INDUCTION OF AUTOIMMUNE-DISEASE IN MICE BY GERMLINE ALTERATION OF THET-CELL RECEPTOR GENE-EXPRESSION

Germline expression of rearranged TCR alpha-chain transgenes with the Ig H chain enhancer reproducibly elicits T cell-mediated autoimmune di sease in the thyroid gland, gastric mucosa, Langerhans islets, salivar y gland, ovaries, and testes in selected strains of normal mice. Multi ple organs are destroyed in a single transgenic mouse and the same org an in transgenic strains with different MHC background, suggesting the transgene expression can elicit self-reactive T cell clones having di fferent Ag specificities and MHC restrictions. Construction of this au toimmune-inducing TCRalphaEH transgene does not require particular Val phaJalpha gene segments or Ag specificities. Moreover, the autoimmune disease can be adoptively transferred to syngeneic normal mice by T ce lls expressing endogenous TCR alpha-chains. Taken together, these resu lts indicate that the TCRalphaEH transgene expression does not suppres s endogenous alpha-chain gene rearrangement and may trigger the expans ion/activation of various self-reactive T cells expressing endogenous TCR alpha- and beta-chains. Furthermore, it appears that the transgene -induced autoimmune T cells are not deleted in the normal thymus or re ndered anergic upon contact with the normal target self Ag, but can be controlled by a T cell-dependent mechanism, since transfer of the tra nsgenic bone marrow cells to histocompatible SCID mice produces the sa me autoimmune disease as in the donors, and the autoimmune development in the SCID mice is effectively prevented by co-transfer of syngeneic nontransgenic T cells. This novel autoimmune model produced by geneti c manipulation of the T cell lineage, not the target self Ag or the en vironment of T cell differentiation/selection, should be useful for el ucidating the immunologic and genetic basis of autoimmune disease.