BREAKDOWN OF T-CELL TOLERANCE TO IGG2A(B) IN IGH(A) MICE BY DE-NOVO EMERGING ANTI-IGG2A(B) T-CELLS AND NOT ANERGY REVERSION

The intrinsic T cell activity of lgh(a) mice against lgG2a(b) (lgG2a f rom the lgh(b) haplotype) can be subjected to profound specific tolera nce, In utero followed by post-natal exposure of lgh(a) mice to solubl e lgG2a(b) results in the loss of the capacity of their T splenocytes to induce specific and chronic lgG2a(b) allotype suppression in histoc ompatible lgh(a/b) recipients. However, this full T cell tolerance has not been definitively acquired as it is spontaneously reversed when i nvestigated 3-6 months after the end of the tolerogen treatment, Even when the lgG2a(b) tolerogen treatment was prolonged to 3, 6 or 9 month s of age, T cell tolerance to lgG2a(b) vanished and the capacity of lg h(a) T splenocytes to induce lgG2a(b) suppression in lgh(a/b) recipien ts was systematically restored, The marked but partial thymus involuti on in 15-month-old lgh(a) mice suggests the existence of some residual thymic output, capable of repopulating the anti-lgG2a(b) peripheral T pool subsequent to tolerogen clearance, in the present study, we show ed that the mechanisms of this tolerance and its reversion involve, at the end of tolerogen treatment, the physical elimination or the irrev ersible inactivation of natural anti-lgG2a(b) T cell clones and their replacement, but neither the establishment of reversible anergy nor th e 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 a t the end of tolerogen administration. Moreover, tolerance reversion d id not occur in peripheral mature Igh(a) T cells, parked in vivo, for up to 20 weeks in histocompatible tolerogen-free nu/nu mice.