Sensitization of T and B cells by a normally tolerogenic macromolecule: the induction of unresponsiveness and of sensitization is polymorphic.

Changes induced in B and T cells by tolerogen were experimentally defined in animals which resist down-regulation. Female A/J, C57BL/6J, MLR/MpJ-lpr/lpr, MLR/MpJ-+/+ and NZB/B1NJ mice were injected at various ages with a tolerogenic form of rabbit gamma globulin (sRGG) or were left uninjected, and all were then immunized with dinitrophenylated RGG (DNP-RGG) on alum. The degree of tolerance was estimated by measuring anti-DNP and anti-RGG spleen plaque-forming cell (PFC) numbers. In some cases, the state of T or B cells deduced from these experiments was further examined by cell transfer experiments. Four types of responsiveness to the tolerogenic form of RGG (sRGG) were distinguished: 1) persistent tolerance inducibility of T and B cells to tolerance induction (A/J); 2) T cells retaining tolerance-inducibility after initiation of age-dependent sensitization of B cells by the tolerogenic form of RGG (C57BL/6J, NZB/B1NJ); 3) age-dependent resistance of T cells to tolerance-induction and age-dependent sensitization of B cells by tolerogen, with the sensitization only manifesting itself in reactivity with T cells from immunized donors (SJL/J); and 4) sensitization of T cells by a usually tolerogenic form of RGG (MLR/MpJ-lpr-lpr). Thus, the development of resistance against tolerance induction is highly polymorphic, not only with respect to the age of onset, but also with respect to the cellular site of its first manifestation and the effect. Possible mechanisms of B-cell sensitization in sRGG-treated C57BL/6 and NZB mice are discussed in relation to the age-dependent emergence of a B-cell subpopulation and of non-specific helper T-cell factors.