Induction of T cell activation by monoclonal antibodies specific for the transferrin receptor (original) (raw)
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A soluble form of the human transferrin receptor is released by activated lymphocytes in vitro
Clinical and Experimental Immunology, 2008
Soluble transferrin receptors (sTfR) were detected in culture supernatants of activated human peripheral blood mononuclcar cells (PBMC) using a sandwich ELISA technique with two non-cross-reacting TfR MoAbs. Mitogenic stimulation of lymphoid cells induced both up-regulation of TfR surface density and release of sTf R to the medium. Peak levels of sTfR in culture supernatants occurred at day 4 after activation, 1 day later than maximum expression of TfR in the plasma membrane. Production of sTfR was independent of proliferation, as demonstrated by measuring sTfR release by PBMC, which had becn irradiated with a dose of 20 Gy before activation. In addition to these in vitro experiments, we tested the sera of 85 patients with systemic lupus erythematosus (SLE). an autoimmune disease accompanied by in vivo activation of lymphocytes, for their sTfR levels. No correlation of these data was detectable to serum concentrations of the soluble α-chain of the IL-2 receptor, an unequivocal marker of lymphocyte activation. However, they correlated negatively to the haemoglobin content of the patients’ erythrocytes. indicating that erythroid progenitors are the predominant source of sTf R in SLE patients’ sera.
Cellular Immunology, 1989
Prior work has suggested that Mabs against the transfenin receptor (ATRAs) may function as selective inhibitors of lymphocyte activation and that T cell activation protocols may be more sensitive to ATRA-mediated inhibition than B cell activation protocols. New side-by-side functional comparisons of three ATRAs are presented. When these studies are considered with our prior work they demonstrate unambiguously that although one particular IgG ATRA consistently fails to inhibit LPS responses and although IgM ATRAs may be slightly more effective inhibitors than IgG ATRAs, ATRAs as a class consistently appear to abolish the MLR at submicrogram concentrations, essentially eliminate cytotoxic cell generation at concentrations between 1 and 5 &ml, and produce no more than about 50% inhibition of LPS responses at concentrations as high as 25 Mg/ml. Therefore, an even stronger case can now be made for the idea that lymphocyte subsets differ in their dependence on transferrin receptor function during activation. This, in turn, makes an even stronger case for the idea that lymphocyte subsets differ in fundamental aspects of the management of their iron economies. New studies also show that IgG ATRAs appear to function by causing down-modulation of surface expression of the transferrin receptor in normal lymphocytes in a manner similar to that previously shown for tumor cells. It is clear that a sophisticated model will ultimately be required to account for all of the data arising from studies with ATRAs, and a new attempt at a more detailed construct is presented.
Quiescent lymphocytes express intracellular transferrin receptors
Biochemical and Biophysical Research Communications, 1984
Both quiescent and concanavalin A stimulated murine splenic lymphocytes were examined for the expression of surface and intracellular binding sites for the serum glycoprotein transferrin. Transferrin binding activity was observed on the surface of mitogen stimulated cells only. When soluble detergent extracts of both populations were studied, quiescent lymphocytes were shown to contain a significant pool of non-surface exposed, intracellular receptors which was approximately 20% of the total receptor complement of proliferating cells. Because the ratio of surface to intracellular binding sites was dramatically increased following mitogen stimulation, the regulation of transferrin receptor expression during this process may involve a substantial alteration in its subcellular distribution in addition to the well documented increase in number of binding sites. Expression of cell surface receptors for the serum glycoprotein transferrin has been associated with the initiation of cell proliferation (1,2) and the significance of this relationship is supported by studies documenting a functional role for transferrin and its specific receptor in this process (3,4). In previous reports, we and others have observed a stringent regulation of cell surface transferrin receptor expression in normal lymphocytes undergoing mitogen induced proliferative responses (5,6). Thus, expression of this receptor on normal lymphocyte cell surfaces appears to be restricted to cells actively involved in DNA synthesis and cell division. Recently, studies from several laboratories have documented the existance of a substantial pool of intraeellular transferrin receptors (7,8) representing nearly 80% of the total complement of cellular binding sites. In the present communication we examined both quiescent and concanavalin A stimulated murine splenic lymphocytes with respect to the existance and size of
Transferrin receptors on human B and T lymphosblastoid cell lines
Biochimica et Biophysica Acta (BBA) - General Subjects, 1979
Experiments demonstrating the existence of receptors for iron-saturated transferrin on both B and T lymphoblastoid cell lines of human origin are described. Binding of '2~I-labeled transferrin is rapid, saturable and reversible. It can be specifically inhibited by unlabeled transferrin but not by other proteins. The number of receptors on T cell lines determined by Scatchard analysis is almost double the number on B cell lines but the binding affinities are equal.
Immunology
Mitogen-activated normal human peripheral blood lymphocytes bind transferrin to specific membrane receptors. In this study, lymphocytes stimulated with phytohaemagglutinin for 0-66 hr were examined to determine the relation of this phenomenon to cellular activation and related metabolic events. Transferrin receptors were first detected at 20-24 hr. This event was consistently preceded by RNA and protein turnover which commenced during the first 6 hr of culture, whereas initiation of DNA synthesis was detected concurrently with the appearance ofreceptors or slightly later (24-30 hr). Exposure of cells to inhibitors of RNA and protein synthesis early during culture (at 0 or 24 hr) prevented the expression of transferrin receptors, but also caused generalized metabolic failure, and abrogated cellular activation. In contrast, later addition ofthese agents at 48 hr did not interfere significantly with the process of activation, but did suppress the terminal increase in receptor-bearing cells observed during the final 18 hr in control cultures lacking inhibitor. reappearance of membrane binding sites which normally occurred within 30 min, was also blocked by cycloheximide, puromycin and actinomycin D. However, similar inhibition of DNA which was induced by hydroxyurea had much less effect upon both the initial appearance of receptors and their reappearance after ligand-induced depletion. These results demonstrate that the appearance of transferrin receptors upon human lymphocytes is dependent upon cellular activation and requires synthesis of protein and RNA.
CD3 pathway of T-cell activation
Cellular Immunology, 1988
The role of distinct regions of HLA class I molecules in regulating T-cell activation via the CD3-antigen receptor complex was investigated. Monoclonal antibodies (MoAbs) which recognize monomorphic and polymorphic epitopes on HLA Class I molecules were shown to inhibit T-cell proliferation to OKT3. These MoAbs have differential effects on the synthesis of interleukin-2 (IL-2) and IL-2 receptor expression. Cell cycle analysis demonstrated that these MoAbs function both in inhibiting cell cycle entry (Go-G, shift) and in blocking cell cycle progression (Gi-S shift) of activated T cells. Furthermore, these MoAbs have regulatory effects on the alternate pathway of T-cell activation via the CD2 molecule, T-cell activation induced by PHA, and activation induced by the phorbol ester PMA in conjunction with the calcium ionophore Ionomycin. Thus these MoAbs have different effects depending upon the pathway of T-cell activation. The results indicate that HLA class I molecules are selectively involved in the sequence of intracellular events leading to T-cell activation and proliferation. o 1988 Academic press, Inc.
Journal of Experimental Medicine, 1987
We investigated the mechanism involved in T cell unresponsiveness that follows the monoclonal antibody-induced surface modulation of the CD3-TCR complex. We determined whether modulation of CD3-TCR affected the early metabolic steps such as [Ca2+]i rise and InsP3 formation. A strong inhibition of the increase on [Ca2+]i mediated by either anti-TCR or anti-CD2 mAbs was detected. In contrast, surface modulation of CD2 molecules did not prevent the [Ca2+]i increase induced by anti-TCR mAb. Similarly, InsP3 increase was strongly reduced only after modulation of CD3-TCR complex (but not of CD2 molecules). Therefore, it appears that surface modulation of CD3-TCR complex causes T cell refractoriness by inhibiting the very early metabolic events that follow receptor-ligand interactions.