Showing papers on "Antigen published in 1989"
TL;DR: Two types of cloned helper T cells are described, defined primarily by differences in the pattern of lymphokines ynthesized, and the different functions of the two types of cells and their lymphokine synthesis are discussed.
Abstract: Effector functions in the immune system are carried out by a variety of cell types, and as our understanding of the complexity of the system expands, the number of recognized subdivisions of cell types also continues to increase. B lymphocytes, producing antibody, were initially distinguished from T lymphocytes, which provide help for B cells (1, 2). The T-cell population was further divided when surface markers allowed separation of helper cells from cytotoxic cells (3). Although there were persistent reports of heterogeneity in the helper T-cell compartment (reviewed below), only relatively recently were distinct types of helper cells resolved. In this review we describe the differences between two types of cloned helper T cells, defined primarily by differences in the pattern of lymphokines ynthesized, and we also discuss the different functions of the two types of cells and their lymphokines. Patterns of lymphokine synthesis are convenient and explicit markers to describe T-cell subclass differences, and evidence increases that many of the functions of helper T cells are predicted by the functions of the lymphokines that they synthesize after activation by antigen and presenting cells. The separation of many mouse helper T-cell clones into these two distinct types is now well established, but their origin in normal T-cell populations is still not clear. Further divisions of helper T cells may have to be recognized before a complete picture of helper T-cell function can be obtained.
7,814 citations
TL;DR: Histological thin sections of the regressing tumor showed that anti-APO-1 was able to induce apoptosis in vivo, suggesting induction of apoptosis as a consequence of a signal mediated through cell surface molecules like APO- 1 may be a useful therapeutic approach in treatment of malignancy.
Abstract: To characterize cell surface molecules involved in control of growth of malignant lymphocytes, monoclonal antibodies were raised against the human B lymphoblast cell line SKW6.4. One monoclonal antibody, anti-APO-1, reacted with a 52-kilodalton antigen (APO-1) on a set of activated human lymphocytes, on malignant human lymphocyte lines, and on some patient-derived leukemic cells. Nanogram quantities of anti-APO-1 completely blocked proliferation of cells bearing APO-1 in vitro in a manner characteristic of a process called programmed cell death or apoptosis. Cell death was preceded by changes in cell morphology and fragmentation of DNA. This process was distinct from antibody- and complement-dependent cell lysis and was mediated by the antibody alone. A single intravenous injection of anti-APO-1 into nu/nu mice carrying a xenotransplant of a human B cell tumor induced regression of this tumor within a few days. Histological thin sections of the regressing tumor showed that anti-APO-1 was able to induce apoptosis in vivo. Thus, induction of apoptosis as a consequence of a signal mediated through cell surface molecules like APO-1 may be a useful therapeutic approach in treatment of malignancy.
1,823 citations
TL;DR: It is suggested that the cell-killing activity of TNF is mediated by Fas antigen associated with the TNF-R, an mAb specific for a human cell surface component (termed anti-Fas mAb).
Abstract: We have prepared an mAb specific for a human cell surface component (termed anti-Fas mAb). Anti-Fas shows cell-killing activity that is indistinguishable from the cytolytic activity of TNF. Fas antigen was characterized by western blotting, indicating that Fas antigen is a cell surface protein with a molecular weight of 200,000, which is different from the molecular weight of TNF-R. Fas antigen, however, is co-downregulated with the TNF-R when cells sensitive to the cytolytic activity of TNF are incubated with either TNF or anti-Fas. In contrast, Fas antigen on cells insensitive to TNF is not co-downregulated with the TNF-R. We suggest that the cell-killing activity of TNF is mediated by Fas antigen associated with the TNF-R.
1,511 citations
TL;DR: A "humanized" antibody is constructed by combining the complementarity-determining regions (CDRs) of the anti-Tac antibody with human framework and constant regions and has an affinity for p55 of 3 x 10(9) M-1, about 1/3 that of murine anti- Tac.
Abstract: The anti-Tac monoclonal antibody is known to bind to the p55 chain of the human interleukin 2 receptor and to inhibit proliferation of T cells by blocking interleukin 2 binding. However, use of anti-Tac as an immunosuppressant drug would be impaired by the human immune response against this murine antibody. We have therefore constructed a "humanized" antibody by combining the complementarity-determining regions (CDRs) of the anti-Tac antibody with human framework and constant regions. The human framework regions were chosen to maximize homology with the anti-Tac antibody sequence. In addition, a computer model of murine anti-Tac was used to identify several amino acids which, while outside the CDRs, are likely to interact with the CDRs or antigen. These mouse amino acids were also retained in the humanized antibody. The humanized anti-Tac antibody has an affinity for p55 of 3 x 10(9) M-1, about 1/3 that of murine anti-Tac.
1,336 citations
TL;DR: The work discussed here offers a unified view of T-cell recognition and suggests that class-I and class-II molecules have a closely related function in the presentation of peptides to T lymphocytes.
Abstract: The work discussed here offers a unified view of T-cell recognition and suggests that class-I and class-II molecules have a closely related function in the presentation of peptides to T lymphocytes. The epitopes recognized by class I-restricted T cells that have been defined with peptides in the 4-6 hr lysis assay have all been derived from endogenously synthesized proteins expressed by virus infected or transfected cells. Evidence is accumulating that a cytoplasmic degradation system may be involved in the generation of these epitopes. The analysis of the specificity of CTL responses with synthetic peptides has demonstrated the control of immune responses to isolated epitopes by class-I genes and the great diversity of the receptor repertoire for individual class-I-restricted epitopes.
1,213 citations
TL;DR: This chimeric receptor provides the T cell with an antibody-like specificity and is able to effectively transmit the signal for T-cell activation and execution of its effector function.
Abstract: To design and direct at will the specificity of T cells in a non-major histocompatibility complex (MHC)-restricted manner, we have generated and expressed chimeric T-cell receptor (TcR) genes composed of the TcR constant (C) domains fused to the antibody's variable (V) domains. Genomic expression vectors have been constructed containing the rearranged gene segments coding for the V region domains of the heavy (VH) and light (VL) chains of an anti-2,4,6-trinitrophenyl (TNP) antibody (SP6) spliced to either one of the C-region gene segments of the alpha or beta TcR chains. Following transfection into a cytotoxic T-cell hybridoma, expression of a functional TcR was detected. The chimeric TcR exhibited the idiotope of the Sp6 anti-TNP antibody and endowed the T cells with a non-MHC-restricted response to the hapten TNP. The transfectants specifically killed and produced interleukin 2 in response to TNP-bearing target cells across strain and species barriers. Moreover, such transfectants responded to immobilized TNP-protein conjugates, bypassing the need for cellular processing and presentation. In the particular system employed, both the TNP-binding site and the Sp6 idiotope reside almost exclusively in the VH chain region. Hence, introduction into T cells of TcR genes containing only the VHSp6 fused to either the C alpha or C beta was sufficient for the expression of a functional surface receptor. Apparently, the VHC alpha or VHC beta chimeric chains can pair with the endogenous beta or alpha chains of the recipient T cell to form a functional alpha beta heterodimeric receptor. Thus, this chimeric receptor provides the T cell with an antibody-like specificity and is able to effectively transmit the signal for T-cell activation and execution of its effector function.
1,209 citations
TL;DR: It is shown that engaging the CD3/TCR complex of immature mouse thymocytes with anti-CD3 antibodies produces DNA degradation and cell death through the endogenous pathway of apoptosis.
Abstract: The receptors found on most T lymphocytes bind to antigen presented on major histocompatibility complex proteins and consist of dimers of alpha- and beta-polypeptides associated with the invariant CD3 complex. A fully competent immune system requires a diverse array of T-cell antigen receptors (TCRs) with different specificities. This diversity is generated by rearrangement of TCR alpha- and beta-chain gene segments within the thymus where the receptors are first expressed. Any cells carrying self-reactive receptors must be eliminated, suppressed or inactivated so that destructive autoimmunity is avoided. Recently, compelling evidence has shown that one process involved in producing such self-tolerance is clonal deletion of autoreactive cells within the thymus by an as-yet-undefined mechanism. Here we show that engaging the CD3/TCR complex of immature mouse thymocytes with anti-CD3 antibodies produces DNA degradation and cell death through the endogenous pathway of apoptosis. Activation of this process in immature T cells by the binding of the TCR to self-antigens may therefore be the mechanism which produces clonal deletion and consequently self-tolerance.
1,163 citations
TL;DR: Because cytokine functions are complex and overlapping, the development of precise, monospecific bioassays, and enzyme-linked immunosorbent assays (ELISAs) was essential, before a clear picture of T cell cytokine synthesis could be obtained.
Abstract: Publisher Summary Because cytokine functions are complex and overlapping, the development of precise, monospecific bioassays, and enzyme-linked immunosorbent assays (ELISAs) was essential, before a clear picture of T cell cytokine synthesis could be obtained. In vitro , some mast cell lines synthesize IL-4 and other cytokines of the Th2 pattern in response to cross-linking of surface IgE. Although functional evidence using mixed cell populations suggested different types of Th cells, the lack of discriminatory cell-surface markers has hampered efforts to define the different subtypes. The development of in vitro T cell clones led to the description of four types of helper T cell clones, and later, two types of Th clones (Th1 and Th2) were defined on the basis of different patterns of cytokine secretion. These patterns have been confirmed in several panels of Th clones and this is currently the most clear-cut criterion for separation of mouse Th subtypes. As the two types differ in the synthesis of many cytokines, and the cytokines have a major role in the regulation of immune responses, the two types of Th cells have markedly different functions. When injected simultaneously with antigen into the footpads of naive mice, Th1 clones cause an antigen-specific and major histocompatibility complex (MHC)-restricted inflammatory reaction that peaks at about 24 hours. Th2 clones do not produce a swelling reaction under these conditions. One of the major functions of helper T cells is to provide signals for activation, proliferation, and differentiation to B cells that have encountered an antigen. Several strategies have been employed for studying the functions of mouse Th clones in micro and for analyzing the roles of specific Th products in these functions. In spite of the clear dichotomy of mouse Th1 and Th2 clones, and the accumulating evidence for their involvement in normal immune responses, human T cells do not appear to segregate into two clear subsets. Many human T cell clones secrete both Th1and Th2 cytokines.
1,100 citations
TL;DR: It is found that, on culture, centrocytes isolated from human tonsil kill themselves within a few hours by apoptosis, not a feature of other tonsillar B cells.
Abstract: The high affinity of antibodies produced during responses to T-cell-dependent antigens is associated with somatic mutation in the variable region of the immunoglobulin. Indirect evidence indicates that: (1) this arises by a process of hypermutation, acting selectively on rearranged immunoglobulin variable-region genes, which is activated in centroblasts within germinal centres; and (2) centrocytes, the progeny of centroblasts, undergo selection on the basis of their ability to receive a positive signal from antigen. We have now performed experiments analysing this selection process, and found that, on culture, centrocytes isolated from human tonsil kill themselves within a few hours by apoptosis. This is not a feature of other tonsillar B cells. Centrocytes can be prevented from entering apoptosis if they are activated both through their receptors for antigen and a surface glycoprotein recognized by CD40 antibodies.
1,091 citations
TL;DR: It is shown that, for mice, the protein in association with major histocompatibility complex class II molecules stimulates virtually all T cells bearing V beta 3 and V beta 8.3, and few others, demonstrating that tolerance to exogenously administered antigen can be caused by clonal deletion of reactive T cells.
TL;DR: The view is put forth that signals originating from separate cell membrane receptors are integrated at the level of the responsive gene and initiate a contingent series of gene activations that bring about proliferation and impart immunologic function.
Abstract: Interaction of antigen in the proper histocompatibility context with the T lymphocyte antigen receptor leads to an orderly series of events resulting in morphologic change, proliferation, and the acquisition of immunologic function. In most T lymphocytes two signals are required to initiate this process, one supplied by the antigen receptor and the other by accessory cells or agents that activate protein kinase C. Recently, DNA sequences have been identified that act as response elements for one or the other of the two signals, but do not respond to both signals. The fact that these sequences lie within the control regions of the same genes suggests that signals originating from separate cell membrane receptors are integrated at the level of the responsive gene. The view is put forth that these signals initiate a contingent series of gene activations that bring about proliferation and impart immunologic function.
TL;DR: B-cell tolerance in transgenic mice using genes for IgM anti-H–2k MHC class I antibody is studied and it is suggested that very large numbers of autospecific B cells can be controlled by clonal deletion.
Abstract: B lymphocytes can be rendered specifically unresponsive to antigen by experimental manipulation in vivo and in vitro1–6, but it remains unclear whether or not natural tolerance involves B-cell tolerance because B cells are controlled by T lymphocytes, and in their absence respond poorly to antigen (reviewed in ref. 7). In addition, autoantibody-producing cells can be found in normal mice and their formation is enhanced by B-cell mitogens such as lipopolysaccharides8–12. We have studied B-cell tolerance in transgenic mice using genes for IgM anti-H–2k MHC class I antibody. In H–2d transgenic mice about 25–50% of the splenic B cells bear membrane immunoglobulin of this specificity, and abundant serum IgM encoded by the transgenes is produced. In contrast, H–2k x H–2d (H–2-d/k) transgenic mice lack B cells bearing the anti-H–2k idiotype and contain no detectable serum anti-H–2k antibody, suggesting that very large numbers of autospecific B cells can be controlled by clonal deletion.
TL;DR: T-cell tolerance in transgenic mice expressing a T-cell receptor with double specificities for lymphocytic choriomeningitis virus (LCMV)-H-2Db and for the mixed-lymphocyte stimulatory (Mlsa) antigen is studied.
Abstract: The crucial role of the thymus in immunological tolerance has been demonstrated by establishing that T cells are positively selected to express a specificity for self major histocompatibility complex (MHC), and that those T cells bearing receptors potentially reactive to self antigen fragments, presumably presented by thymic MHC, are selected against. The precise mechanism by which tolerance is induced and the stage of T-cell development at which it occurs are not known. We have now studied T-cell tolerance in transgenic mice expressing a T-cell receptor with double specificities for lymphocytic choriomeningitis virus (LCMV)-H-2Db and for the mixed-lymphocyte stimulatory (MIsa) antigen. We report that alpha beta TCR transgenic mice tolerant to LCMV have drastically reduced numbers of CD4+CD8+ thymocytes and of peripheral T cells carrying the CD8 antigen. By contrast, tolerance to MIsa antigen in the same alpha beta TCR transgenic MIsa mice leads to deletion of only mature thymocytes and peripheral T cells and does not affect CD4+CD8+ thymocytes. Thus the same transgenic TCR-expressing T cells may be tolerized at different stages of their maturation and at different locations in the thymus depending on the antigen involved.
TL;DR: This review provides an overview of the current understanding of the role of immune mechanisms in atherosclerosis and suggests that immune modulation as well as immunization can reduce the progression of the disease.
Abstract: Atherosclerosis is an inflammatory disease. Its lesions are filled with immune cells that can orchestrate and effect inflammatory responses. In fact, the first lesions of atherosclerosis consist of macrophages and T cells. Unstable plaques are particularly rich in activated immune cells, suggesting that they may initiate plaque activation. We have seen a rapid increase in the understanding of the mechanisms that govern the recruitment, differentiation, and activation of immune cells in atherosclerosis. Experimental research has identified several candidate antigens, and there are encouraging data suggesting that immune modulation as well as immunization can reduce the progression of the disease. This review provides an overview of our current understanding of the role of immune mechanisms in atherosclerosis.
TL;DR: No difference in preoperative or postoperative prostate specific antigen levels, cancer volume, seminal vesicle invasion or incidence of pelvic lymph node metastasis was seen, providing the first quantitative evidence that small amounts of capsular penetration may not be of biological or prognostic significance.
TL;DR: Identity between the receptor for the major group of rhinoviruses and ICAM-1 is demonstrated, suggesting that the host immune response to rh inovirus may facilitate spread to uninfected cells.
TL;DR: The analysis of specific clones indicates that both p2 and p30 are very promiscuous in their capacity to bind to class II.
Abstract: To understand the effect of human MHC class II polymorphism on antigen recognition, we analyzed the memory T cell response to three tetanus toxin epitopes defined by three short synthetic peptides (p2, p4 and p30). We found that p2 and p30 are universally immunogenic, since they are recognized by all primed donors, irrespective of their MHC haplotypes. The analysis of specific clones indicates that both peptides are very promiscuous in their capacity to bind to class II. p30 can be recognized in association with DRw11(5), 7, 9 and with DPw2 and DPw4, while p2 can be recognized in association with DR1, DRw15(2), DRw18 (3), DR4Dw4, DRw11(5), DRw13(w6), DR7, DRw8, DR9, DRw52a and DRw52b. On the contrary, the third peptide, p4, can be recognized by only half of the donors in association with only DRw52a and DRw52c. Analysis of truncated peptides shows that p30 contains three distinct epitopes, each recognized in association with different class II molecules. Therefore, the restriction specificity is already set at the level of the peptide-MHC complex and, in all cases, T cells discriminate p30 bound to different class II molecules. On the contrary, p2 contains only one epitope, which is recognized in association with all DR molecules. In this case we found two different restriction patterns. Some clones are monogamous, since they recognize the peptide in association with one DR allele, while others are promiscuous, since they recognize by peptide in association with several different DR molecules. Thus, in this case, the restriction specificity is also set at the level of the T cell receptor. We suggest that both the promiscuous binding of peptides and the promiscuous recognition by T cells are dependent on the particular structure of the DR molecules, having a monomorphic alpha chain associated with a polymorphic beta chain.
TL;DR: The ability to purify these two populations independently shows that the LTC and clonogenic assays identify distinct, although not necessarily nonoverlapping cell types in human marrow.
TL;DR: The leukocyte-common antigen (L-CA) family is a group of high molecular weight glycoproteins uniquely expressed on the surface of all leukocytes and their hemopoietic progenitors and is a major cell surface component of lymphocytes and carries much of the carbohydrate of these cells.
Abstract: The leukocyte-common antigen (L-CA) family is a group of high molecular weight glycoproteins uniquely expressed on the surface of all leukocytes and their hemopoietic progenitors ( 114). Members of this family differ by both protein sequence and carbohydrate structures and are expressed by leukocyte populations in specific patterns ( 15-27). An example of the differential expression is shown for the rat L-CA family in Figure 1 ( 19). Thymocytes express the lowest apparent molecular weight form of 1 80 kd; B lymphocytes express the highest form, 220 kd; and T lymphocytes express multiple forms. Differences also exist between T-cell subsets (Figure 1 C); CD8 T cells (Te/s) express the higher molecular weight forms more abundantly than do CD4 T cells (T H) ' The cell-type-specific patterns of expression are conserved throughout mammalian evolution ( 1, 2, 91 1, 19, 28), and there appear to be similar patterns of expression in chicken lymphocytes (29). L-CA is referred to in the literature by different names, including T200 (30), B220 for the B cell form ( 1 2) , the mouse allotypic marker Ly-5 ( 3 1 ) and more recently CD45 (32). L-CA is the most accurate descriptive name and is used for the purpose of this review. The L-CA family is a major cell surface component of lymphocytes and carries much of the carbohydrate of these cells. It has been estimated that 10% of the lymphocyte surface is occupied by one or more L-CA members (33). Because of this abundance, L-CA was easily detected on SDS-poly acrylamide gels of lymphocyte membranes (36-39) (Figure lA). It was also initially characterized as the major specificity of antilymphocyte sera (34) and as an allotypic marker (31 , 35). The primary protein structure has been determined from the analysis of cDNA clones, and this information,
TL;DR: High level of infection with HIV-1 may be the primary cause for the progressive decline in number and function of CD4+ T cells in patients with AIDS.
Abstract: Human immunodeficiency virus type 1 (HIV-1) selectively infects cells expressing the CD4 molecule, resulting in substantial quantitative and qualitative defects in CD4+ T lymphocyte function in patients with acquired immunodeficiency syndrome (AIDS). However, only a very small number of cells in the peripheral blood of HIV-1-infected individuals are expressing virus at any given time. Previous studies have demonstrated that in vitro infection of CD4+ T cells with HIV-1 results in downregulation of CD4 expression such that CD4 protein is no longer detectable on the surface of the infected cells. In the present study, highly purified subpopulations of peripheral blood mononuclear cells (PBMCs) from AIDS patients were obtained and purified by fluorescence-automated cell sorting. They were examined with the methodologies of virus isolation by limiting dilution analysis, in situ hybridization, immunofluorescence, and gene amplification. Within PBMCs, HIV-1 was expressed in vivo predominantly in the T cell subpopulation which, in contrast to the in vitro observations, continued to express CD4. The precursor frequency of these HIV-1-expressing cells was about 1/1000 CD4+ T cells. The CD4+ T cell population contained HIV-1 DNA in all HIV-1-infected individuals studied and the frequency in AIDS patients was at least 1/100 cells. This high level of infection may be the primary cause for the progressive decline in number and function of CD4+ T cells in patients with AIDS.
TL;DR: The specificity of these toxins for V beta s puts them in the recently described class of superantigens and may account for the differential sensitivity of different individuals to the toxic effects of these proteins.
Abstract: The staphylococcal toxins are responsible for a number of diseases in man and other animals. Many of them have also long been known to be powerful T cell stimulants. They do not, however, stimulate all T cells. On the contrary, each toxin reacts with human T cells bearing particular V beta sequences as part of their receptors for major histocompatibility complex protein-associated antigen. The specificity of these toxins for V beta s puts them in the recently described class of superantigens and may account for the differential sensitivity of different individuals to the toxic effects of these proteins.
Journal Article•
TL;DR: The properties and uses of a monoclonal antibody, H57-597, produced from hamsters, which reacts with surface receptors on all alpha beta TCR-bearing cells and does not react with receptors on gamma delta+ T cells.
Abstract: Research on the specificities, functions, and maturation of T cells would be greatly aided by a collection of monoclonal antibodies which distinguishes different types of TCR. With this end in mind hamsters were immunized and tested for production of pan-reactive anti-mouse alpha beta TCR antibodies. In this report we describe the properties and uses of a mAb, H57-597, produced from one of these animals. The mAb reacts with surface receptors on all alpha beta TCR-bearing cells and does not react with receptors on gamma delta+ T cells. In an immobilized form, this antibody can directly activate T cells bearing alpha beta TCR. It can be used in immunoprecipitation reactions to precipitate receptor from the appropriate cell types. In combination with anti-CD3, the antibody can be used in cytofluorographic analyses to measure numbers of CD3+, alpha beta+, and CD3+, gamma delta+ cells in the thymus and periphery.
TL;DR: Comparison with the recently identified sequence of theMel-14 antigen shows that CDw44 and Mel-14 are unrelated.
TL;DR: This work has produced TCR-transgenic mice expressing a receptor specific for a fragment of pigeon cytochrome c and the Ek (class II MHC) molecule, demonstrating that the MHC specificity of the TCR determines the phenotype of T cells during selection in the thymus.
Abstract: T lymphocytes are predisposed to recognition of foreign protein fragments bound to cell-surface molecules encoded by the major histocompatibility complex (MHC). There is now compelling evidence that this specificity is a consequence of a selection process operating on developing T lymphocytes in the thymus. As a result of this positive selection, thymocytes that express antigen receptors with a threshold affinity for self MHC-encoded glycoproteins preferentially emigrate from the thymus and seed peripheral lymphoid organs. The specificity for both foreign antigen and MHC molecules is imparted by the alpha and beta chains of the T-cell antigen receptor (TCR). Two other T-cell surface proteins, CD4 and CD8, which bind non-polymorphic regions of class II and class I MHC molecules respectively, are also involved in these recognition events and play an integral role in thymic selection. In order to elucidate the developmental pathways of class II MHC-restricted T cells in relation to these essential accessory molecules, we have produced TCR-transgenic mice expressing a receptor specific for a fragment of pigeon cytochrome c and the Ek (class II MHC) molecule. The transgenic TCR is expressed on virtually all T cells in mice expressing Ek. The thymuses of these mice contain an abnormally high percentage of mature CD4+CD8- cells. In addition, the peripheral T-cell population is almost exclusively CD4+, demonstrating that the MHC specificity of the TCR determines the phenotype of T cells during selection in the thymus.
TL;DR: The sequence of CD59 antigen is unlike that of other complement components or regulatory proteins, but shows 26% identity with that of the murine LY- 6 antigen, and is likely to be absent from the surface of affected erythrocytes in the disease paroxysmal nocturnal hemoglobinuria.
Abstract: A novel cell surface antigen has been identified on a wide range of lymphoid cells and erythrocytes. A mAb YTH 53.1 (CD59) against this antigen enhanced the lysis of human red cells and lymphocytes by homologous complement. Studies of reactive lysis using different species of C56, and of whole serum used as a source of C7-9, indicated that the inhibitory activity of the CD59 antigen is directed towards the homologous membrane attack complex. CD59 antigen was purified from human urine and erythrocyte stroma by affinity chromatography using the mAb YTH 53.1 immobilized on Sepharose, and, following transient expression of a human T cell cDNA library in COS cells, the corresponding cDNA also identified using the antibody. It was found that the CD59 antigen is a small protein (approximately 20 kD as judged by SDS-PAGE, 11.5 kD predicted from the isolated cDNA) sometimes associated with larger components (45 and 80 kD) in urine. The sequence of CD59 antigen is unlike that of other complement components or regulatory proteins, but shows 26% identity with that of the murine LY-6 antigen. CD59 antigen was released from the surface of transfected COS cells by phosphatidylinositol-specific phospholipase C, demonstrating that it is attached to the cell membrane by means of a glycolipid anchor; it is therefore likely to be absent from the surface of affected erythrocytes in the disease paroxysmal nocturnal hemoglobinuria.
Journal Article•
TL;DR: Two distinct calcium-sensitive cell- cell adhesion molecules were identified in human epithelial tissues and carcinomas using two monoclonal antibodies raised against vulvar epidermoid carcinoma A-431 and human mammary carcinoma MCF-7 and selected on the basis of their activities to disrupt cell-cell adhesion.
Abstract: Two distinct calcium-sensitive cell-cell adhesion molecules were identified in human epithelial tissues and carcinomas using two monoclonal antibodies raised against vulvar epidermoid carcinoma A-431 and human mammary carcinoma MCF-7 and selected on the basis of their activities to disrupt cell-cell adhesion. In immunoblot analysis, these antibodies, designated NCC-CAD-299 and HECD-1, detected main bands of Mr 118,000 and 124,000, respectively. Purified tryptic fragments of the antigen recognized by NCC-CAD-299 showed cross-reactivity with a rabbit antiserum against mouse P-cadherin, indicating that this molecule was the human homologue of P-cadherin. On the other hand, the antigen recognized by HECD-1 showed essentially the same tissue distribution pattern as E-cadherin in the mouse, suggesting that this molecule is the human homologue of E-cadherin. Availability of these monoclonal antibodies to human P- and E-cadherin allowed us to examine their distributions in human tissues immunohistochemically. Both antigens were detected in epithelial tissues, but they showed distributions that were distinct from each other. The antigen recognized by HECD-1 was expressed in almost all epithelial tissues, while distribution of the other one recognized by NCC-CAD-299 was restricted to the basal or lower layers of stratified epithelia in which both antigens were coexpressed. Moreover, immunohistochemical examination of 44 lung carcinomas showed that both molecules were coexpressed in all of them, and suggested that expression of P-cadherin was closely related to the differentiation of carcinoma cells.
Journal Article•
TL;DR: It is demonstrated that the B7 gene encodes a unique molecule belonging to the Ig superfamily and that B7 expression is limited to normal activated B cells and noncirculating B cell malignancies.
Abstract: The human B cell restricted activation antigen B7 identifies an in vivo primed subpopulation of B cells that demonstrate an accelerated response to triggers of B cell activation and proliferation. The cDNA encoding B7 was molecularly cloned by cDNA expression. The identity of the B7 cDNA was confirmed by indirect immunofluorescence and immunoprecipitation of a 44/54-kDa protein from B7 transfected COS cells. The sequence of the B7 polypeptide predicts a type I membrane protein of 262 amino acids with eight potential N-linked glycosylation sites in the extracellular region and a short, highly positively charged cytoplasmic tail. The extracellular region is homologous to the Ig gene superfamily and consists of two contiguous Ig-like domains. The first Ig domain has the characteristics of a variable domain and the second that of a constant region domain. B7 mRNA was detected only on anti-Ig activated B lymphocytes and not in other hematopoietic cells. After in vitro activation of B cells with anti-Ig, B7 mRNA was maximally expressed between 4 and 12 h with four RNA transcripts of 1.7, 2.9, 4.2, and 10 kb. The 2.9-kb mRNA predominated in in vitro-activated B cells whereas the 1.7-kb mRNA was most abundant in tumor cells of B cell origin. B7 expression was confined to several histologically defined subgroups of B cell malignancies. The majority of non-Hodgkin's lymphomas were B7+ whereas the B cell leukemias and circulating non-Hodgkin's lymphomas were generally negative. These results demonstrate that the B7 gene encodes a unique molecule belonging to the Ig superfamily and that B7 expression is limited to normal activated B cells and noncirculating B cell malignancies.
TL;DR: This is the first report demonstrating the use of a synthetic T CR V-region peptide to induce specific regulatory immunity and has important implications for the regulation of human disease characterized by common TCR V-gene usage.
Abstract: T CELLS expressing the αβ T-cell receptor (TCR) for antigen can elicit anti-idiotypic antibodies specific for the TCR that regulate T-cell function1–4. Defined sequences of the TCR, however, have not been used to elicit specific antibodies and the role of cellular immunity directed against TCR determinants has not been studied. We immunized Lewis rats with a synthetic peptide representing a hypervariable region of the TCR β8 molecule. Subsequent induction of experimental autoimmune encephalomyelitis, a paralytic disease of the central nervous system mediated primarily by Vβ8+ T cells specific for myelin basic protein5,6 was prevented. T cells specific for the TCR Vβ8 peptide conferred passive protection against the disease to naive rats, apparently by shifting the predominant T-cell response away from the major encephalitogenic epitope of basic protein. This is the first report demonstrating the use of a synthetic TCR V-region peptide to induce specific regulatory immunity and has important implications for the regulation of human disease characterized by common TCR V-gene usage.
TL;DR: It is reported here that in contrast to the normal low frequency of γδ-bearing cells in lymphoid tissues, peripheral blood, or normal skin, the frequency is increased five to eightfold in particular granulomatous reactions of leprosy.
Abstract: THE majority of T cells bear the T-cell receptor (TCR) αβ complex which recognizes foreign antigen peptides only in the context of self major histocompatibility complex (MHC) molecules1. Such T cells function in a variety of effector roles and secrete cytokines that mediate the activation and differentiation of other cells in the immune system. Recently, a small subpopulation T cells was found to bear a distinct TCR composed of γ and δ subunits2. In man, TCR γδ+ cells are distributed as ~5 per cent of the CD3+ cells in all organized lymphoid organs as well as in the skin- and gut-associated lymphoid tissues3. Although a limited number of germ-line genes encode the TCR γ and δ subunits, extensive junctional variation particularly in the δ gene, results in unprecedented diversity for this receptor4,5 The nature of the specificity and immunological functions of these T cells remains enigmatic. We report here that in contrast to the normal low frequency of γδ-bearing cells in lymphoid tissues, peripheral blood, or normal skin, the frequency is increased five to eightfold in particular granulomatous reactions of leprosy. TCR γδ+lymphocyte lines from these leprosy skin lesions proliferate in vitro specifically to mycobacterial antigens. This reactivity to foreign antigens appears to require presentation in the context of self-molecules. Moreover, culture supernatants from activated γδT lymphocytes induce adhesion and aggregation of bone-marrow monocytes in the presence of granulocyte monocyte-colony stimulating factor (CSF), suggesting that products of γδ-bearing T cells may play a role in the immune response, possibly by stimulating granuloma formation.