Summary 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 respond to and be sensitized by the normally tolerogenic sRGG. There are reasonable grounds for the assumption that some subsets of B cells may display such reactivity. Ahmed and Scher  showed that Lyb5 + B cells but not Lyb5 − B cells were able to respond to T-cell replacing factor (TRF). Singer et al. [ 47] observed that Lyb5 + B cells, as opposed to Lyb5 − B cells, were able to respond to non-specific helper T-cell factors present in ConA supernatants. We have reported a marked heterogeneity in the age-dependent increase of a non-specific helper factor (Thf), which resembles TRF [ 30]. Age-dependent changes in this factor occur earlier in animals which develop early resistance against tolerance induction [ 30–34]. It is thus conceivable that B-cell priming in sRGG-treated NZB/B1NJ and C57BL/6J may be connected with the effect of a non-specific helper factor. The differences in the age at which sensitized B cells can be demonstrated in strains which have tolerogen-sensitized B cells might reflect age-dependent differences in the appearance of Thf. It remains to be seen whether B-cell sensitization can be induced prematurely by transfer of TRF and whether it would fail to be transferred to such strains as DBA/1, which seems to lack receptors for Thf and/or TRF [ 32]. In short, we propose that: 1) a non-specific helper factor such as TRF is produced by T cells activated by environmental or autologous antigens prior to sRGG treatment; and 2) that this non-specific helper factor is available when B cells encounter sRGG, and that normally tolerogenic sRGG ontogenetically sensitizes later-maturing B cells in the presence of the non-specific helper factors. We found a relatively strong response directed against RGG in tolerogentreated DNP-RGG-immunized 15-week old SJL animals (fig. 1) compared to previously reported responses to RGG. This may well be attributable to responses against configurationally altered native determinants of the DNP-RGG molecule [ 20, 7, 45, 17]. It will be interesting to determine the strain dependence of this effect and, in particular, to compare the relative response to RGG and DNP-RGG of sRGG-treated older NZB/B1NJ and MRL/MpJ- lpr/lpr mice. This might provide us with an additional parameter of age-dependent changes. The explorations discussed in this paper have gained and will gain much from detailed studies of isotypes, as described by L. A. Herzenberg et al. ( Immunol. Rev., 1982, 67, 5–31) and by Y. L. Rosenberg ( Immunol. Rev., 1982, 67, 33–58).