A novel form of self tolerance dictated in the thymus of transgenic mice with autoreactive TCR alpha and beta chain genes.

Transgenic (TG) mice with TCR alpha and beta chain genes from a CD4-dependent auto-I-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 autoimmunity. The cells were not anergic, as they could respond to autologous antigen presenting cells and anti-TCR antibodies in vitro to proliferate and to produce interleukins. Various degrees of down-regulation of CD2 and CD44 was observed in TG mice, indicating the presence of a defective co-stimulatory 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 atypical form of positive selection of autoreactive T cells was suggested by the abnormal surface expression of CD69 and HSA.