Direct link between mhc polymorphism,T cell avidity,and diversity in immune defense

Major histocompatibility complex (mhc)-encoded molecules govern immune responses by presenting antigenic peptides to T cells. The extensive polymorphism of genes encoding these molecules is believed to enhance immune defense by broadening the array of antigenic peptides available for T cell recognition, but direct evidence supporting the importance of this mechanism in combating pathogens is limited. Here we link mhc polymorphism-driven diversification of the cytotoxic T lymphocyte (CTL) repertoire to the generation of high-avidity, protective antiviral T cells and to superior antiviral defense. Thus, much of the beneficial effect of the mhc polymorphism in immune defense may be due to its critical influence on the properties of the selected CTL repertoire.     

Rap1 GTPase regulation of adherens junction positioning and cell adhesion

Cell-cell junctions are distributed evenly around the lateral circumference of cells within an epithelium. We find that the even distribution of adherens junctions is an active process that requires the small guanosine triphosphatase Rap1. Cells mutant for Rap1 condensed their adherens junctions to one side of the cell. This disrupted normal epithelial cell behavior, and mutant cell clones dispersed into the surrounding wild-type tissue. Rap1 is enriched at adherens junctions, particularly between newly divided sister cells where it may reseal the adherens junction ring. The regulation of adherens junction positioning could play a role in cell mobility and cell division.     

Uncoupling of an epithelial cell membrane junction by calcium-ion removal

Calcium takes part in maintaining ion communication between salivary gland cells (Chironomus thummi). Its withdrawal from the cell systems results in virtual disconnection of ion communication, at Ca(++) concentrations which do not noticeably affect cell adhesion. The junctional membrane surfaces. which are normally quite freely permeable to ions, become as impermeable as the nonjunctional membrane surfaces; each cell seals itself off irreversibly as a unit. In maintaining ion communication Mg(++) substitutes for Ca(++)     

Reciprocal control of T helper cell and dendritic cell differentiation

It is not known whether subsets of dendritic cells provide different cytokine microenvironments that determine the differentiation of either type-1 T helper (TH1) or TH2 cells. Human monocyte (pDC1)-derived dendritic cells (DC1) were found to induce TH1 differentiation, whereas dendritic cells (DC2) derived from CD4+CD3-CD11c- plasmacytoid cells (pDC2) induced TH2 differentiation by use of a mechanism unaffected by interleukin-4 (IL-4) or IL-12. The TH2 cytokine IL-4 enhanced DC1 maturation and killed pDC2, an effect potentiated by IL-10 but blocked by CD40 ligand and interferon-gamma. Thus, a negative feedback loop from the mature T helper cells may selectively inhibit prolonged TH1 or TH2 responses by regulating survival of the appropriate dendritic cell subset.     

Structural mutations of the T cell receptor zeta chain and its role in T cell activation

T cell hybridomas that express zeta zeta, but not zeta eta, dimers in their T cell receptors (TCRs) produce interleukin-2 (IL-2) and undergo an inhibition of spontaneous growth when activated by antigen, antibodies to the receptor, or antibodies to Thy-1. Hybridomas without zeta and eta were reconstituted with mutated zeta chains. Cytoplasmic truncations of up to 40% of the zeta molecule reconstituted normal surface assembly of TCRs, but antigen-induced IL-2 secretion and growth inhibition were lost. In contrast, cross-linking antibodies to the TCR activated these cells. A point mutation conferred the same signaling phenotype as did the truncations and caused defective antigen-induced tyrosine kinase activation. Thus zeta allows the binding of antigen/major histocompatibility complex (MHC) to alpha beta to effect TCR signaling.     

Uncoupling of a nerve cell membrane junction by calcium-ion removal

Calcium ion participates in maintaining electrical connections between the nerve cells of Retzius (Hirudo medicinalis). The conductance across the junction between these cells decreases with decreasing concentration of free, extracellular Ca(++) At a certain level of Ca(++) withdrawal from the cell system, junctional conductance reaches a critical low point at which the cells become functionally disconnected: the nerve impulses which are normally discharged in synchrony by the cells become asynchronous. These effects of Ca(++) on junctional connection are irreversible, in contrast to those on nonjunctional surface membrane permeability.     

The T cell receptor

The primary structure of T cell receptor proteins and genes is well understood. Immunologists are now trying to understand the properties of these interesting molecules. Evidence suggests that T cell alpha beta receptors recognize a complex of an antigen-derived peptide bound to one of the cell-surface products of the major histocompatibility complex (MHC) genes. It is likely that alpha beta receptors and MHC proteins have coevolved to have some affinity for each other. During T cell development in the thymus, cells bearing self-reactive receptors are deleted by the mechanisms of tolerance, and cells are preferentially allowed to mature if they bear receptors that will be able to recognize antigen plus self-MHC after they have become full-fledged T cells. Some explanations for these phenomena have been tested, but no satisfactory theory can yet be proposed to account for them.     

Wolbachia enhance Drosophila stem cell proliferation and target the germline stem cell niche

Wolbachia are widespread maternally transmitted intracellular bacteria that infect most insect species and are able to alter the reproduction of innumerous hosts. The cellular bases of these alterations remain largely unknown. Here, we report that Drosophila mauritiana infected with a native Wolbachia wMau strain produces about four times more eggs than the noninfected counterpart. Wolbachia infection leads to an increase in the mitotic activity of germline stem cells (GSCs), as well as a decrease in programmed cell death in the germarium. Our results suggest that up-regulation of GSC division is mediated by a tropism of Wolbachia for the GSC niche, the cellular microenvironment that supports GSCs.     

Murine MHC polymorphism and T cell specificities

The major histocompatibility complex (MHC) genes are polymorphic in mouse and man. The products of these genes are receptors for peptides, which while bound, are displayed to T lymphocytes. When bound peptides from antigens are recognized by T lymphocytes, an immune response is initiated against the antigens. This study assessed the relation of the polymorphic MHC molecules to their peptide specificity. The results indicate that although an individual of the species has a limited ability to recognize antigens, the species as a whole has broad reactivity. This rationalizes the extreme polymorphism observed.     

Induction of CD4+ human cytolytic T cells specific for HIV-infected cells by a gp160 subunit vaccine

Cytolytic T lymphocyte (CTL) responses were evaluated in humans immunized with recombinant human immunodeficiency virus type 1 (HIV) envelope glycoprotein gp160. Some vaccinees had gp160-specific CTLs that were shown by cloning to be CD4+. Although induced by exogenous antigen, most gp160-specific CTL clones also recognized gp160 synthesized endogenously in target cells. These clones lysed autologous CD4+ T lymphoblasts infected with HIV. Of particular interest were certain vaccine-induced clones that lysed HIV-infected cells, recognized gp160 from diverse HIV isolates, and did not participate in "innocent bystander" killing of noninfected CD4+ T cells that had bound gp120.     

Developmental biology of T cell receptors

T cell receptors are the antigen-recognizing elements found on the effector cells of the immune system. Two isotypes have been discovered, TCR-gamma delta and TCR-alpha beta, which appear in that order during ontogeny. The maturation of prothymocytes that colonize the thymic rudiment at defined gestational stages occurs principally within the thymus, although some evidence for extrathymic maturation also exists. The maturation process includes the rearrangement and expression of the T cell receptor genes. Determination of these mechanisms, the lineages of the cells, and the subsequent thymic selection that results in self-tolerance is the central problem in developmental immunology and is important for the understanding of autoimmune diseases.     

Activation-driven programmed cell death and T cell receptor zeta eta expression

Activation of spontaneously dividing T cell hybridomas induces interleukin-2 (IL-2) production, a cell cycle block, and programmed cell death. T cell hybridomas that express the T cell antigen receptor (TCR) zeta homodimer (zeta 2), but not the TCR zeta eta heterodimer, were studied. The zeta eta- cells produced little or no inositol phosphates (IP) when stimulated with antigen. In most cases the hydrolysis of phosphoinositides was also impaired after stimulation with antibody to CD3, although one zeta eta- cell produced normal concentrations of IP. The zeta eta- cells slowed their growth and secreted IL-2 in response to both stimuli. However, the zeta eta- cells did not die after activation with antigen. Since activated thymocytes also undergo programmed cell death, these results may have important implications for the role of the zeta eta.TCR in negative selection.     

Alloantigen recognition is preceded by nonspecific adhesion of cytotoxic T cells and target cells

T-cell receptors bind antigens only when the antigens are exposed on the cell surface. This can be studied best in the interaction of cytolytic T lymphocytes (CTL) with target cells because the recognition and binding event can be separated from the lytic phase. Studies with CTL clones specific for HLA-A2 and HLA-B7 demonstrated that conjugates of CTL's and target cells can be formed in the absence of specific antigen recognition. Furthermore, T-cell receptor and target antigen cannot interact unless there is conjugate formation. This indicates that nonspecific conjugate formation between CTL's and target cells precedes the recognition of specific antigen by the T-cell receptor.     

Defective CD8 T cell memory following acute infection without CD4 T cell help

The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.     

Surface structures involved in target recognition by human cytotoxic T lymphocytes

Cloned human cytotoxic T lymphocytes and monoclonal antibodies inhibiting their function (anti-T3A, anti-T4A, and anti-T8A) were used to elucidate the role of T cell surface glycoproteins in cell-mediated lympholysis involving individual classes of gene products of the major histocompatibility complex on target cells. The results indicate that several surface molecules are required for specific target recognition: T3 and T4 on T4+ cytotoxic T lymphocytes and T3 and T8 on T8+ cytotoxic T lymphocytes.     

Requirement for CD4 T cell help in generating functional CD8 T cell memory

Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.     

Programmed cell death of T cells signaled by the T cell receptor and the alpha 3 domain of class I MHC

As well as being activated or rendered unresponsive, mature T lymphocytes can be deleted, depending on the signals received by the cell. Deletion by programmed cell death (apoptosis) is triggered if a T cell that has received a signal through its T cell receptor complex also receives a signal through the alpha 3 domain of its class I major histocompatibility complex (MHC) molecule. Such a signal can be delivered by a CD8 molecule, which recognizes the alpha 3 domain, or by an antibody to this domain. Precursors of both cytotoxic T lymphocytes (CTL's) and T helper cells are sensitive to this signal but become resistant at some point before completing differentiation into functioning CTL's or T helper cells. Because CTL's carry CD8, they can induce cell death in T cells that recognize them. This pathway may be important in both removal of autoreactive T cells and immunoregulation.     

苏云金杆菌溶细胞毒素及相关基因研究进展

苏云金芽孢杆菌(Bacillusthuringiensis,Bt)是一种革兰氏阳性土壤细菌,在其芽孢形成期能够产生多种杀虫晶体蛋白,这些蛋白在靶害虫中肠内被激活为毒素并使细胞膜穿孔,从而达到杀虫目的。近年来,关于溶细胞毒素分布、分类、杀虫机理、昆虫抗性等问题的研究已成为新的热点。文章综述了各国实验室在这些方面的最新进展。