A novel form of self tolerance dictated in the thymus of transgenic mice with autoreactive TCR α and β chain genes

Transgenic (TG) mice with TCR α and β chain genes from a CD4-dependent auto-l-Ak reactive T cell clone were generated. H-2k TG mice had a large number of thymic and splenic CD4 T cells expressing the autoreactive TCR without manifestation of autolmmunlty. The cells were not anergic, as they could respond to autologous antigen presenting cells and antl-TCR antibodies in vitro to proliferate and to produce interleuklns. Various degrees of down-regulation of CD2 and CD44 was observed in TG mice, Indicating the presence of a defective co-stlmulatory process in TG T cells. These features indicate that the self tolerance in autoreactive TCR TG mice is due not to clonal deletion and anergy but to a novel mechanism where T cells cannot sufficiently respond to normally existing self ligand in vivo. That such an in vivo unresponsiveness of autoreactive T cells is dictated in the thymus during CD4 T cell differentiation as an atypical form of positive selection of autoreactive T cells was suggested by the abnormal surface expression of CD69 and HSA.