T cell-induced IgG2ab allotype suppression provides a physiological model for the study of T cell responsiveness or tolerance to this Ig allotype. Normal, untreated mice of the Igha haplotype possess a basic and easily amplifiable T cell reactivity against the expression of IgG2ab, while their Ighb congenic mice produce substantial levels of this Ig and thereby are tolerant to this self-protein antigen. Therefore, the involved TCR repertoire in Igha and Ighb congenic mice is different. We have previously shown, in Ighb and Igha/b mice perinatally deprived of IgG2ab expression, that T lymphocytes bearing anti-IgG2ab TCR can emerge and induce an autoimmune suppression of IgG2ab. Correlatively, full and IgG2ab-specific T cell tolerance can be induced in Igha mice by their perinatal exposure to this Ig allotype. In this physiological model, which involves neither superantigens nor TCR-transgenic T cells, the responsive or tolerant state in Igha mice is assessed in vivo by the capacity to induce or not a T CD8(+)-dependent suppression of IgG2ab allotype production in Igha/b recipients of these cells. Taking advantage of this system, we were able to demonstrate here that, over the long term, this perinatally induced, IgG2ab-specific T cell tolerance was not definitively acquired, and that a spontaneous and total tolerance breakdown was observed by the age of 6 months. Furthermore, we showed that perinatal followed by prolonged tolerogen treatments up to 3, 6 and even 9 months of age were no longer sufficient to assure definitive T cell tolerance acquisition to IgG2ab, as the T cell suppression-induction capacity of Igha mice was partially and then entirely restored 3-6 months after the end of the tolerogen administration.

The intrinsic T cell activity of Igha mice against IgG2ab (IgG2a from the Ighb haplotype) can be subjected to profound specific tolerance. In utero followed by post-natal exposure of Igha mice to soluble IgG2ab results in the loss of the capacity of their T splenocytes to induce specific and chronic IgG2ab allotype suppression in histocompatible Igha/b recipients. However, this full T cell tolerance has not been definitively acquired as it is spontaneously reversed when investigated 3-6 months after the end of the tolerogen treatment. Even when the IgG2ab tolerogen treatment was prolonged to 3, 6 or 9 months of age, T cell tolerance to IgG2ab vanished and the capacity of Igha T splenocytes to induce IgG2ab suppression in Igha/b recipients was systematically restored. The marked but partial thymus involution in 15-month-old Igha mice suggests the existence of some residual thymic output, capable of repopulating the anti-IgG2ab peripheral T pool subsequent to tolerogen clearance. In the present study, we showed that the mechanisms of this tolerance and its reversion involve, at the end of tolerogen treatment, the physical elimination or the irreversible inactivation of natural anti-IgG2ab T cell clones and their replacement, but neither the establishment of reversible anergy nor the recruitment of T cells which could actively maintain tolerance. The spontaneous breakdown of this T cell unresponsiveness was effectively prevented when de novo T cell maturation was inhibited by thymectomy at the end of tolerogen administration. Moreover, tolerance reversion did not occur in peripheral mature Igha T cells, parked in vivo, for up to 20 weeks in histocompatible tolerogen-free nu/nu mice.

No abstract

No abstract