Publikationen

Journal of Clinical Investigation 120 (11): 3869-3877 (2010-11-01)

Leisegang M.; Wilde S.; Spranger S.; Milosevic S.; Frankenberger B.; Uckert W.; Schendel D.J.

MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors

Description:
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.

Keywords: Animals, Transgenes, T-Lymphocytes, T-Cell Antigen Receptors, Microtubule-Associated Proteins, Major Histocompatibility Complex, Lymphocytes, HLA-A2 Antigen, Cell Line, Cell Death

Type: Article

PubMed: 20978348
Official URL: https://doi.org/10.1172/JCI43437
MDC Repository: https://edoc.mdc-berlin.de/11252/