Suppressive mechanisms in alloantigen-induced T cell responses.

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Abstract
In this report we examined the possibility that suppression of the mixed lymphocyte response by MLR-TsF results from interference with IL-2 regulation of T cell proliferation. Two distinct processes of inhibition involving both a direct effect on IL-2-driven proliferation of responder T cells, and induction of a second-order suppressor cell (Ts2) were described. Exogenous IL-2 did not abrogate MLR-TsF-induced suppression, and activated responder cells from suppressed cultures expressed functional IL-2 receptors by IL-2 adsorption analysis. Thus, suppression is not due to lack of available IL-2 or to abnormal acquisition of receptors for IL-2 during T cell activation. In contrast, a profound MLR-TsF effect on IL-2-induced proliferation of HT2 cells as well as MLR-activated cells was observed even after presaturation of receptors with excess IL-2. These results differentiated the direct responder cell effect of MLR-TsF from its Ts2 inductive capacity, and localized the defect in responder cell proliferation to events occurring subsequent to IL-2 binding. When analyzed in terms of proposed models for hormone-receptor interactions, characteristic dose-response curves similarly predict a postreceptor defect. Examination of the Ts2 pathway of suppression revealed a late-acting inhibitory effect peaking 72 h after MLR initiation. A minor part of Ts2 activity was susceptible to exogenous IL-2, and may reflect a requirement for IL-2 during Ts2 expansion. However, the most significant component of Ts2-mediated suppression was resistant to excess IL-2, and IL-2 production was normal in Ts2-regulated cultures, thus ruling out limitation of IL-2 for responder cell use as the major mechanism of Ts2 suppression. The complete pathway of Ts2 suppression and its functional relationship to other MLR-TsF inhibitory activities is not yet fully understood. However, these results suggest that the ultimate mechanisms of alloantigen-induced suppression involve late events of the IL-2-dependent lymphokine cascade.

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