T细胞记忆的理论研究

基于CD8⁺ T记忆细胞的线性和逆线性分化假说分别建立了数学模型,并研究了各种T细胞亚类的动力学.发现在优化剂量抗原入侵的条件下,两个模型均能产生记忆,并可较好地模拟实验结果.通过进一步模拟发现CD8⁺ T细胞记忆与抗原的存在紧密相关,再次证实了抗原在维持T细胞记忆中的作用.另外还讨论了记忆细胞寿命的问题.认为逆线性假说具有更强的反应性和记忆性.     

杆状病毒疫苗载体的应用研究进展

人源病毒基因载体存在的记忆免疫和毒性阻碍了其在临床上的应用.自从发现杆状病毒能够有效进入多种哺乳动物细胞系和原代细胞后,其在基因治疗中的应用引人注目,候选杆状病毒载体迅速兴起.在哺乳动物细胞中,杆状病毒既不能复制也不能引起明显的细胞毒性作用,不存在哺乳动物病毒载体的相关记忆免疫.另外,含有新的穿梭启动子且包膜修饰的重组...     

巨噬细胞的固有免疫记忆研究进展

根据免疫效应机制和作用特征,通常把免疫分为固有免疫和适应性免疫两种类型.长久以来,免疫学界普遍认为只有适应性免疫存在记忆特性,而近年的研究表明固有免疫也存在记忆现象.经过刺激的固有免疫细胞,通过表观遗传重编程和细胞代谢的改变获得记忆性质,在二次刺激下表现出增强或减弱的免疫反应,这种现象被定义为"训练免疫"或"固有免疫记...     

流感病毒感染中的T细胞应答

本文中总结了应用T细胞受体转基因模型和主要组织相容性复合物Ⅰ类四聚体研究流感感染时的效应细胞和记忆细胞应答,包括抗原特异性CDC4CD+T细胞的生成,多样性及其向肺部的移动,以及其在清除病毒中的作用.对于效应细胞和记忆细胞在病毒感染中的作用以及效应细胞如何转变为记忆细胞,都有比较详尽的阐述.     

生命信息安全控制原理的再探讨

建立生命信息安全控制原理的理论性平台,由该平台的视野分析免疫学所涉及的诸多理论问题,譬如免疫记忆、免疫功能等方面,并针对性进行归纳以及绘制出相关图形,试图将免疫学理论中所呈现的纷繁复杂性的方面以及过于分散的条块更加条理化、清晰化及整体化。由逻辑学的层面讨论免疫学学名的形成,分析结果:免疫学学名应归结为主观是非逻辑意识产物,并主张认识论应回归自然生成逻辑的观点。免疫记忆在本质上是对遗传信息的记忆,离开了遗传信息的识别与分析就不存在免疫记忆。众多学者的系列研究资料表明,CD4+T细胞在CD8+T细胞反应的起始就辅助其发挥作用,并维持其记忆细胞功能,而CD4+T细胞的记忆是由TCR-MHCⅡ信号所决定。X线晶体衍射及三维结构图所显示MHCII类肽结合凹槽内的多肽更能显示出呈递多肽遗传信息的功能,而MHCI类分子肽结合凹槽内的多肽难以与呈递多肽遗传信息的功能联系起来。只有辅助性T细胞是决定与辅助记忆的细胞,其不仅决定B细胞胸腺依赖性抗原的记忆,而且决定CD8+T细胞的记忆性。对生命信息识别从记忆属性层面进行分类,即分为遗传信息密码识别(记忆属性)和非遗传信息密码识别(非记忆属性)2大类。通过危险因素、生命信息感应器、信息识别及应答调控这样4个相连贯环节的分析,绘制出生命信息安全控制原理图。从功能效应层面进行讨论,将生命信息安全控制的功效分类为正面功能效应和负面功能效应2大类,其中将组织修复归结为正面功能效应,创伤引起的无菌性炎症归结为负面功能效应。绘制出生命信息安全控制功效图,并讨论了生命信息安全控制功效图的建立在理论方面的重要意义。     

记忆性T细胞的形成、维持和功能

免疫记忆是指机体在对某一抗原产生特异性识别及应答的同时,记住该抗原,当再次遭遇同一抗原时,能发生快速和强烈的免疫应答。树突状细胞吞噬病原微生物后,通过主要组织相容性复合体分子提呈抗原短肽段,与T细胞相互作用。在T细胞抗原受体信号和共刺激信号的协同作用下,抗原特异性T细胞增殖,收缩,小部分细胞作为记忆细胞长期存活。免疫记忆T细胞在表型特征和功能上都存在多样性。深入研究机体记忆性T细胞的特征,不仅能指导新型疫苗的设计,而且可望帮助治疗疾病。     

驱动蛋白的研究进展

驱动蛋白是一类典型的分子马达蛋白,它在胞内运输、有丝分裂、细胞形成、细胞功能等方面起着至关重要的作用.驱动蛋白不仅负责运输各种膜细胞器、蛋白复合体、mRNA等以保证细胞的基本活性,还在大脑的发育、记忆功能以及神经元的活性等方面扮演着极其重要的角色,可以说驱动蛋白是生命体系赖以生存的基础之一.     

记忆T细胞平行分化模型的理论研究

为了从理论上讨论T细胞记忆维持机制的问题,基于T细胞的平行分化假说建立了非线性理论模型,利用此模型,在不同的抗原初值下得到了三种不同类型的应答。用优化剂量的抗原免疫生物体并且抗原存在时记忆能持续很长的时间,而失去抗原的同时将失去记忆,得出记忆T细胞平行分化模型确有记忆机制;并发现记忆强度与剩余抗原量有直接的关系,还进一步讨论了记忆细胞寿命的问题,并对体外情况作了预言。     

抗独特型抗体与T细胞记忆的关系

记忆T细胞作为人体免疫系统中的一个组成部分,在免疫应答中发挥着至关重要的作用,因此利用抗独特型抗体制备诱导产生记忆T细胞的疫苗是免疫学领域的一个重要方向。抗独特型抗体Fab段具有与特异性抗原相似的抗原决定簇的结构,其作为抗原替代物制备的疫苗所激发机体产生的记忆T细胞具有特异性强和安全性高的特点,成为一种比较理想的疫苗.就抗独特型抗体与T细胞记忆之间的联系及其应用效果作一简要综述。     

小鸡早期记忆形成的神经机制

小鸡是研究早期记忆形成机制的理想动物模型.一日龄小鸡在一次性被动回避实验（one-trial-passive-avoidance-test）后,与记忆形成相关脑区的神经元在时间和空间上发生了一系列复杂的生理生化反应.综述了小鸡记忆形成过程的最新研究进展,分析了与记忆形成相关的神经回路、细胞和分子机制.     

Antigen modulation of the immune response: IV. Selective triggering of antibody production and memory cell proliferation

When memory cells are transferred to syngeneic irradiated recipients and then challenged at various times after transfer, a precipitous decline in the ability of these cells to mount a secondary response is seen. Using this model we have investigated some of the influences which antigen can exert on the memory cell population. The results indicate that antigen may: 1) either stimulate the memory cells to proliferate and form new memory cells or stimulate memory cells to become antibody forming cells and 2) selectively trigger the memory cells for low or high affinity antibody production. This selective antigen triggering appeared to depend upon its concentration: high dose antigen challenge led to the production of large amounts of lower affinity antibody but stimulated less memory cell proliferation while low dose challenge showed just the opposite. Control experiments indicated that recruitment of new memory cells from a virgin precursor population was not responsible for these observations. Our results thus suggest that an asymmetrical division of memory cells is occurring in which antigen can exert selective influences in much the same way as seen with virgin precursor cells.     

Morpho-functional interrelations in the development of immunologic memory

Data available in literature on immunomorphological aspects of the immunological memory formation are summarized. Features of B memory cells and mechanisms of their activation are analyzed. Relations between antigen localization in the lymphoid follicles, the formation of virgin centres there and induction of B memory cells and organs of the immune system in the immunological memory are discussed.     

Maintenance and amplification of cell-associated immunological memory in in vivo culture system

By employing bovine serum albumin as antigen and the capsular polysaccharide of Klebsiella pneumoniae as adjuvant, maintenance and amplification of immunological memory were analyzed in an in vivo culture system in mice. For this purpose, the double cell transfer technique was employed to minimize the influence of regulatory factors on memory expression. Memory associated with primed cells is maintained at the original level during in vivo culture for at least a month in the absence of antigen. In contrast, memory is amplified more than 30 times during this period by stimulation with antigen. This secondary increase in memory does not require the action of adjuvant. Neither the residual primary antigen nor preformed primary antibody seems to play a significant role in the maintenance and amplification of memory of the primed cells. From these results it is probable that the enduring immunological memory in actively immunized mice is conveyed by long-lived memory cells, and additional antigenic stimulating on once-established memory cells serve to amplify (not simply to maintain) memory in a secondary fashion.     

The effectiveness and limitations of immune memory: understanding protective immune responses

Immune memory is the foundation of the practise of vaccination. Research on the molecular and cellular events leading to generation and development of memory T and B lymphocytes explain why there are heightened secondary immune responses after an initial encounter with antigen. In this review, we discuss how clonal expansion, targeted tissue localisation, more efficient antigen recognition and more proficient effector functions contribute to the improved effectiveness of memory cells. Despite the enhanced efficacy of memory cells and the recall immune response, there are numerous experimental and empirical examples in which protection provided by vaccines are short-lived, particularly against pathogens that replicate and cause pathology at their site of entry. In the absence of active immune effector activities, the ability of memory cells to respond quickly enough to control this type of infection is limited. The protective efficacy of bovine herpes virus-1 vaccines in experimental and field challenge conditions are used to illustrate the concept that full protection from disease conferred by vaccination requires the presence of active immune effector mechanisms. Thus, regardless of the many successful technological advances in vaccine design and better understanding of mechanisms underlining induction of memory responses by vaccination, we should recognise that vaccine immunoprophylaxis has limitations. Expectations for vaccines should be realistic and linked to the understanding of host immune responses and knowledge regarding the pathogen and disease pathogenesis.     

A CD8+ T cell clone specific for antigen also recognizes peptidomimics present in anti-idiotypic antibody: implications for T cell memory

The relay hypothesis [R. Nayak, S. Mitra-Kaushik, M.S. Shaila, Perpetuation of immunological memory: a relay hypothesis, Immunology 102 (2001) 387-395] was earlier proposed to explain perpetuation of immunological memory without requiring long lived memory cells or persisting antigen. This hypothesis envisaged cycles of interaction and proliferation of complementary idiotypic B cells (Burnet cells) and anti-idiotypic B cells (Jerne cells) as the primary reason for perpetuation of immunological memory. The presence of peptidomimics of antigen in anti-idiotypic antibody and their presentation to antigen specific T cells was postulated to be primary reason for perpetuation of T cell memory. Using a viral hemagglutinin as a model, in this work, we demonstrate the presence of peptidomimics in the variable region of an anti-idiotypic antibody capable of functionally mimicking the antigen derived peptides. A CD8+ CTL clone was generated against the hemagglutinin protein which specifically responds to either peptidomimic synthesizing cells or peptidomimic pulsed antigen presenting cells. Thus, it appears reasonable that a population of activated antigen specific T cells is maintained in the body by presentation of peptidomimic through Jerne cells and other antigen presenting cells long after immunization.     

Memory and anergy: challenges to traditional models of T lymphocyte differentiation.

Traditional paradigms suggest that encounter with an antigen converts naive peripheral T cells into memory cells with less stringent requirements for activation and increased capacities for lymphokine production. Recent evidence argues that this view may be over-simplified in two ways. First, an encounter with antigen in the absence of certain costimulatory factors can render a T cell anergic--that is, unable to respond to antigen under normal conditions. Second, although cells of the memory T cell population are more responsive than naive cells to some stimuli, these cells are hyporesponsive in other situations. Intrinsic resistance of memory T cells to elevation of intracellular calcium ion concentrations may contribute to their poor responsiveness to agents that activate naive cells. Thus, aspects of the costimulatory environment can determine whether a resting T cell is activated or rendered anergic and may also influence the kinds of stimuli to which a memory T cell will respond.     

CD4 T-cell memory can persist in the absence of class II

To understand how memory CD4 T cells are generated we have re-examined the requirements for continuing antigen stimulation in the generation and persistence of this population. We find that specific antigen is only required for a short period during the activation of naive CD4 T cells and is not required for memory generation from activated CD4 T cells or for persistence of resting memory cells generated by transfer of activated CD4 to adoptive hosts. Moreover, transfer of activated CD4 T cells to class-II-deficient hosts, indicates that TcR-class II major histocompatibility interaction is also unnecessary for either the transition from activated CD4 T cell to resting memory cells or for persistence over an eight-week period. Thus the signals regulating generation and maintenance of memory are fundamentally different from those which regulate the expansion of effector CD4 T-cell populations which include antigen itself and the CD4 T-cell autocrine cytokines induced by antigen.     

Analysis of somatic mutation and class switching in naive and memory B cells generating adoptive primary and secondary responses

Clonal progeny of naive B cells (producing a primary antibody response) and of memory B cells (producing a secondary response) were identified in a cell transfer system. Primary response clones are typically derived from IgM precursors and express unmutated V regions. Multiple isotype switches occur in these clones. Secondary response clones derive from IgG1 precursors and express highly mutated V regions. Additional switches do not occur. With one exception, there was no evidence for somatic mutation during clonal expansion. The generation of mutated memory cells may thus represent a distinct differentiation pathway. Evidence is presented that, in this pathway, mutants that have lost antigen binding specificity but that remain available for stimulation by a different antigen arise upon antigenic stimulation.     

Resolution of infection promotes a state of dormancy and long survival of CD4 memory T cells

Memory T cells survive throughout the lifetime of an individual and are protective upon recall. It is not clear how memory T cells can live so long. Here, we demonstrate that at the resolution of a viral infection, low levels of antigen are captured by B cells and presented to specific CD4(+) memory T cells to render a state of unresponsiveness. We demonstrate in two systems that this process occurs naturally during the fall of antigen and is associated with a global gene expression program initiated with the clearance of antigen. Our study suggests that in the absence of antigen, a state of dormancy associated with low-energy utilization and proliferation can help memory CD4(+) T cells to survive nearly throughout the lifetime of mice. The dormant CD4(+) memory T cells become activated by stimulatory signals generated by a subsequent infection. We propose that quiescence might be a mechanism necessary to regulate long-term survival of CD4 memory T cells and to prevent cross-reactivity to self, hence autoimmunity.