Induction of T cell responses to a self-antigen following allotransplantation.

T cell tolerance to self-antigens is established through the recognition by immature T cells of dominant self-peptides presented in association with self-MHC molecules in the developing thymus (negative selection). The self-peptide D 61-80 is dominant in syngeneic BALB/c mice (H2 d ). T cell tolerance to D d 61-80 in this mouse strain resulted in the absence of T cell proliferation following in vivo priming with D d 61-80 peptide. Here, we show that transplantation of BALB/c mice with allogeneic B10.A (H2 a ) splenocytes led to an autoimmune T cell response toward the dominant self-peptide D d 61-80. No T cell responses to D d 61-80 peptide were observed after transplantation of c57BL/6 (H2 b ) splenocytes into BALB/c recipients. In addition, we provide evidence indicating that the breakdown of tolerance to D d 61-80 self-peptide resulted from the presentation of the donor crossreactive peptide K k 61-80 at the surface of recipient antigen-presenting cells. Taken together, our results suggest that following allotransplantation, T cell responses to donor antigens could spread to crossreactive determinants on self-proteins, thus perpetuating and amplifying the rejection process and presumably initiating tissue-specific autoimmune disorders.