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Previously it has been reported that hapten-specific B cell unresponsiveness could be elicited by macrophages pulsed with the tolerogen deaggregated fluoresceinated sheep gamma globulin (FL-SGG; R. P. Phipps and D. W. Scott, J. Immunol. 1983. 131:2122). In contrast, FL-SGG-pulsed P388AD.2, a lymphoid dendritic cell-like tumor line, presents this signal as an immunogenic one leading to augmented anti-FL antibody responses. In the present study, we examined the role of T cells and their secreted lymphokines in the immunogenic presentation of FL-SGG by P388AD.2. Lymphocytes and FL-SGG-pulsed P388AD.2 form large clusters in vitro. In order to examine whether the clustered lymphocytes were responsible for the augmented antibody responses, cultures of P388AD.2 and lymphocytes were separated into P388AD.2 adherent (clustered) and nonadherent fractions. Interestingly, the clustered fraction was entirely responsible for the augmented responses and contained Ly-1+ T cells and B cells primed by FL-SGG on P388AD.2. Moreover, a requirement for T cells in the presentation of a normally tolerogenic signal as an immunogenic one was demonstrated as responses of T-depleted spleen cells could be reconstituted by addition of normal T cells or by an autoreactive T cells clone. Furthermore, the requirement for T cells could be bypassed using supernatant from concanavalin A-stimulated spleen cells or by culture supernatant from AOFS, an IL 2-secreting T cell hybridoma. This suggested that a cognate interaction between T and B cells was not required to induce B cell priming and the augmented anti-FL antibody responses. Further studies revealed that doses of recombinant IL 2 greater than 12.5 units/ml, in conjunction with FL-SGG-pulsed P388AD.2, replaced the need for T cells. Overall, our data suggest that one mechanism of presentation of FL-SGG in an immunogenic fashion involves T cell secretion of IL2 by autoreactive T cells triggered by close association with P388AD.2.
Previously it has been reported that hapten-specific B cell unresponsiveness could be elicited by macrophages pulsed with the tolerogen deaggregated fluoresceinated sheep gamma globulin (FL-SGG; R. P. Phipps and D. W. Scott, J. Immunol. 1983. 131:2122). In contrast, FL-SGG-pulsed P388AD.2, a lymphoid dendritic cell-like tumor line, presents this signal as an immunogenic one leading to augmented anti-FL antibody responses. In the present study, we examined the role of T cells and their secreted lymphokines in the immunogenic presentation of FL-SGG by P388AD.2. Lymphocytes and FL-SGG-pulsed P388AD.2 form large clusters in vitro. In order to examine whether the clustered lymphocytes were responsible for the augmented antibody responses, cultures of P388AD.2 and lymphocytes were separated into P388AD.2 adherent (clustered) and nonadherent fractions. Interestingly, the clustered fraction was entirely responsible for the augmented responses and contained Ly-1+ T cells and B cells primed by FL-SGG on P388AD.2. Moreover, a requirement for T cells in the presentation of a normally tolerogenic signal as an immunogenic one was demonstrated as responses of T-depleted spleen cells could be reconstituted by addition of normal T cells or by an autoreactive T cells clone. Furthermore, the requirement for T cells could be bypassed using supernatant from concanavalin A-stimulated spleen cells or by culture supernatant from AOFS, an IL 2-secreting T cell hybridoma. This suggested that a cognate interaction between T and B cells was not required to induce B cell priming and the augmented anti-FL antibody responses. Further studies revealed that doses of recombinant IL 2 greater than 12.5 units/ml, in conjunction with FL-SGG-pulsed P388AD.2, replaced the need for T cells. Overall, our data suggest that one mechanism of presentation of FL-SGG in an immunogenic fashion involves T cell secretion of IL2 by autoreactive T cells triggered by close association with P388AD.2.
Previous work indicated that macrophages and a lymphoid dendritic cell-like tumor line, P388AD.2, possessed a differential ability to present a haptenated immunoglobulin (tolerogen) in vitro. Macrophages presented fluorescein-conjugated sheep gamma globulin (FL-SGG) and elicited B-cell unresponsiveness. In contrast, P388AD.2 presented this normally tolerogenic signal as an immunogenic one and induced augmented anti-hapten antibody responses. The objective of the present study was to determine whether differential tolerogen presentation could occur in vivo using defined accessory cells pulsed with FL-SGG. Interestingly, the intravenous (IV) injection of FL-SGG-pulsed thioglycollate-elicited macrophages, which secreted prostaglandin E2, induced hapten-specific B-cell unresponsiveness in syngeneic recipients. One thousand times as much FL-SGG in soluble form was required to produce the same degree of unresponsiveness. In contrast to macrophage-elicited negative signalling, non-prostaglandin secreting P388AD.2, when pulsed with FL-SGG, induced hapten-specific responses 2-3 times control values. Moreover, as few as 2 x 10(4) FL-SGG-pulsed P388AD.2 induced significant augmentation of the anti-FL antibody response. The presentation of FL-SGG in an immunogenic fashion by P388AD.2 was rapid and long lasting since increased responses were demonstrated as early as 1 day or as long as 21 days after IV injection. P388AD.2 were not simply acting as a passive carrier, nor permitting host presentation of FL-SGG, since there were requirements for P388AD.2 viability, and for syngeneic recipients in order to generate augmented anti-FL antibody responses. Moreover, inappropriate presentation of FL-SGG by P388AD.2 injected into allogeneic recipients did not elicit positive or negative signalling. In order to demonstrate that the ability of P388AD.2 to present FL-SGG in an immunogenic fashion was not simply a property of all tumor cells, the P388D1 cell line was pulsed with FL-SGG and injected. Neither tolerance nor augmentation was induced. Overall these results demonstrate that the type of antigen-presenting cell which introduces the immune system to an immunoglobulin tolerogen is critical to the induction of B-cell unresponsiveness or priming.
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