Peter C. L. Beverley

Bio: Peter C. L. Beverley is an academic researcher from University College Hospital. The author has contributed to research in topics: Antigen & T cell. The author has an hindex of 8, co-authored 12 publications receiving 4366 citations.

The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus

Abstract: Acquired immune deficiency syndrome (AIDS) is characterized by opportunistic infections and by 'opportunistic neoplasms' (for example, Kaposi's sarcoma). Persistent generalized lymphadenopathy (PGL) is epidemiologically associated with AIDS, especially in male homosexuals. A subset of T lymphocytes positive for the CD4 antigen (also termed T4 antigen), is depleted in AIDS and PGL patients. A retrovirus found in T-cell cultures from these patients is strongly implicated in the aetiology of AIDS because of the high frequency of isolation and the prevalence of specific antibodies in the patients. Here we have detected cell-surface receptors for the AIDS retrovirus (human T-cell leukaemia virus-III (HTLV-III) and lymphadenopathy-associated virus-1 (LAV-1) isolates) by testing the susceptibility of cells to infection with pseudotypes of vesicular stomatitis virus bearing retroviral envelope antigens, and by the formation of multinucleated syncytia on mixing virus-producing cells with receptor-bearing cells. Receptors were present only on cells expressing CD4 antigen; among 155 monoclonal antibodies tested, each of the 14 anti-CD4 antibodies inhibited formation of syncytia and blocked pseudotypes. Productive infection of CD4+ cells with HTLV-III or LAV-1 markedly reduced cell-surface expression of CD4. In contrast, receptors for HTLV-I and HTLV-II were not restricted to CD4+ cells, were not blocked by anti-CD4 antibodies; cells productively infected with HTLV-I and HTLV-II expressed surface CD4. Hence, we conclude that the CD4 antigen is an essential and specific component of the receptor for the causative agent of AIDS.

Distinctive functional characteristics of human „T”︁ lymphocytes defined by E rosetting or a monoclonal anti‐T cell antibody

Abstract: The properties of human lymphocyte fractions isolated either by sheep red cell(E) rosetting or by fluorescence-activated cell sorting after staining with UCHT1 monoclonal anti-T cell antibody have been compared. Two populations of E+ cells with very different phenotype and function have been identified. E+/UCHT1+ cells respond well to the T cell mitogens phytohemagglutinin and concanavalin A and provide help for an in vitro specific antibody response. They can also suppress the antibody response of allegeneic peripheral blood mononuclear cells. In contrast, the E+/UCHT1- population, which has no other markers characteristic of T cells, fails to respond to mitogens or to provide help or suppression for an antibody response. These cells, however, are highly active natural killers. They possess Fc gamma receptors and have a characteristic staining pattern of nonspecific esterase enzyme activity. It is concluded that not all cells capable of forming E rosettes are thymus-processed cells and that this heterogeneity can be revealed by staining with the monoclonal anti-T cell reagent UCHT1.

Isolation of human haematopoietic progenitor cells using monoclonal antibodies.

Abstract: Studies of the differentiation of human haematopoietic cells have been greatly advanced by the use of in vitro cloning techniques to enumerate the myeloid and erythroid progenitor cells which form colonies in semi-solid medium1–3. The granulocytic/monocytic colony-forming cells (CFU-GM) and erythroid burst-forming cells (BFU-E) are thought to be mononuclear cells, similar in size to medium size lymphocytes, but their ontogenetic relationship to other progenitor cells and the putative pluripotential stem cell remains obscure4,5. This is partly because elucidation of parent-progeny relationships requires the isolation of precursor cells before they acquire mature phenotypic characters. Physical methods have failed to separate CFU-GM cleanly from other cells because of their heterogeneity, and immunologically specific markers for human progenitor cells have not been reported6,7. We report here that a fraction containing all the granulocytic/monocytic and erythroid progenitor cells, as well as cells which may be lymphoid progenitors, can be isolated from bone marrow using a combination of monoclonal antibodies.

T cell activation by anti-T3 antibodies: comparison of IgG1 and IgG2b switch variants and direct evidence for accessory function of macrophage Fc receptors

Abstract: The human T3 antigen is closely associated with the T cell receptor. Some anti-T3 antibodies cause T cell proliferation in the presence of monocytes which have Fc receptors (FcR) that bind particular antibody subclasses. Such an interaction is thought to determine whether or not an anti-T3 antibody is mitogenic. We examined the mitogenicity of an IgG1 antibody, UCHT1, and an IgG2b switch variant of identical specificity, UCHT1B. With autologous monocytes, 76% of individuals responded to UCHT1 and 9% to UCHT1B, falling into three patterns of responsiveness. Both antibodies in the absence of monocytes induced responsiveness to recombinant interleukin 2, even for UCHT1B nonresponder T cells. The proliferation induced by UCHT1B, however, was always less than that induced by UCHT1. These findings demonstrate the critical role played by the Fc region for mitogenesis, and suggest a possible role for the hinge region. We then obtained direct evidence that mitogenicity can be mediated exclusively via FcR. Mouse macrophages have distinct FcR: FcRI binds IgG2a but FcRII binds IgG1 and IgG2b and its function can be inhibited by the specific antibody 2.4G2. Because UCHT1 and UCHT1B were of the correct subclass to interact with FcRII we examined the accessory function of mouse peritoneal macrophages. Without exception, human T cells now responded to both antibodies. Proliferation was drastically inhibited by 2.4G2 but not by an irrelevant anti-macrophage antibody, F4/80, nor by an anti-human neutrophil FcR antibody, 3G8. Furthermore, 2.4G2 did not inhibit the accessory function of mouse macrophages for OKT3, an IgG2a antibody that presumably interacts with FcRI, and did not inhibit the function of human monocytes for UCHT1 and UCHT1B. Mouse B cells, in contrast to macrophages, have an FcR which binds all three subclasses, but which can be inhibited by 2.4G2. B cells, however, were not accessory cells for mitogenesis with UCHT1, UCHT1B or OKT3. These findings are discussed in relation to other requirements for T cell activation by anti-T3 antibodies.

Phenotype of human T helper and suppressor cells in an in vitro specific antibody response.

Abstract: Monoclonal anti-human T cell antibodies have been used to identify cells which provide help for an in vitro specific antibody response to influenza virus and also those which suppress the response of allogeneic peripheral blood mononuclear cells. The helper cells carry antigens defined by the Leu 3a and OKT4-antisera, whereas the suppressor cells are predominantly Leu 2a- and OKT8-positive. Help and suppression in this secondary in vitro antibody response are therefore provided by antigenically distinct T cell subsets.

Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes).

Abstract: A murine monoclonal antibody specific for calf intestinal alkaline phosphatase has been prepared and used in an unlabeled antibody bridge technique for labeling monoclonal antibodies. This procedure--the alkaline phosphatase monoclonal anti-alkaline phosphatase (APAAP) method--gives excellent immunocytochemical labeling of tissue sections and cell smears, comparable in clarity and intensity to that achieved with immunoperoxidase labeling. If the enzyme label is developed with a naphthol salt as a coupling agent and Fast Red or hexazotized new fuchsin as a capture agent, a vivid red reaction product is obtained which is very easily detected by the human eye. For this reason the APAAP technique was found particularly suitable for labeling cell smears (for both cytoplasmic and surface-membrane antigens) and for detecting low numbers of antigen-bearing cells in a specimen (e.g., carcinoma cells in a malignant effusion). It was found possible to enhance the intensity of the APAAP labeling reaction substantially by repeating the second and third incubation steps (i.e., the unlabelled "bridge" antibody and APAAP complexes). The APAAP technique was superior to immunoperoxidase labeling for staining tissues rich in endogenous peroxidase, and could be used in conjunction with immunoperoxidase methods for double immunoenzymatic staining. The method was also applicable to the detection of antigenic molecules following their electrophoretic transfer from SDS-polyacrylamide gels to nitrocellulose sheets ("immunoblotting").

Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone.

Abstract: We constructed an infectious molecular clone of acquired immunodeficiency syndrome-associated retrovirus. Upon transfection, this clone directed the production of infectious virus particles in a wide variety of cells in addition to human T4 cells. The progeny, infectious virions, were synthesized in mouse, mink, monkey, and several human non-T cell lines, indicating the absence of any intracellular obstacle to viral RNA or protein production or assembly. During the course of these studies, a human colon carcinoma cell line, exquisitely sensitive to DNA transfection, was identified.

T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV

Abstract: Many viruses, including retroviruses, are characterized by their specific cell tropism. Lymphadenopathy-associated virus (LAV) is a human lymphotropic retrovirus isolated from patients with acquired immune deficiency syndrome (AIDS) or related syndromes, that displays selective tropism for a subset of T lymphocytes defined by the expression of a surface glycoprotein of relative molecular mass 62,000 (62K) termed T4 (refs 6-8). This glycoprotein delineates a subset of T lymphocytes with mainly helper/inducer functions, while T lymphocytes of the reciprocal subset express a glycoprotein termed T8, have mainly cytotoxic/suppressor activities, and are unable to replicate LAV. Such a tropism may be controlled at the genomic level by regulatory sequences, as described for the human T-cell leukaemia viruses HTLV-I and -II (refs 2, 3). Alternatively or concomitantly, productive cell infection may be controlled at the membrane level, requiring the interaction of a specific cellular receptor with the virus envelope, as demonstrated recently for Epstein-Barr virus (EBV). Therefore, we have investigated whether the T4 molecule itself is related to the receptor for LAV. We report here that preincubation of T4+ lymphocytes with three individual monoclonal antibodies directed at the T4 glycoprotein blocked cell infection by LAV. This blocking effect was specific, as other monoclonal antibodies--such as antibody to histocompatibility locus antigen (HLA) class II or anti-T-cell natural killer (TNK) target--directed at other surface structures strongly expressed on activated cultured T4+ cells, did not prevent LAV infection. Direct virus neutralization by monoclonal antibodies was also ruled out. These results strongly support the view that a surface molecule directly involved in cellular functions acts as, or is related to, the receptor for a human retrovirus.

Complete nucleotide sequence of the AIDS virus, HTLV-III

Abstract: The complete nucleotide sequence of two human T-cell leukaemia type III (HTLV-III) proviral DNAs each have four long open reading frames, the first two corresponding to the gag and pol genes. The fourth open reading frame encodes two functional polypeptides, a large precursor of the major envelope glycoprotein and a smaller protein derived from the 3′-terminus long open reading frame analogous to the long open reading frame (lor) product of HTLV-I and -II.