The role of the T cell receptor in positive and negative selection of developing T cells

Although many combinations of alpha beta T cell receptors are available to the T cells in any given organism, far fewer are actually used by mature T cells. The combinations used are limited by two selective processes, positive selection of T cells bearing receptors that will be useful to the host, and clonal elimination or inactivation of T cells bearing receptors that will be damaging to the host. The ways in which these two apparently contradictory processes occur, and the hypotheses that have been suggested to reconcile them, are discussed.     

Peripheral clonal elimination of functional T cells

A major mechanism for generating tolerance in developing T cells is the intrathymic clonal deletion of T cells that have receptors for those self antigens that are presented on hematopoietic cells. The mechanisms of tolerance induction to antigens not expressed in the thymus remain unclear. Tolerance to self antigens can be generated extrathymically through the induction of clonal nonresponsiveness in T cells with self-reactive receptors. A second mechanism of extrathymic tolerance was identified: clonal elimination of mature T cells with self-reactive receptors that had previously displayed functional reactivity.     

Variability and robustness in T cell activation from regulated heterogeneity in protein levels

In T cells, the stochasticity of protein expression could contribute to the useful diversification of biological functions within a clonal population or interfere with accurate antigen discrimination. Combining computer modeling and single-cell measurements, we examined how endogenous variation in the expression levels of signaling proteins might affect antigen responsiveness during T cell activation. We found that the CD8 co-receptor fine-tunes activation thresholds, whereas the soluble hematopoietic phosphatase 1 (SHP-1) digitally regulates cell responsiveness. Stochastic variation in the expression of these proteins generates substantial diversity of activation within a clonal population of T cells, but co-regulation of CD8 and SHP-1 levels ultimately limits this very diversity. These findings reveal how eukaryotic cells can draw on regulated variation in gene expression to achieve phenotypic variability in a controlled manner.     

Peripheral selection of the T cell repertoire

T lymphocytes undergo selection events not only in the thymus, but also after they leave the thymus and reside in the periphery. Peripheral selection was found to be dependent on T cell receptor (TCR)-ligand interactions but to differ from thymic selection with regard to specificity and mechanism. Unlike thymic selection, peripheral selection required binding of antigen to the TCR, and it induced expansion of T cell clones. Tolerance to self antigens that are restricted to the periphery occurred through the elimination of self-reactive T cells and by the clonal anergy, which was associated with down-regulation of the alpha beta TCR and CD8.     

A transforming ras gene in tumorigenic guinea pig cell lines initiated by diverse chemical carcinogens

Fetal guinea pig cells were transformed by treatment with four different chemical carcinogens including nitroso compounds and polycyclic hydrocarbons. As a consequence of this treatment, oncogenes capable of transforming NIH/3T3 cells became activated in each of five independently established clonal guinea pig cell lines. Molecular characterization of representative NIH/3T3 transformants revealed that the same oncogene was present in each of the cell lines tested. Moreover, detection of this transforming gene paralleled the acquisition of tumorigenic properties by these neoplastic cells.     

Thymic requirement for clonal deletion during T cell development

During T cell differentiation, self tolerance is established in part by the deletion of self-reactive T cells within the thymus (negative selection). The presence of T cell receptor (TCR)-alpha beta + T cells in older athymic (nu/nu) mice indicates that some T cells can also mature without thymic influence. Therefore, to determine whether the thymus is required for negative selection, TCR V beta expression was compared in athymic nu/nu mice and their congenic normal littermates. T cells expressing V beta 3 proteins are specific for minor lymphocyte stimulatory (Mlsc) determinants and are deleted intrathymically due to self tolerance in Mlsc+ mouse strains. Here it is shown that V beta 3+ T cells are deleted in Mlsc+ BALB/c nu/+ mice, but not in their BALB/c nu/nu littermates. Thus, the thymus is required for clonal deletion during T cell development.     

Division of labor with a workforce of one: challenges in specifying effector and memory T cell fate

In the course of the immune response against microbes, na?ve T cells proliferate and generate varied classes of effector cells, as well as memory cells with distinct properties and functions. Owing to recent technological advances, some of the most imposing questions regarding effector and memory T cell differentiation are now becoming experimentally soluble: How many classes of antigen-specific T cells exist, and how malleable are they in their fate and in their functional state? How might a spectrum of cell fates be imparted to the clonal descendants of a single lymphocyte? Where, when, and how does pathogen-associated information refine the instruction, selection, and direction of newly activated T cells as they perform their tasks in different locations and times? Some surprising new glimpses ahead on these subjects and other yet-unanswered questions are discussed.     

Naive and memory CD4+ T cell survival controlled by clonal abundance

Immunity to a plethora of microbes depends on a diverse repertoire of na?ve lymphocytes and the production of long-lived memory cells. We present evidence here that low clonal abundance in a polyclonal repertoire favors the survival and activation of na?ve CD4(+) T cells as well as the survival of their memory cell progeny. The inverse relation between clonal frequency and survival suggests that intraclonal competition could help maintain an optimally diverse repertoire of T cells and an optimal environment for the generation of long-lived memory cells.     

Recent expansion of Toxoplasma through enhanced oral transmission

The global predominance of three clonal Toxoplasma gondii lineages suggests that they are endowed with an exceptional trait responsible for their current parasitism of nearly all warm-blooded vertebrates. Genetic polymorphism analyses indicate that these clonal lineages emerged within the last 10,000 years after a single genetic cross. Comparison with ancient strains (approximately 1 million years) suggests that the success of the clonal lineages resulted from the concurrent acquisition of direct oral infectivity. This key adaptation circumvented sexual recombination, simultaneously promoting transmission through successive hosts, hence leading to clonal expansion. Thus, changes in complex life cycles can occur rapidly and can profoundly influence pathogenicity.     

Interleukin-2: inception, impact, and implications

Interleukin-2 (IL-2), the first of a series of lymphocytotrophic hormones to be recognized and completely characterized, is pivotal for the generation and regulation of the immune response. A T lymphocyte product, IL-2 also stimulates T cells to undergo cell cycle progression via a finite number of interactions with its specific membrane receptors. Because T cell clonal proliferation after antigen challenge is obligatory for immune responsiveness and immune memory, the IL-2-T cell system has opened the way to a molecular understanding of phenomena that are fundamental to biology, immunology, and medicine.     

对丛生克隆植物种群丛生克隆觅养功能和资源转移的新认识

论述了在地球上 ,特别是在草原和稀树干草原丛生克隆植物的分布与数量。近年来 ,大多数植物种群生态学家都把注意力集中于研究根茎克隆植物或葡伏茎克隆植物的许多重要问题 ,而轻视研究丛生克隆植物分株和分株集团的觅养功能和资源转移。因此 ,直到现在许多植物种群生态学家仍然不清楚丛生克隆的觅养和资源转移。作者等研究了丛生禾草 Stipa baicalensis和 Festuca ovina丛生克隆的觅养和资源转移 ,并发现丛生克隆不但具有泛资源整合作用也具有有限资源整合作用 ,不但具有克隆集合内分株集团觅养 ,而且也具有分株集团内分株觅养 ,而根茎和葡伏茎克隆仅具有分株觅养和泛资源整合作用 ,丛生克隆的觅养和资源转移较根茎或葡伏茎克隆复杂得多     

A cell culture model for T lymphocyte clonal anergy

T lymphocytes respond to foreign antigens both by producing protein effector molecules known as lymphokines and by multiplying. Complete activation requires two signaling events, one through the antigen-specific receptor and one through the receptor for a costimulatory molecule. In the absence of the latter signal, the T cell makes only a partial response and, more importantly, enters an unresponsive state known as clonal anergy in which the T cell is incapable of producing its own growth hormone, interleukin-2, on restimulation. Our current understanding at the molecular level of this modulatory process and its relevance to T cell tolerance are reviewed.     

A nondeletional mechanism of thymic self tolerance

T cells become tolerant of self antigens during their development in the thymus. Clonal deletion of thymocytes bearing self-reactive T cell receptors is a major mechanism for generating tolerance and occurs readily for antigens expressed by bone marrow-derived cells. Tolerance to antigens expressed on the radioresistant thymic stromal elements is demonstrated here to occur via a nondeletional mechanism. For minor lymphocyte stimulatory (Mls-1a) and major histocompatibility complex (MHC) antigens, this alternate form of tolerance induction results in clonal anergy.     

入侵植物南美蟛蜞菊克隆繁殖特性初探

[目的]揭示不同生境条件下南美蟛蜞菊的克隆繁殖能力和生态适应性,为探明南美蟛蜞菊的入侵能力提供基础性资料。[方法]选取3个生境(潮州市东丽湖、慧如公园、泰佛殿)的蟛蜞菊植株,比较不同生境下土壤含水量与其克隆繁殖能力之间的关系。[结果]土壤含水量对南美蟛蜞菊的克隆繁殖特性影响显著,土壤含水量越高,其克隆繁殖特性越强。南美蟛蜞菊克隆繁殖特性强弱在3个生境的顺序为:东丽湖(21%土壤含水量)>慧如公园(13%)>泰佛殿(3%),说明在含水量为21%的东丽湖地区,南美蟛蜞菊处于最佳生活状态,具有较长的根和基株匍匐茎,较短的间隔子,较高的克隆分株。[结论]土壤含水量对南美蟛蜞菊的克隆繁殖特性具有重要的影响。     

Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo

In order to examine the mechanisms by which clonal deletion of autoreactive T cells occurs, a peptide antigen was used to induce deletion of antigen-reactive thymocytes in vivo. Mice transgenic for a T cell receptor (TCR) that reacts to this peptide contain thymocytes that progress from the immature to the mature phenotype. Intraperitoneal administration of the peptide antigen to transgenic mice results in a rapid deletion of the immature CD4+ CD8+ TCRlo thymocytes. Apoptosis of cortical thymocytes can be seen within 20 hours of treatment. These results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance.     

Neonatal thymectomy results in a repertoire enriched in T cells deleted in adult thymus

In B6AF1 mice, T lymphocytes that use the V beta 11-positive (and not V beta 6-positive or V beta 8-positive) segment in their receptor for antigen are greatly reduced in the thymus and peripheral lymphoid tissues, most likely as a result of clonal deletion. The relative number of V beta 11-positive cells in adult lymph nodes was ten times as high in B6AF1 mice thymectomized 1 to 4 days after birth as in normal mice. Moreover, for the first 10 days of life of B6AF1 mice, mature V beta 11-positive T cells were readily detected in the thymus and spleen. Thus neonatal thymectomy results in the maintenance of the receptor repertoire of early postnatal life, and this correlates with the subsequent development of organ-specific autoimmune diseases.     

Bayesian inference towards the resolution of molecular evolution:application to the "Trichoderma harzianum sensu lato" clade

The Hypocrea lixii/Trichoderma harzianum species aggregate contains a group of taxa (H. lixii /T. harzianum, T. aggressivum, T. tomentosum, T. cerinum, T. velutinum, H. tawa) of which some (e.g. T. harzianum) are important for biocontrol of plant pathogenic fungi in agriculture, whereas others are aggressive pathogens of Agaricus spp. and Pleurotus spp. in mushroom farms (T. aggressivum), or opportunistic pathogens of immunocompromised mammals including humans (T. harzianum). We ch…     

Downregulation of L3T4+ cytotoxic T lymphocytes by interleukin-2

Proliferation of activated cytotoxic T lymphocytes (CTLs) that recognize foreign histocompatibility antigens is induced by interleukin-2, a potent immunoregulatory molecule originally described as T cell growth factor. Interleukin-2 (IL-2) is widely used to isolate and induce clonal expansion of CTLs for functional studies in vitro and in vivo. However, in studies with CTLs specific for class I and class II histocompatibility antigens, IL-2 rapidly downregulated the lytic activity of some class II-specific CTLs in a time- and dose-dependent manner. Lytic activity of L3T4+ CTLs specific for the murine class II antigen I-Ek was repeatedly up- and downregulated in vitro by alternate exposure to specific (alloantigen) and nonspecific (recombinant IL-2) signals, respectively. These results demonstrate that some CTLs modulate their functional property (cytolysis) while undergoing IL-2-driven cell proliferation without loss of antigen specificity or ability to revert to a lytic phenotype.     

毛白杨无性系年龄效应及根萌条幼化效果的初步研究

研究了毛白杨优树花枝基因库中的年龄效应以及来源于根萌条的无性系测量林的幼化效果,结果表明：１．毛白杨生长性状的年龄效应较明显,与优树年龄呈线性相关,煤污病,叶部性状等与优树年龄的１￣３次多项式回归均不显著,基本上不受年龄效应的影响,树干通直度与优树年龄呈３次多项式回归关系;２．无性系测定林各无性系的生长正常,与原优树的年龄相关不显著,年龄或龄级的方差分量也未达显著性水平,因此根萌条幼化效果良好,且