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

J Clin Invest. 2010 Nov;120(11):3869-77. doi: 10.1172/JCI43437. Epub 2010 Oct 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / immunology
  • Cell Line
  • HLA-A2 Antigen* / genetics
  • HLA-A2 Antigen* / immunology
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Lymphocytes / immunology*
  • Major Histocompatibility Complex* / genetics
  • Major Histocompatibility Complex* / immunology
  • Microtubule-Associated Proteins / immunology*
  • Receptors, Antigen, T-Cell* / genetics
  • Receptors, Antigen, T-Cell* / immunology
  • Survivin
  • T-Lymphocytes / immunology
  • Transgenes*


  • BIRC5 protein, human
  • HLA-A2 Antigen
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Receptors, Antigen, T-Cell
  • Survivin