Spontaneous breakdown of T cell tolerance in the mouse IgG2ab-suppression model despite long-term tolerogenesis since the perinatal period.

Abstract

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.