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

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Official URL:https://doi.org/10.1172/JCI43437
PubMed:View item in PubMed
Creators Name:Leisegang, M. and Wilde, S. and Spranger, S. and Milosevic, S. and Frankenberger, B. and Uckert, W. and Schendel, D.J.
Journal Title:Journal of Clinical Investigation
Journal Abbreviation:J Clin Invest
Volume:120
Number:11
Page Range:3869-3877
Date:1 November 2010
Keywords:Cell Death, Cell Line, HLA-A2 Antigen, Lymphocytes, Major Histocompatibility Complex, Microtubule-Associated Proteins, T-Cell Antigen Receptors, T-Lymphocytes, Transgenes, Animals
Abstract: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.
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Item Type:Article

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