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.     

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.     

MHC-linked protection from diabetes dissociated from clonal deletion of T cells

The I-E molecule of the major histocompatibility complex (MHC) can prevent the spontaneous development of diabetes in nonobese diabetic (NOD) mice. The mechanism of this protection has been investigated by breeding wild-type and promoter-mutated E kappa alpha transgenes onto the NOD genetic background. Animals carrying the various mutated transgenes expressed I-E on different subsets of immunocompetent cells, and thus cells important for the I-E protective effect could be identified. Although the wild-type transgene prevented the infiltration of lymphocytes into pancreatic islets, none of the mutants did. However, all of the transgenes could mediate the intrathymic elimination of T cells bearing antigen receptors with variable regions that recognize I-E. Thus, the I-E molecule does not protect NOD mice from diabetes simply by inducing the deletion of self-reactive T cells.     

Requirement for cotolerogenic gene products in the clonal deletion of I-E reactive T cells

T cells that express the T cell receptor V beta 5.2 domain react with the class II major histocompatibility complex (MHC) molecule I-E, and V beta 5.2+ T cells are deleted in mouse strains that express I-E glycoproteins. By examination of genetically defined recombinant inbred (RI) mouse strains, it was found that the deletion was dependent on the expression of I-E and one of a limited number of non-MHC gene products (cotolerogens). The gene encoding one of these cotolerogens maps to chromosome 12 and is linked to the endogenous provirus Mtv-9. These observations suggest that the I-E-mediated and minor lymphocyte-stimulating antigen (Mls)-mediated deletions of alpha beta T cells from the repertoire are similar; both require the expression of a class II MHC glycoprotein and a second non-MHC gene product.     

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.     

A LAT mutation that inhibits T cell development yet induces lymphoproliferation

Mice homozygous for a single tyrosine mutation in LAT (linker for activation of T cells) exhibited an early block in T cell maturation but later developed a polyclonal lymphoproliferative disorder and signs of autoimmune disease. T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma1 (PLC-gamma1) and of nuclear factor of activated T cells, calcium influx, interleukin-2 production, and cell death were reduced or abrogated in T cells from LAT mutant mice. In contrast, TCR-induced Erk activation was intact. These results identify a critical role for integrated PLC-gamma1 and Ras-Erk signaling through LAT in T cell development and homeostasis.     

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.     

Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance

During development in the thymus, T cells are rendered tolerant to self antigens. It is now apparent that thymocytes bearing self-reactive T cell receptors can be tolerized by processes that result in physical elimination (clonal deletion) or functional inactivation (clonal anergy). As these mechanisms have important clinical implications for transplantation and autoimmunity, current investigations are focused on understanding the cellular and molecular interactions that generate these forms of tolerance.     

Regulation of CD8+ T cell development by thymus-specific proteasomes

Proteasomes are responsible for generating peptides presented by the class I major histocompatibility complex (MHC) molecules of the immune system. Here, we report the identification of a previously unrecognized catalytic subunit called beta5t. beta5t is expressed exclusively in cortical thymic epithelial cells, which are responsible for the positive selection of developing thymocytes. Although the chymotrypsin-like activity of proteasomes is considered to be important for the production of peptides with high affinities for MHC class I clefts, incorporation of beta5t into proteasomes in place of beta5 or beta5i selectively reduces this activity. We also found that beta5t-deficient mice displayed defective development of CD8(+) T cells in the thymus. Our results suggest a key role for beta5t in generating the MHC class I-restricted CD8(+) T cell repertoire during thymic selection.     

植物边缘细胞发育和功能的研究进展

边缘细胞是从根冠表面脱落下来并聚集在根部周围的一群特化细胞,对植物的生长和发育具有重要意义。从边缘细胞的特征、发育和生理功能等方面对植物边缘细胞的研究进行了综述,并对其发展前景进行了展望。     

T细胞表位预测及其在抗口蹄疫病毒疫苗研发中的应用研究进展

随着分子免疫学研究的不断发展,对T淋巴细胞免疫分子机制的阐释,大量T细胞表位信息以及功能基因组学资料的积累,使得基于数据驱动的预测T细胞表位的研究受到重视,可能成为疫苗研发的重要工具之一.本文阐述了T细胞表位预测的理论和方法及其在抗口蹄疫病毒疫苗研发中的应用,并讨论了未来的研究方向.     

Requirement for the SLP-76 adaptor GADS in T cell development

GADS is an adaptor protein implicated in CD3 signaling because of its ability to link SLP-76 to LAT. A GADS-deficient mouse was generated by gene targeting, and the function of GADS in T cell development and activation was examined. GADS- CD4-CD8- thymocytes exhibited a severe block in proliferation but still differentiated into mature T cells. GADS- thymocytes failed to respond to CD3 cross-linking in vivo and were impaired in positive and negative selection. Immunoprecipitation experiments revealed that the association between SLP-76 and LAT was uncoupled in GADS- thymocytes. These observations indicate that GADS is a critical adaptor for CD3 signaling.     

光照和氮素对芒萁克隆繁殖特性及生物量分配的影响

  目的  研究不同光照和施氮水平对芒萁Dicranopteris dichotoma克隆繁殖特性和生物量分配的影响,旨在为芒萁单优层片发育过程提供理论依据。  方法  采用盆栽控制试验,设置3种光照[透光率35.96%(L₁)、13.00%(L₂)和4.75%(L₃)]和2种氮素水平[施氮(N₁)和不施氮(N₀)],比较分析光照和氮素对芒萁克隆繁殖特性及生物量分配的影响。  结果  ①在2种氮素水平下,L₂处理的根状茎芽数出现最大值,L₃处理的克隆分株数显著低于L₁和L₂(P＜0.05)。施氮显著提高了各遮光下克隆分株数和芽数(P＜0.05),分别增加了124.7%(L₁)、82.8%(L₂)、53.8%(L₃)和70.0%(L₁)、125.7%(L₂)、122.5%(L₃)。②在2种氮素水平下,克隆分株株高随遮光程度增加显著增加(P＜0.05),L₃处理的羽叶长显著高于L₁和L₂(P＜0.05),叶宽无显著差异(P＞0.05)。施氮水平下,L₁和L₃处理的克隆分株株高显著增加(P＜0.05),L₁处理的羽叶长显著增加(P＜0.05),L₃处理的羽叶长显著降低(P＜0.05),L₂处理的株高和叶长增加均不显著(P＞0.05)。③在2种氮素水平下,L₃处理的克隆分株地上与地下生物量(干质量)比、生物量羽叶分配比例显著高于L₁和L₂处理(P＜0.05),根状茎分配比例显著低于L₁和L₂(P＜0.05),各遮光处理芒萁克隆分株生物量羽叶分配比例显著高于根状茎(P＜0.05),根状茎显著高于茎和细根(P＜0.05)。  结论  L₂处理更有利于芒萁克隆分株的形成,施氮有利于芒萁克隆繁殖能力的增强;L₃处理的克隆分株可通过增加株高、叶长以及生物量叶分配比例适应弱光生境;无论何种光强资源及氮素水平,芒萁均优先保证羽叶的生长,其次保证根状茎生长。图2表5参38     

维生素A缺乏对大鼠胚胎生长发育的影响

将雌鼠随机分为对照组和维生素A缺乏组,通过胎鼠的大体标本和骨骼标本观察维生素A缺乏对大鼠胚胎生长发育的影响, 结果表明,维生素A缺乏导致胎鼠的体重、身长、尾长明显小于对照组,囟门明显大于对照组,第2、5、6胸骨残缺以及前爪骨化不完全者、脑淤血、脑水肿以及肾盂积水者明显多于对照组.     

外源T3对鸭胚骨骼肌发育和MyoD mRNA表达的影响

甲状腺激素(thyroid hormones,THs)是体内肌肉发育的重要调节因子,MyoD在骨骼肌特异基因的转录调控,肌细胞的定向和分化中起着主要作用。为探讨三碘甲状腺原氨酸(triiodothyronine,T3)对鸭胚骨骼肌生长发育和Myod mRNA表达的影响,分别注射100μL含0.25μg(注射组)和0μg(对照组)T3的生理盐水溶液到入孵前的鸭种蛋蛋清内,检测鸭胚骨骼肌发育和MyoD mRNA的表达情况。结果表明,外源T3对鸭胚胸肌率、腿肌重和腿肌率的影响不显著(P0.05),但显著提高27胚龄鸭胚的体重和胸肌重(P0.05);胸肌MyoD mRNA表达与胸肌重的变化趋势相一致,其中27胚龄注射组胸肌的表达水平显著高于对照组(P0.05);注射组腿肌MyoD mRNA表达在13胚龄显著提高(P0.05),与腿肌发育早于胸肌相一致;注射组胸肌MyoD mRNA表达与胸肌重呈显著正线性相关,胸肌率呈负相关,腿肌MyoD mRNA与腿肌重呈负线性相关。结果显示,外源T3提高了出雏前鸭胚的体重和胸肌重,可能是通过调节MyoD mRNA表达参与胸肌的生长发育。     

水稻稻米香味基因的遗传研究及其在育种中应用的研究进展

目的通过对杂交粳稻滇禾优34香味的分子基础进行研究,为选育有香味的杂交粳稻新品种奠定理论基础。方法对滇禾优34的母本不育系H479A和父本恢复系南34中的与香味相关的甜菜碱脱氢酶基因Osbadh2-E7进行克隆分析;利用KOH浸泡法对滇禾优34的F₂代群体叶片进行香味表型鉴定,并利用Osbadh2-E7等位基因特异引物对滇禾优34的F₂代群体进行基因型鉴定。结果南34中的OsBADH2基因可表达1个正常、有功能的甜菜碱脱氢酶蛋白,而在H479A中是1个典型的、广泛存在于香稻品种中的功能缺陷突变型基因Osbadh2-E7。对滇禾优34的F₂群体植株香味的表型鉴定表明：有香味的植株占总株数的31.8%,χ²检验表明：无香与香味植株符合1对基因控制的3∶1的分离比例,且有香味为隐性。利用Osbadh2-E7等位基因的特异分子标记对F₂群体基因型鉴定结果表明：23.1%的杂合基因型植株也会产生香味。结论由于H479A中的Osbadh2-E7突变等位基因,导致滇禾优34种植生产的籽粒中有1/4的籽粒是纯合突变基因型,从而使食用的稻米产生香味。除此之外,F₂群体中部分杂合基因型的籽粒也可能产生香味,对这些籽粒产生香味的机制有待于更深入的研究。     

Stem cell depletion through epidermal deletion of Rac1

Mammalian epidermis is maintained by self-renewal of stem cells, but the underlying mechanisms are unknown. Deletion of Rac1, a Rho guanosine triphosphatase, in adult mouse epidermis stimulated stem cells to divide and undergo terminal differentiation, leading to failure to maintain the interfollicular epidermis, hair follicles, and sebaceous glands. Rac1 exerts its effects in the epidermis by negatively regulating c-Myc through p21-activated kinase 2 (PAK2) phosphorylation. We conclude that a pleiotropic regulator of cell adhesion and the cytoskeleton plays a critical role in controlling exit from the stem cell niche and propose that Rac and Myc represent a global stem cell regulatory axis.     

Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration

Phosphoinositide 3-kinases (PI3Ks) regulate fundamental cellular responses such as proliferation, apoptosis, cell motility, and adhesion. Viable gene-targeted mice lacking the p110 catalytic subunit of PI3Kgamma were generated. We show that PI3Kgamma controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells. PI3Kgamma-deficient neutrophils exhibited severe defects in migration and respiratory burst in response to heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) agonists and chemotactic agents. PI3Kgamma links GPCR stimulation to the formation of phosphatidylinositol 3,4,5-triphosphate and the activation of protein kinase B, ribosomal protein S6 kinase, and extracellular signal-regulated kinases 1 and 2. Thus, PI3Kgamma regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst.