TY - JOUR AU - Leisegang, Matthias AU - Wilde, Susanne AU - Spranger, Stefani AU - Milosevic, Slavoljub AU - Frankenberger, Bernhard AU - Uckert, Wolfgang AU - Schendel, Dolores J. T1 - MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors PY - 2010/11/01/ AB - The apoptosis inhibitor protein survivin is overexpressed in many tumors, making it a candidate target molecule for various forms of immunotherapy. To explore survivin as a target antigen for adoptive T cell therapy using lymphocytes expressing survivin-specific transgenic T cell receptors (Tg-TCRs), we isolated HLA-A2–allorestricted survivin-specific T cells with high functional avidity. Lymphocytes expressing Tg-TCRs were derived from these T cells and specifically recognized HLA-A2+ survivin+ tumor cells. Surprisingly, HLA-A2+ but not HLA-A2– lymphocytes expressing Tg-TCRs underwent extensive apoptosis over time. This demise was caused by HLA-A2–restricted fratricide that occurred due to survivin expression in lymphocytes, which created ligands for Tg-TCR recognition. Therefore, survivin-specific TCR gene therapy would be limited to application in HLA-A2–mismatched stem cell transplantation. We also noted that lymphocytes that expressed survivin-specific Tg-TCRs killed T cell clones of various specificities derived from HLA-A2+ but not HLA-A2– donors. These results raise a general question regarding the development of cancer vaccines that target proteins that are also expressed in activated lymphocytes, since induction of high-avidity T cells that expand in lymph nodes following vaccination or later accumulate at tumor sites might limit themselves by self-MHC–restricted fratricide while at the same time inadvertently eliminating neighboring T cells of other specificities. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI43437 VL - 120 IS - 11 UR - https://doi.org/10.1172/JCI43437 SP - 3869 EP - 3877 PB - The American Society for Clinical Investigation ER -