Partial tyrosinase‐specific self tolerance by HLA‐A*0201‐restricted cytotoxic T lymphocytes in mice and man

AbstractThe human tyrosinase (hTyr) (369–377) cytotoxic T lymphocyte (CTL) epitope is presented by malignant melanoma and various nontransformed cells in association with human leukocyte antigen (HLA)‐A*0201 (A2.1) and used for vaccination‐based immunotherapy of melanoma patients. Its mouse homologue, mTyr (369‐377), is naturally processed and bound by A2.1 with equivalent efficacy and thus enabled us to explore the effect of self tolerance on Tyr‐specific T cells in different lines of A2.1 transgenic (Tg) mice and man. We found that self Tyr‐reactive CTL in Tg mice and, importantly, in man were affected by partial tolerance resulting in only residual T lymphocytes of higher avidity for self Tyr along with low‐avidity T cells to be present in the periphery. Immunizing mice with the xenogeneic nonself Tyr peptide facilitated the generation of self Tyr‐reactive CTL. As compared to Tyr‐reactive CTL induced by high amounts of the self Tyr epitope, however, the nonself antigen (Ag) had no effect on improving the avidity of self Tyr‐specific mouse and human T cells. Depleting mice of CD25+ T cells with and without CTL‐associated Ag 4 (CTLA‐4) blockade demonstrated that tolerance of Tyr‐specific CTL was not regulated by CD4+CD25+ T regulatory cells (Treg) or CTLA‐4. Our studies have important implications for the design of anti‐Tyr‐based immunotherapeutics. © 2003 Wiley‐Liss, Inc.