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Showing papers on "Cytotoxic T cell published in 1987"


Journal ArticleDOI
24 Apr 1987-Cell
TL;DR: The results show that in normal animals tolerance to self-MHC is due to clonal elimination rather than suppression, and indicate that tolerance induction may occur in the thymus at the time immature thymocytes are selected to move into the mature thymocyte pool.

2,187 citations


Journal Article
TL;DR: Evidence is presented here to show that one type of helper T cell clone (TH1) causes delayed-type hypersensitivity (DTH) when injected with the appropriate antigen into the footpads of naive mice.
Abstract: We have previously shown that at least two types of Lyt-1+, Lyt-2-, L3T4+ helper T cell clones can be distinguished in vitro by different patterns of lymphokine secretion and by different forms of B cell help. Evidence is presented here to show that one type of helper T cell clone (TH1) causes delayed-type hypersensitivity (DTH) when injected with the appropriate antigen into the footpads of naive mice. The antigen-specific, major histocompatability complex (MHC)-restricted footpad swelling reaction peaked at approximately 24 hr. Footpad swelling was induced by all TH1 clones tested so far, including clones specific for soluble, particulate, or allogeneic antigens. In contrast, local transfer of TH2 cells and antigen did not produce a DTH reaction, even when supplemented with syngeneic spleen accessory cells. Similarly, local transfer of an alloreactive cytotoxic T lymphocyte clone into appropriate recipients did not produce DTH. The requirements for the DTH reaction induced by TH1 cells were investigated further by using TH1 clones with dual specificity for both foreign antigens and M1s antigens. Although these clones responded in vitro to either antigen + syngeneic presenting cells, or M1s disparate spleen cells, they responded in vivo only to antigen + MHC and did not cause footpad swelling in an M1s-disparate mouse in the absence of antigen. Moreover, in vitro preactivation of TH1 or TH2 cells with the lectin concanavalin A was insufficient to induce DTH reactions upon subsequent injection into footpads. From these results, we conclude that the lack of DTH given by TH2 clones in vivo could be due to the inability of the TH2 cells to produce the correct mediators of DTH, or to a lack of stimulation of TH2 clones in the footpad environment.

1,201 citations


Journal ArticleDOI
TL;DR: The results suggest that nonmitogenic T cell recognition of antigen/MHC on ECDI-modified APCs results in the functional inactivation of T cell clones.
Abstract: We investigated the antigen specificity and presentation requirements for inactivation of T lymphocytes in vitro and in vivo. In vitro studies revealed that splenocytes treated with the crosslinker 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI) and soluble antigen fragments failed to stimulate significant proliferation by normal pigeon cytochrome c-specific T cell clones, suggesting that the chemical treatment inactivated full antigen presentation function. However, T cell clones exposed to ECDI-treated splenocytes and antigen in vitro were rendered unresponsive for at least 8 d to subsequent antigen stimulation with normal presenting cells. As predicted by the in vitro results, specific T cell unresponsiveness was also induced in vivo in B10.A mice injected intravenously with B10.A, but not B10.A(4R), splenocytes coupled with pigeon cytochrome c via ECDI. The antigen and MHC specificity of the induction of this T cell unresponsiveness in vitro and in vivo was identical to that required for T cell activation. These results suggest that nonmitogenic T cell recognition of antigen/MHC on ECDI-modified APCs results in the functional inactivation of T cell clones.

1,199 citations


Journal ArticleDOI
TL;DR: FFK-506, a novel immunosuppressant, has been isolated from the fermentation broth of Streptomyces tsukubaenis No. 9993 as colorless prism and the molecular formula was determined as C44H69NO12.H2O.
Abstract: The immuno-pharmacological profile of a novel immunosuppressive agent, FK-506 produced by a streptomycete, is presented here. We proceeded to test the effect of the agent on various in vitro immune systems. It showed that mixed lymphocyte reaction, cytotoxic T cell generation, the production of T cell-derived soluble mediators such as interleukin 2 (IL-2), interleukin 3 and gamma-interferon and the expression of the IL-2 receptor were suppressed by this agent. The IC50 values of FK-506 and ciclosporin (CS) in all tests were approximately 0.1nM and 10nM, respectively. Therefore, the novel agent, FK-506 suppressed in vitro immune systems at about hundred times lower concentration than CS.

1,193 citations


Journal ArticleDOI
TL;DR: Evidence for this subdivision obtained with T-cell clones grown in vitro is reviewed and the implications of differences in function and lymphokine synthesis between the two types of cloned helper T cell are discussed.

833 citations


Journal ArticleDOI
01 Nov 1987-Nature
TL;DR: The CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule.
Abstract: The CD4 glycoprotein is expressed on T-helper and cytotoxic lymphocytes which are restricted to class II major histocompatibility complex (MHC) antigens on target cells1–5. Antibody inhibition studies imply that CD4 acts to increase the avidity of effector-target cell interactions6–8. These observations have led to the speculation that CD4 binds to a monomorphic class II antigen determinant, thereby augmenting low affinity T-cell receptorantigen interactions9–11. However, no direct evidence has been presented indicating that CD4 and class II molecules interact. To address this issue, we have used a vector derived from simian virus 40 (SV40)12 to express a complementary DNA (cDNA) encoding the human CD4 glycoprotein13. When CV1 cells expressing large amounts of the CD4 protein at the cell surface are incubated with human B cells bearing MHC-encoded class II molecules, they are bound tightly to the infected monolayer, whereas mutant B cells which lack class II molecules fail to bind. Furthermore, the binding reaction is specifically inhibited by anti-class II and anti-CD4 antibodies. Thus, the CD4 protein, even in the absence of T-cell receptor-antigen interactions, can interact directly with class II antigens to function as a cell surface adhesion molecule.

825 citations


Journal ArticleDOI
23 Jul 1987-Nature
TL;DR: This demonstration of a cytotoxic T-cell immune response to HIV in infected individuals should prove useful in investigating the immunopathogenesis of HIV infection further and in evaluating AIDS vaccine strategies.
Abstract: Virus-specific cytotoxic T lymphocytes (CTL) which kill virus-infected cells are thought to be a major host defence against viral infections. Here we report the existence of human immunodeficiency virus (HIV)-specific CTL in persons infected with this virus, the aetiological agent of AIDS (acquired immunodeficiency syndrome). Recombinant HIV-vaccinia viruses were used to express HIV antigens in B-cell lines established from subjects seropositive for HIV and seronegative controls. Circulating lymphocytes capable of killing HIV env-expressing autologous B cells were detected in eight of eight seropositive subjects; in addition, at least three seropositive subjects demonstrated gag-specific cytotoxic responses. No HIV-specific cytotoxicity was observed in seronegative subjects. Selective inhibition of the env-specific cytotoxicity by a CD3-specific monoclonal antibody indicates that the effectors are T cells. This demonstration of a cytotoxic T-cell immune response to HIV in infected individuals should prove useful in investigating the immunopathogenesis of HIV infection further and in evaluating AIDS vaccine strategies.

800 citations


Journal ArticleDOI
17 Dec 1987-Nature
TL;DR: Surgical immunity to sporozoite challenge requires the neutralization of sporozoites by antibodies and the inhibition of EEF development by γIFN with the participation of CD8+ cells, and transfer of both immune components resulted in significantly greater protection.
Abstract: This study was designed to test the hypothesis that T-cell effector mechanisms are required for protective immunity to malaria sporozoites. Administration of neutralizing monoclonal antibodies against gamma interferon (gamma IFN) to immune hosts, reversed sterile immunity to sporozoite challenge, by allowing the growth of exoerythrocytic forms (EEF) and thus the development of parasitaemia. Immune animals also developed infections when depleted in vivo of their suppressor/cytotoxic T cells expressing the CD8 antigen (CD8+) but not when depleted of helper T cells expressing CD4 antigen (CD4+), before sporozoite challenge. Passive transfer of immune immunoglobin alone, or adoptive transfer of immune T cells alone, conferred partial protection to naive recipients. Transfer of both immune components resulted in significantly greater protection. This transferred immunity was reversed by the in vivo neutralization of gamma IFN. Thus, sterile immunity to sporozoite challenge requires the neutralization of sporozoites by antibodies and the inhibition of EEF development by gamma IFN with the participation of CD8+ cells.

702 citations


Journal ArticleDOI
01 Jul 1987-Nature
TL;DR: The hypothesis that interactions between HIV-specific CTL and infected macrophages induce major inflammatory reactions in seropositive patients is proposed.
Abstract: Human immunodeficiency virus (HIV) is implicated in the development of AIDS (acquired immune deficiency syndrome). HIV infection leads to the generation of HIV-specific thymus-derived (T) lymphocytes in humans and apes. We describe an experimental system permitting the quantitative and systematic analysis of HIV-specific cytotoxic T lymphocytes (CTL). Functional, HIV-specific CTL are obtained by broncho-alveolar lavage (BAL) from the lungs of seropositive patients with lymphocytic alveolitis. These alveolar CTL: (1) recognize and kill HIV-infected alveolar macrophages in vitro under autologous, but not heterologous, conditions; (2) correspond to standard CTL as they express the CD3 and CD8 surface markers, but not the CD4 marker; and (3) are restricted by class I HLA transplantation antigens in their cytotoxic activities. We propose the hypothesis that interactions between HIV-specific CTL and infected macrophages induce major inflammatory reactions in seropositive patients.

538 citations


Journal ArticleDOI
20 Nov 1987-Science
TL;DR: 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.
Abstract: 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.

512 citations


Journal Article
TL;DR: Ex expression of Pgp-1 among peripheral T cells is an important differentiation marker for identifying antigen-stimulated memory T cells and a model consistent with all of these data proposes that mature thymocytes lacking surface P gp-1 upon emigration to the periphery acquire its expression at the time of primary antigenic stimulation.
Abstract: The Pgp-1 glycoprotein was identified on a minor (27%) subset of peripheral Lyt-2+ or L3T4+ T cells. In contrast, mature medullary-type thymocytes (Lyt-2+ L3T4-, Lyt-2- L3T4+) were nearly devoid of cells expressing detectable surface Pgp-1. The appearance of peripheral Pgp-1- T cells was found to be thymus dependent, as demonstrated by the diminished proportion of Pgp-1- T cells after thymectomy and their virtual absence in athymic nude mice. The subsequent acquisition of surface Pgp-1 was found to be a stable differentiation event occurring concomitantly with primary antigenic stimulation; selected Pgp-1- mature T cells from thymus or periphery acquired constitutive expression of Pgp-1 after stimulation in vitro with alloantigen or mitogens. These observations were extended by studies in vivo showing that immunization with various antigens augmented the percentage of Pgp-1+ spleen cells within the Lyt-2+ subset. Furthermore, the frequencies of antigen-specific CTLp, after immunization by any of three different antigens tested, were greatly enriched in the Pgp-1+ compared with the Pgp-1- subpopulations. Peritoneal exudate Lyt-2+ cells, after a localized allograft rejection, demonstrated a particularly prominent Pgp-1+ subpopulation (78%) that contained virtually all the allospecific cytolytic activity. A model consistent with all of these data proposes that mature thymocytes lacking surface Pgp-1 upon emigration to the periphery acquire its expression at the time of primary antigenic stimulation. Hence, expression of Pgp-1 among peripheral T cells is an important differentiation marker for identifying antigen-stimulated memory T cells.

Journal Article
TL;DR: It is demonstrated that the melanoma-bearing patient raises an immune response against autologous tumor and a method for the generation of human lymphocytes with antitumor reactivity that may be useful in the adoptive immunotherapy of tumors is presented.
Abstract: Tumor-infiltrating lymphocytes from six patients with metastatic malignant melanoma were expanded by culture in recombinant interleukin 2. Three of the preparations were highly cytotoxic against autologous fresh melanoma tumor cells, but not against autologous fresh normal cells or allogeneic fresh tumor targets. The other three were highly cytotoxic against autologous fresh melanoma tumor cells and also had a limited capacity to kill allogeneic fresh tumor targets. The tumor-associated specific killer cells could be expanded from threefold to 95,652-fold with maintenance of specific antitumor lysis. The expanded tumor-infiltrating cells were Leu-4+ T cells, and in five of six patients the majority were Leu-3+. These studies demonstrate that the melanoma-bearing patient raises an immune response against autologous tumor and presents a method for the generation of human lymphocytes with antitumor reactivity that may be useful in the adoptive immunotherapy of tumors.

Journal Article
TL;DR: Data indicate that TNF-alpha may regulate growth and functional activities of normal T cells and was effective as a co-stimulator of IL 2-dependent IFN-gamma production.
Abstract: The expression of specific tumor necrosis factor (TNF) membrane receptors and biological effects of recombinant TNF (rTNF)-alpha on normal human T lymphocytes were studied. Although resting T cells lacked specific binding capacity for rTNF-alpha, high affinity (Kd 70 pM) TNF receptors were de novo induced upon primary activation of T cells. Comparison of TNF receptor expression with that of high affinity interleukin 2 (IL-2) and interferon-gamma (IFN-gamma) receptors, respectively, revealed similarities to IL 2-receptor expression with respect to kinetics of induction. However, maximum expression of TNF receptors (approximately equal to 5000/cell at day 6) and subsequent decline occurred approximately 3 days after the peak of IL 2-receptor expression. In contrast, no change in the expression of IFN-gamma receptors (Kd 10 pM, 300 to 400 receptors/cell) was found in the course of T cell activation. On activated TNF receptor positive T cells, TNF-alpha exerted multiple stimulatory activities. Thus TNF increased the expression of HLA-DR antigens and high affinity IL 2 receptors. As a consequence, TNF-treated T cells showed an enhanced proliferative response to IL 2. Moreover, TNF-alpha was effective as a co-stimulator of IL 2-dependent IFN-gamma production. These data indicate that TNF-alpha may regulate growth and functional activities of normal T cells.

Journal ArticleDOI
TL;DR: Using freshly isolated Ia+ gut epithelial cells, it is demonstrated that these cells can function as accessory cells in an immune response and are capable of taking up the soluble antigen, tetanus toxoid, processing it, and presenting it to tetanus-primed T cells.
Abstract: Using freshly isolated Ia+ gut epithelial cells we have been able to demonstrate that these cells can function as accessory cells in an immune response. The cells can act as stimulators in both autologous and allogeneic MLRs. More importantly, these cells are capable of taking up the soluble antigen, tetanus toxoid, processing it, and presenting it to tetanus-primed T cells. These functions appear to relate to the presence of surface Ia in that a hetero-anti-Ia antibody can block these effects. Noteworthy is the finding that the subpopulation of T cells stimulated when epithelial cells are used as accessory cells is the T8+, 9.3-T cell. These cells function as potent antigen-nonspecific suppressor cells in both MLR, T cell antigen responses, and induction of B cell differentiation by PWM. These findings have significant implications in local gut immune responses and may help explain several poorly characterized phenomena of mucosal immunity.

Journal Article
TL;DR: Stimulation of rat astrocytes in vitro by calcium ionophore A23187 and/or lipopolysaccharide results in the generation of a cytotoxic factor that is functionally similar to the previously described macrophage-derived cytot toxic factor, tumor necrosis factor.
Abstract: Stimulation of rat astrocytes in vitro by calcium ionophore A23187 and/or lipopolysaccharide results in the generation of a cytotoxic factor that is functionally similar to the previously described macrophage-derived cytotoxic factor, tumor necrosis factor. Like the macrophage product, the astrocyte cytotoxic factor kills murine L 929 cell targets. In addition, it kills rat oligodendrocytes, the myelin-producing cells of the central nervous system. Human recombinant tumor necrosis factor also has cytotoxic activity directed against rat oligodendrocytes.

Journal ArticleDOI
26 Mar 1987-Nature
TL;DR: It is reported that purified CD2 binds to a cell-surface antigen known as lymphocyte function-associated anti-gen-3 (LFA-3) with high affinity, and can mediate adhesion of lymphoid cells via interaction with L FA-3, suggesting that CD2 can function in signalling as well as being an adhesion molecule.
Abstract: CD2 (known also as T11 (ref. 1), LFA-2 (ref. 2) and the erythrocyte rosette receptor (ref. 3)) is a functionally important T lymphocyte surface glycoprotein of relative molecular mass 50,000 to 58,0004 (Mr 50–58 K) which appears early in thymocyte ontogeny and is present on all mature T cells5. Monoclonal antibodies to CD2 inhibit cytotoxic T-lymphocyte (CTL)-mediated killing by binding to the T lymphocyte and blocking adhesion to the target cell2–4,6. Such antibodies also inhibit T helper cell responses including antigen-stimulated proliferation, interleukin-2 (IL-2) secretion, and IL-2 receptor expression2–4,7–9. Certain combinations of monoclonal antibodies to CD2 epitopes trigger proliferation of peripheral blood T lymphocytes1, cytotoxic effector function10 and expression of IL-2 receptors by thymocytes, resulting in thymocyte proliferation in the presence of exogenous IL-2 (ref. 11). These findings suggest that CD2 can function in signalling as well as being an adhesion molecule. To understand the role of CD2 in T-cell adhesion and activation, it is essential to define its natural ligand. Our previous observation that purified CD2 inhibits resetting of T lymphocytes with sheep erythrocytes and can be absorbed by sheep erythrocytes12 suggested it also might bind with detectable affinity to human cells. We now report that CD2 binds to a cell-surface antigen known as lymphocyte function-associated anti-gen-3 (LFA-3) with high affinity, and can mediate adhesion of lymphoid cells via interaction with LFA-3.

Journal ArticleDOI
30 Apr 1987-Nature
TL;DR: A peptide derived from the influenza matrix protein is described that is recognized by human CTL in association with the HLA-A2 molecule, which is similar to other peptide epitopes identified in the nucleoprotein.
Abstract: Both human and murine cytotoxic T cells (CTL) elicited in response to infection with influenza A viruses have been shown to be specific for internal viral proteins, such as the matrix and nucleoprotein1–3. Individual CTL epitopes have been identified in the nucleoprotein by successfully substituting short synthetic peptides for the intact virus in the preparation of target cells in cytotoxicity assays4. The defined peptide epitopes have each been recognized by CTL in association with individual class I major histocompatibility complex (MHC) proteins, H–2Db (ref. 4), H–2Kk (ref. 5), H–2Kd (Taylor, P. et al., unpublished data) and HLA-B37 (refs 4,6). A logical strategy to investigate the molecular details of the interaction between antigen and MHC class I proteins would be to define an epitope recognized by the MHC class I molecule HLA-A2. This is because the amino-acid sequence is known, several variants of A2 have been characterized and the protein has been purified and crystallized7–11. Here we describe a peptide derived from the influenza matrix protein that is recognized by human CTL in association with the HLA-A2 molecule.

Journal ArticleDOI
24 Apr 1987-Cell
TL;DR: A bias in the germ-line T cell receptor repertoire toward recognition of MHC proteins is suggested and it is indicated that the V beta portion of the receptor may form the most important contact points with MHC ligands.

Journal Article
TL;DR: Macrophage cytotoxicity against this cell but not against the TNF-resistant P815 mastocytoma, was completely inhibitable by a specific anti-TNF serum also in the absence of measurable secreted TNF.
Abstract: Different macrophage populations were investigated for their abilities to secrete tumor necrosis factor (TNF) and to lyse TNF-susceptible tumor cells. In this way we could demonstrate that TNF-secretion, although a feature of all activated macrophage populations, is no absolute requirement for the killing of the TNF-sensitive Wehi 164 target. Macrophage cytotoxicity against this cell but not against the TNF-resistant P815 mastocytoma, was completely inhibitable by a specific anti-TNF serum also in the absence of measurable secreted TNF. Moreover the TNF-dependent lysis of tumor cells could also be performed by activated macrophages that had been fixed with paraformaldehyde before the addition of the target cells. In the indirect radioimmunoassay, TNF could be demonstrated on the surface of fixed effector cells. Our results must be interpreted in terms of membrane-associated TNF as the lytic principle for TNF-susceptible tumor cells.

Journal ArticleDOI
TL;DR: It is shown that CR3 alone of the LFA-family is necessary for the recruitment of myelomonocytic cells to inflammatory stimuli such as thioglycollate broth and provides a novel approach to antiinflammatory therapy.
Abstract: Macrophage interactions with extracellular matrix and other cells are important in phagocytosis, inflammation, and immunity. To learn more about the surface molecules involved in adhesion we compared the binding of murine macrophages and polymorphonuclear leukocytes (PMN) with artificial substrate in vitro. A distinctive type of adhesion of thioglycollate-elicited peritoneal macrophages (TPM) to bacteriologic plastic (BP) was defined, which was pronase-sensitive, Mg2+-dependent, and required cytoskeletal stabilization. A rat mAb designated 5C6 was isolated because it inhibited TPM attachment to BP, as well as mediating detachment of TPM adherent to that substratum. In addition, it inhibited the attachment of PMN to tissue culture plastic. This antiadhesive property of 5C6 mAb required intact IgG; the F(ab')2 fragment was partially effective and Fab was ineffective. 5C6 recognized the type 3 complement receptor, inhibiting rosetting of EAC3bi to TPM and immunoprecipitating a heterodimer of 160 and 95 kD that comigrated with the M1/70 immunoprecipitate. 5C6 recognized a pronase-stable epitope distinct from that of M1/70. Other mAbs, including M1/70 (CR3) and 2.4G2 (FcR), failed to have any antiadhesive effect in vitro. The inhibitory activity of 5C6 in short-term adhesion assays correlated with its inhibition of recruitment of myelomonocytic cells to a thioglycollate-elicited peritoneal exudate in vivo, after intravenous injection of mAb. 5C6 IgG inhibited recruitment of myelomonocytic cells by 84 +/- 3% at 1 d compared with saline-injected controls. The F(ab')2 fragment and a class-matched control IgG had little effect. Recruitment of TPM at 4 d was also efficiently inhibited by 5C6 IgG. 5C6 IgG was not cytotoxic, had no effect on marrow egress, did not cause increased phagocytic clearance of circulating neutrophils, and had no adverse effect on chemotaxis in vitro. We show that CR3 alone of the LFA-family is necessary for the recruitment of myelomonocytic cells to inflammatory stimuli such as thioglycollate broth. This strategy may be of general use in isolating reagents that inhibit the adhesive function of CR3 and provides a novel approach to antiinflammatory therapy.

Journal ArticleDOI
19 Feb 1987-Nature
TL;DR: The T-cell receptor (TCR) γ polypeptide is expressed associated with CD3(T3) on the surface of normal human peripheral blood lymphocytes and thus may play an important role in host immune defence.
Abstract: The T-cell receptor (TCR) γ polypeptide is expressed associated with CD3(T3) on the surface of normal human peripheral blood lymphocytes. These cells function as non-MHC-restricted cytotoxic T lymphocytes (CTL) and thus may play an important role in host immune defence. The TCR γ polypeptide occurs as a dimer in at least two molecular forms based on the absence or presence of disulphide linkage. These forms use TCR γ polypeptides with strikingly different peptide backbone sizes.

Journal ArticleDOI
TL;DR: It appears that production of the bone-resorbing cytokine lymphotoxin is related to osteoclastic bone destruction and hypercalcemia in patients with myeloma.
Abstract: Myeloma cells destroy bone by producing an osteoclast-stimulating factor that has chemical and biological characteristics similar to the bone-resorbing activity present in the supernatants of activated leukocyte cultures. Recently, a number of bone-resorbing leukocyte cytokines have been identified, including interleukin-1, lymphotoxin, and tumor necrosis factor. We have examined the products of human myeloma cells for the presence of these bone-resorbing cytokines. In a tumor cell line derived from a patient who had myeloma with osteolytic bone lesions and hypercalcemia, we found that the myeloma cells induced bone-resorbing activity and cytotoxic activity in vitro. Most of the bone-resorbing activity and all cytotoxic activity were suppressed by neutralizing antibodies to lymphotoxin. The myeloma cells expressed both lymphotoxin and tumor necrosis factor mRNA, but no tumor necrosis factor could be detected in the cell-culture medium. Interleukin-1 mRNA was not detected in the myeloma cells, and biologic activity of interleukin-1 was not measurable in the medium harvested from the cultured cells. The bone-resorbing activity induced by recombinant tumor necrosis factor and recombinant interleukin-1 was not affected by treatment with the lymphotoxin antibodies. When lymphotoxin was infused subcutaneously into normal mice (10 micrograms per day for three days), their plasma calcium levels increased. We also evaluated four established cell lines derived from three other patients with myeloma, and found a similar pattern of lymphotoxin expression in each. It appears that production of the bone-resorbing cytokine lymphotoxin is related to osteoclastic bone destruction and hypercalcemia in patients with myeloma.

Journal ArticleDOI
TL;DR: Purified glioblastoma‐derived T cell suppressor factor and transforming growth factor‐beta from porcine platelets inhibit both IL‐2‐induced proliferation of ovalbumin‐specific T helper cells and lectin‐induced thymocyte proliferation with similar specific activities.
Abstract: T cell suppressor factor produced by human glioblastoma cells inhibits T cell proliferation in vitro and more specifically interferes with interleukin-2 (IL-2)-dependent T cell growth. Here we report the purification of this factor from conditioned medium of the human glioblastoma cell line 308. Amino-terminal sequence analysis of the 12.5-kd protein demonstrates that eight out of the first 20 amino acids are identical to human transforming growth factor-beta. Purified glioblastoma-derived T cell suppressor factor and transforming growth factor-beta from porcine platelets inhibit both IL-2-induced proliferation of ovalbumin-specific T helper cells and lectin-induced thymocyte proliferation with similar specific activities. If released by glioblastoma cells in vivo, the factor may contribute to impaired immunosurveillance and to the cellular immunodeficiency state detected in the patients.

Journal ArticleDOI
01 Jul 1987-Nature
TL;DR: It is reported that C57BL/6J and AKR/J mice, when functionally depleted of CD4+ cells by in vivo treatment with the CD4-specific rat monoclonal antibody GK1.5, responded to ectromelia virus infection and subsequently recovered from the disease that was lethal for similarly infected nude mice (CD4−, CD8−).
Abstract: Cytotoxic T lymphocytes (CTL) seem to provide the major line of defence against many viruses. CTL effector functions are mediated primarily by cells carrying the CD8 (Ly-2) antigen (CD8+ cells) and are triggered by interactions of the T-cell receptor with an antigenic complex, often termed 'self plus X', composed of viral determinants in association with class I molecules of the major histocompatibility complex (MHC). The mechanism(s) of induction of virus-specific CTL in vivo is poorly understood, but data from in vitro experiments suggest that their generation is strictly dependent on functions provided by CD4+ helper T cells (also referred to as L3T4+; or TH) that respond to antigens in the context of class II (Ia) MHC determinants. The prevailing opinion that induction of most functions of CD8+ cells requires help provided by CD4+ cells has recently been challenged by the observation that CD8+ cells alone can mediate a variety of responses to alloantigens in vitro and in vivo; however, the possibility that CTL to self plus X could be generated in vivo in the absence of TH cells has not been evaluated. We report here that C57BL/6J (B6) and AKR/J mice, when functionally depleted of CD4+ cells by in vivo treatment with the CD4+-specific rat monoclonal antibody GK1.5 (refs 8-14) responded to ectromelia virus infection by developing an optimal in vivo virus-specific CTL response, and subsequently recovered from the disease (mousepox) that was lethal for similarly infected nude mice (CD4-, CD8-).

Journal ArticleDOI
01 Aug 1987-Nature
TL;DR: A xenogeneic system in which human CD4 complementary DNA was transfected into the murine CD4−, CD8− T-cell hybridoma 3DT-52, strongly indicates that CD4:HLA-DR binding occurs in this system and that this interaction augments T- cell activation.
Abstract: Mature T cells segregate phenotypically into one of two classes: those that express the surface glycoprotein CD4, and those that express the glycoprotein CD8. The CD4 molecule is expressed primarily on helper T cells whereas CD8 is found on cytotoxic and suppressor cells. A more stringent association exists, however, between these T-cell subsets and the major histocompatibility complex (MHC) gene products recognized by their T-cell receptors (TCRs). CD8+ lymphocytes interact with targets expressing class I MHC gene products, whereas CD4+ cells interact with class II MHC-bearing targets. To explain this association, it has been proposed that these 'accessory' molecules bind to monomorphic regions of the MHC proteins on the target cell, CD4 to class II and CD8 to class I products. This binding could hold the T cell and its target together, thus improving the probability of the formation of the trimolecular antigen: MHC: TCR complex. Because the TCR on CD4+ cells binds antigen in association with class II MHC, it has been difficult to design experiments to detect the association of CD4 with a class II molecule. To address this issue, we devised a xenogeneic system in which human CD4 complementary DNA was transfected into the murine CD4-, CD8- T-cell hybridoma 3DT-52.5.8, the TCR of which recognizes the murine class I molecule H-2Dd. The murine H-2Dd-bearing target cell line, P815, was cotransfected with human class II HLA-DR alpha, beta and invariant chain cDNAs. Co-culture of the parental T-cell and P815 lines, or of one parental and one transfected line resulted in a low baseline response. In contrast, a substantial increase in response was observed when CD4+ 3DT-52.5.8 cells were co-cultured with HLA-DR+ P815 cells. This result strongly indicates that CD4:HLA-DR binding occurs in this system and that this interaction augments T-cell activation.

Journal Article
TL;DR: The working hypothesis is that the initial induction of T cells to antigen in LN is controlled by resident dendritic cells (or other non-B antigen-presenting cells), the main role of B cells being to control the clonal expansion of activated T cells.
Abstract: Previous studies have shown that lymph node (LN) T cells from mice given repeated injections of anti-mu antisera from birth (mu sm) fail to mount secondary T proliferative responses to antigen in vitro after s.c. priming in vivo. This finding raised the possibility that priming of T cells in LN depends on the presence of B cells, Ig+ B lymphocytes being absent in mu sm. In support of this idea, the present paper shows that the priming defect in LN of mu sm can be largely overcome by injecting B cell populations s.c. 1 day before s.c. priming with antigen. Restoration of LN priming was observed with s.c. injection of highly purified populations of small B cells but not with heat-killed or lightly irradiated B cells. Homing studies indicated that approximately 10% of s.c.-injected B cells reached the draining LN. In other studies, irradiated mice injected i.v. with purified T cells manifested poor priming in LN after s.c. injection of antigen. It was reasoned that the LN priming defect in this situation reflected the lack of B cells in irradiated mice, B cells being highly radiosensitive. In support of this notion, it was found that s.c. injection of B cells into irradiated recipients of T cells led to high priming of T cells in LN after s.c. injection of antigen. Although T cells exposed to antigen in B-depleted LN of mu sm and irradiated mice gave negligible T proliferative responses in vitro, low but significant levels of primed T helper function were detected in a sensitive T helper assay in vivo. In light of this finding, our working hypothesis is that the initial induction of T cells to antigen in LN is controlled by resident dendritic cells (or other non-B antigen-presenting cells), the main role of B cells being to control the clonal expansion of activated T cells.

Journal ArticleDOI
TL;DR: In this review, the germline genomic and cDNA structures and the evolution of the human TcR-alpha-, T cR-beta-, and Tc gamma-chain genes have been reviewed and discussed.
Abstract: In this review, the germline genomic and cDNA structures and the evolution of the human TcR-alpha-, TcR-beta-, and Tc gamma-chain genes have been reviewed and discussed. The estimated V-gene segment repertoires established for the human TcR-alpha-, TcR-beta-, and Tc gamma-chain genes have also been summarized. The use of TcR and Tc gamma genes in the evaluation of hematopoietic malignancies and identification of chromosomal translocations has also been presented. It is hoped that such information will serve as a reference point from which the study of TcR genes can further progress. This will almost certainly include the use of TcR and perhaps Tc gamma genes in the study of the dual recognition of antigen and MHC gene products, the role of these genes in thymic education/selection, and the role(s) of these genes in oncogenesis processes and autoimmune settings.

Journal ArticleDOI
TL;DR: There is a marked deregulation of Bcl-2 when it is introduced into the Ig locus in t(14;18) lymphomas, which has implications for hematopoietic lineages including T cells.
Abstract: We examined the expression of the Bcl-2 gene at chromosome segment 18q21, that is translocated into the Ig heavy chain gene locus in t(14;18) bearing lymphomas. Bcl-2, while B cell associated, is expressed in a variety of hematopoietic lineages including T cells. Bcl-2 mRNA levels are high during pre-B cell development, the time at which the t(14;18) translocation occurs, but are down regulated with maturation. Like certain other oncogenes, Bcl-2 is quiescent in resting B cells but up-regulated with B cell activation. Mature B cell lymphomas with a t(14;18) have log-folds more mRNA than matched counterparts without the translocation. A sensitive S1 protection assay revealed that all transcripts in t(14;18) B cells were Bcl-2-Ig fusion mRNAs and originated from the translocated allele. Thus, there is a marked deregulation of Bcl-2 when it is introduced into the Ig locus in t(14;18) lymphomas.

Journal Article
TL;DR: It is concluded that BSF-1 is a potent macrophage activation factor.
Abstract: Macrophages are activated by lymphokines (LK) to kill tumor cell and microbial targets Interferon-gamma (IFN) is the major LK activity in conventional, antigen or mitogen-stimulated spleen cell culture fluids for induction of these macrophage effector functions In view of the recent demonstration that murine macrophage-like cell lines have receptors for B cell stimulatory factor-1/interleukin 4 (BSF-1), a possible role for BSF-1 in regulation of macrophage function was considered In this communication, thioglycollate-elicited murine peritoneal macrophages were shown to express about 2300 high affinity (Ka approximately 2 X 10(10) M-1) BSF-1 receptors/cell Peritoneal macrophages treated with purified, T cell-derived BSF-1 developed potent tumoricidal activity against fibrosarcoma target cells The concentration of BSF-1 that induced 50% of maximal tumor cytotoxicity was 38 +/- 4 U/ml for seven experiments; similar dose-responses were observed with recombinant BSF-1 That BSF-1 dose-responses for induction of macrophage-mediated tumor cytotoxicity were not affected by 5 micrograms/ml polymyxin B suggested that contaminant endotoxins played little or no role in cytotoxic activity BSF-1 alone (less than or equal to 500 U/ml) was not directly toxic to tumor cells or macrophages Macrophage tumoricidal activity induced by BSF-1 but not by IFN was inhibited greater than or equal to 90% with monoclonal anti-BSF-1 antibody BSF-1 induced Ia antigen expression on peritoneal macrophages and increased (twofold to threefold) FcR(II)-dependent binding of murine IgG immune complexes to bone marrow-derived macrophages (greater than 98% macrophages) Based on these findings, it was concluded that BSF-1 is a potent macrophage activation factor

Journal ArticleDOI
TL;DR: The data indicate that CD4+ and CD8+ lymphocytes can be activated by a similar mechanism, and illustrate the special role of dendritic cells in the sensitization stage of cell-mediated immunity.
Abstract: Recent experiments (11-13) have shown that antigen-specific, CD8+, CD4- T lymphocytes can be induced to proliferate and become killer cells in the absence of a second population of "helper" CD8-, CD4+ cells. We have studied early events in the activation of CD4+ and CD8+ T cell subsets in the primary mixed leukocyte reaction. Dendritic cells are a major if not essential accessory cell for the activation of both subpopulations. Antigen-bearing macrophages fail to stimulate unprimed CD8+ cells, but act as targets for the sensitized cytolytic lymphocytes that are induced by dendritic cells. The initial proliferative response is comparable for CD4+ and CD8+ lymphocyte subsets. For both subpopulations, dendritic cells efficiently cluster the responding lymphocytes on the first day and induce the release of IL-2. The data indicate that CD4+ and CD8+ lymphocytes can be activated by a similar mechanism, and illustrate the special role of dendritic cells in the sensitization stage of cell-mediated immunity.