Breakdown of T cell tolerance to IgG2ab in Igha mice by de novo emerging anti-IgG2ab T cells and not anergy reversion

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.