The mechanism of tolerance induction in thymus-derived lymphocytes; I. intracellular inactivation of hapten-reactive helper T lymphocytes by hapten-nonimmunogenic copolymer of D-amino acids.

Treatment of a p-azobenzoate (PAB) derivative of a copolymer of D-glutamic acid and D-lysine (D-GL) induced a profound state of unresponsiveness to PAB-reactive helper T lymphocytes generated in PAB-mouse gamma globulin (MGG)-primed mice. This unresponsiveness in T lymphocytes was specific for PAB-reactive cells, since the bacterial alpha-amylase-, keyhole limpet hemocyanin-, or ovalbumin-primed helper T lymphocytes were not suppressed by PAB-D-GL treatment. Taking advantage of the relative ease with which PAB-D-GL can induce specific unresponsiveness to helper T lymphocytes in an animal previously primed with PAB-MGG, it was possible to approach certain questions concerning the mechanisms of tolerance-induction and the fate of tolerant helper T lymphocytes in the PAB-D-GL model by utilizing a classical adoptive cell transfer systemmelimination of the possibility of carry-over of the tolerogen with cells or of the generation of suppressor cells as the result of PAB-D-GL treatment as an explanation of the suppression of helper T-cell activity strongly inplicates the existence of a central intracellular mechanism of specific tolerance on the helper T-cell level. The possibility that suppression of the activity of PAB-reactive helper T lymphocytes by PAB-D-GL reflects simple blocking of surface receptor molecules on T lymphocytes was ruled out as it was found that the helper activity of PAB-reactive cells was minimally suppressed even when PAB-D-GL was directly exposed in vitro to helper T lymphocytesmmoreover, the most conclusive evidence on te the tolerant state induced by in vivo exposure of primed T cells to PAB-D-GL. It appears, therefore, that specific tolerance induced by PAB-D-GL' TO PAB-reactive helper T lymphocytes is an example of irreversible inhibition of T-cell reactivity to antigen, reflecting yet to be determined events at the intra- and subcellular levels.