小鼠模型,并探讨其胸腺T细胞重要膜型分子的改变及其意义。方法:8周龄雌性昆明种小鼠,12.5 mL/(kg.d)颈后部皮下注射100 g/LD-半乳糖溶液,连续注射42 d;逐日观察小鼠的生存状态和行为变化,并通过对小鼠血清中SOD活力和MDA含量的检测,对此衰老模型进行生物学鉴定;在D-半乳糖亚急性衰老小鼠模型成功建立的基础上,采用免疫荧光标记技术和流式细胞仪检测技术对胸腺T细胞重要膜型分子进行检测分析。结果:造模过程中小鼠逐渐表现出脊椎隆起,体形消瘦,皮肤松弛等衰老体征;血清中SOD活力下降[模型组:(2.16±0.43)mKat/L,对照组:(5.52±1.55)mKat/L,P<0.01],MDA含量上升[模型组:(4.14±0.82)μmol/L,对照组:(1.24±0.21)μmol/L,P<0.01];小鼠胸腺初始T细胞相关分子CD45RA表达下降[模型组:(2.16±0.47)%,对照组:(2.98±0.53)%,P<0.05];小鼠胸腺T细胞活化相关分子CD28[模型组:(91.52±1.68)%,对照组:(95.12±1.21)%,P<0.05]和CD25[模型组:(7.42±0.75)%,对照组:(8.84±0.58)%,P<0.05]表达下降;小鼠胸腺T细胞活化负性调控分子PD-1表达上升[模型组:(21.25±1.95)%,对照组:(12.92±3.28)%,P<0.01];小鼠胸腺记忆T细胞相关分子CD196表达上升,但与对照组相比没有显著性差异[模型组:(21.13±1.44)%,对照组:(19.73±2.02)%]。结论:成功建立了D-半乳糖亚急性衰老小鼠模型,机体衰老时胸腺中初始和活化T细胞减少,记忆T细胞有增加的趋势。     

免疫衰老及其免疫学预警指标

增龄导致胸腺萎缩,成为免疫衰老的直接原因。免疫衰老是免疫系统全方位多系统的并由基因严格控制的循序渐进的自然过程,在这一过程中,免疫系统发生了许多明显的变化,细胞免疫、体液免疫以及天然免疫均有不同程度的改变。免疫学预警指标(immunologicalriskphenotypes,IRP),不仅可以评价机体的免疫状态,而且可以提前预知疾病的发生,为免疫干预提供客观数据。     

B淋巴细胞与免疫老化

免疫老化(immunosenescence)是机体免疫系统随年龄增长而出现的退行性变化,免疫细胞是免疫系统的重要组成部分.其中B淋巴细胞既是机体产生抗体的惟一细胞,同时又是专职性的抗原提呈细胞.因此,B淋巴细胞在机体的细胞免疫及体液免疫中均发挥重要作用.研究发现,随着年龄的增长,B淋巴细胞的生成环境、数量及功能等均发生渐进性改变,从而导致机体正常免疫应答功能紊乱.致使年长者易罹患肿瘤、感染及自身免疫性等疾病.     

衰老与适应性免疫

近十年中,有关获得性免疫的研究成为热点,研究涉及胸腺、B细胞、T细胞和细胞因子产生等多方面的退化机制.然而,年龄对适应性免疫应答的影响机制仍未完全清楚,尤其在人类中.本文总结了适应性免疫应答中主要增龄性变化,包括B细胞数量和特异性变化,CD4+ T的辅助作用下降,CD8+ T细胞多样性改变等.     

T淋巴细胞免疫功能的研究进展

经典免疫细胞中T淋巴细胞是参与机体细胞免疫反应,并在免疫应答中起重要调节作用的免疫细胞。正常情况下T细胞及其亚群的数目在周围组织中相对稳定,机体正常免疫应答过程依赖于各种免疫细胞之间的恒定,从而形成适度的免疫应答,使之既能清除抗原性异物,又不损伤机体自身组织。近年来,随着对机体免疫功能研究的不断深入,对T细胞的研究越来越全面。本文从T淋巴细胞的发育、抗原识别、T淋巴细胞亚群进行综述。     

Age related changes in population of peripheral T cells: towards a model of immunosenescence

In this paper, we presented the results of analysis of experimental evidence for the decline of the human immune system functioning with age using mathematical model of immunosenescence. The most prominent changes in this system are related to the decline in the T-cellular immunity. These include the decline in the nai;ve T cells generation rate, shrinkage of the volume of the peripheral lymphoid tissue, decline of absolute and relative concentrations of nai;ve T cells in the blood, shortening of the average telomere length of T cells. These alterations in the immune system are responsible for sharp increase of morbidity and mortality caused by infectious agents at old ages. Analysis shows that concentrations of memory and nai;ve T cells in peripheral lymphoid tissue are the key variables in this process. Simulation experiments with our model show that the average life span of memory T cells must grow with age, and that decreasing of antigenic load led to considerable increase in organism's resistance in middle ages, but only to slight increase in old ages. Restriction in the rate of thymus involution resulted in an increase of organism's resistance to infections in old ages. However, this growth is accompanied by the decline of concentration of memory T cells and shortening of their life span. The proposed model describes the trade-off between concentrations of nai;ve and memory T cells and their potential to proliferate in human organism.     

Human cytomegalovirus infection and T cell immunosenescence: a mini review

The mammalian immune system defends the organism against pathogens, and possibly cancer, but is known to become dysregulated with increasing age. This results in greater morbidity and mortality due to infectious disease in old people. The most important changes occur in T cell immunity, manifested sometimes dramatically as altered clonal expansions of cells of limited antigen specificity and a marked shrinkage of the T cell antigen receptor repertoire. At the same time, it was independently reported that CMV seropositivity was associated with many of the same T cell changes that were being identified as biomarkers of immune ageing. It has now become clear that CMV is commonly the driving force behind the oligoclonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. These changes are much less obvious in centenarians and most extreme in people whom longitudinal studies have shown to possess an "immune risk profile". This is a cluster of immunological parameters of which CMV seropositivity is one component and which predicts incipient mortality in an elderly population. Taken together, these findings suggest the hypothesis that persistence of CMV as a chronic antigenic stressor is a major contributor to immunosenescence and associated mortality.     

Immunoproteasomes and immunosenescence

Aging is a complex process which is accompanied with the decline and the reshaping of different functions of the body. In particular the immune system is characterized, during ageing (immunosenescence) by a remodeling of innate immunity (well preserved, up-regulated) and clonotypical immunity (severely altered) and by the occurrence of a chronic inflammatory process (inflammaging) which are, at least in part, genetically controlled. In this scenario, it can be anticipated that a crucial role is played by age-related structural and functional alterations and modifications of proteasomes and immunoproteasomes, the last being a key component of antigen processing and MHC class I antigen presentation. A variety of experimental data are available, suggesting that proteasomes are affected by age, and that in centenarians they are relatively preserved. On the contrary, few data are available on immunoproteasomes, likely as a consequence of the poverty of suitable cellular models. Lymphoblastoid cell lines from EBV immortalized B cells from old donors is envisaged as a possible model for the study of immunoproteasomes in humans and their changes with age. Thus, basic questions such as those related to possible consequences, for immune responses in infectious diseases and cancer, of age-related alterations of antigen processing and presenting, change with age of self-antigen repertoire, and the genetic basis of immunoproteasome activity and its change with age, remain largely unanswered.     

Senescent endothelial cells: Potential modulators of immunosenescence and ageing

Recent studies have demonstrated that the accumulation of senescent endothelial cells may be the primary cause of cardiovascular diseases. Because of their multifunctional properties, endothelial cells actively take part in stimulating the immune system and inflammation. In addition, ageing is characterized by the progressive deterioration of immune cells and a decline in the activation of the immune response. This results in a loss of the primary function of the immune system, which is eliminating damaged/senescent cells and neutralizing potential sources of harmful inflammatory reactions.In this review, we discuss cellular senescence and the senescence-associated secretory phenotype (SASP) of endothelial cells and summarize the link between endothelial cells and immunosenescence. We describe the possibility that age-related changes in Toll-like receptors (TLRs) and microRNAs can affect the phenotypes of senescent endothelial cells and immune cells via a negative feedback loop aimed at restraining the excessive pro-inflammatory response. This review also addresses the following questions: how do senescent endothelial cells influence ageing or age-related changes in the inflammatory burden; what is the connection between ECs and immunosenescence, and what are the crucial hypothetical pathways linking endothelial cells and the immune system during ageing.     

Chronic antigenic stress,immunosenescence and human survivorship over the 3 last centuries: heuristic value of a mathematical model

In previous investigations we pursued the hypothesis that lifelong, chronic antigenic load (CAL) is the major driving force of immunosenescence, which impacts on human lifespan by reducing the number of virgin antigen-non experienced (ANE) T cells, and filling the immunological space with expanded clones of memory and effector, antigen-experienced (AE) T cells. A model has been proposed to relate CAL with the conversion rate from ANE to AE CD8+ T cells. In addition, in order to account for individual variations of immunosenescence and lifespan, a noise term has been introduced to describe the individual fluctuations of CAL. This model was able to follow with a reasonable approximation the age-related decrease of ANE CD8+ T cells, as well as human survival curves. In this paper we extend this approach to historical survival curves, starting from 1750 until present days, and show that the quality of the fit of historical demographic data improves as we approach the recent, quantitative and qualitative decrease of CAL. Indeed, the almost linearity in the increase of lifespan and in the decrease of the noise fluctuation amplitude within this historical period suggests that the improvement of life conditions has steadily lowered the intensity of CAL and restricted the variability which results from the interaction between the individuals and their immunological environment. On the whole, this approach allows to appreciate when and how immunosenescence has started to impact on survivorship, and predicts its increasing, crucial role in explaining human mortality in hygienized, economically developed societies.     

T淋巴细胞凋亡及其调控机制的研究进展

T淋巴细胞凋亡是免疫系统维持稳定的一种重要机制,在多种疾病中起着重要作用.fas/FasL、Trail/trail受体等死亡受体信号传导可介导T淋巴细胞凋亡,线粒体在诱导细胞凋亡中也起着重要作用;而bcl-2家族、v-FLIP等抗细胞凋亡蛋白和转录因子Nur77等对T淋巴细胞凋亡起调控作用.     

The emerging role of ECM crosslinking in T cell mobility as a hallmark of immunosenescence in humans

Immunosenescence is thought to result from cellular aging and to reflect exposure to environmental stressors and antigens, including cytomegalovirus (CMV). However, not all of the features of immunosenescence are consistent with this view, and this has led to the emergence of the sister theory of “inflammaging”. The recently discovered diffuse tissue distribution of resident memory T cells (T_RM) which don't recirculate, calls these theories into question. These cells account for most T cells residing in barrier epithelia which sit in and travel through the extracellular matrix (ECM). With almost all studies to date carried out on peripheral blood, the age-related changes of the ECM and their consequences for T cell mobility, which is crucial for the function of these cells, have been largely ignored. We propose an update of the theoretical framework of immunosenescence, based on a novel hypothesis: the increasing stiffness and cross-linking of the senescent ECM lead to a progressive immunodeficiency due to an age-related decrease in T cell mobility and eventually the death of these cells. A key element of this mechanism is the mechanical stress to which the cell cytoplasm and nucleus are subjected during passage through the ECM. This hypothesis is based on an “evo-devo” perspective bringing together some major characteristics of aging, to create a single interpretive framework for immunosenescence.     

Increased T cell immunosenescence and accelerated maturation phenotypes in older kidney transplant recipients

Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens.We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis.This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation.     

Oxidative inactivation of CD45 protein tyrosine phosphatase may contribute to T lymphocyte dysfunction in the elderly

The decline in T lymphocyte function during ageing has been linked to changes in intracellular signalling pathways. Oxidative damage has long been thought to be involved in the ageing process and we investigated a link between ageing, oxidation and T cell signalling focusing on the membrane phosphatase CD45. We investigated the relative sensitivity of CD45 to oxidative inactivation and then compared the phosphatase activity of CD45 in blood lymphocytes from elderly and young volunteers and related this to intracellular levels of the antioxidant glutathione. The CD45 phosphatase was particularly sensitive to oxidative inactivation compared to total Jurkat T cell PTP activity. The IC50 with H(2)O(2) was 3 mM for CD45 at which concentration there was a minimal decrease in global PTP activity. In normal peripheral blood CD4(+) T cells the IC50 was much lower at 54 microM. In a group of elderly healthy individuals, whose T cell responses to mitogen were depressed, PB lymphocyte CD45 phosphatase activity was decreased by about 60% compared to young controls. There was no difference in intracellular levels of glutathione. The loss of CD45 activity in lymphocytes from the elderly may underlie poor T cell function associated with ageing. The relative sensitivity of CD45 to oxidative damage may result from its location in the plasma membrane, where it might be more accessible to extracellular oxidants.     

MicroRNAs与T细胞关系的研究进展

MicroRNAs(miRNAs)是非编码蛋白质的单链小分子RNA,其主要在转录后水平通过降解靶mRNA或抑制蛋白质翻译来调控目的基因的表达,参与细胞的发育、分化、信号转导及肿瘤的发生、发展等多种重要的生物学进程。近年来的研究表明,miRNAs对机体免疫细胞具有多种调控功能。本文主要就近年来与T细胞的胸腺发育、分化及功能相关的miRNAs研究进展作一综述。