MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors.
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.
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Matthias
M
Leisegang
Susanne
S
Wilde
Stefani
S
Spranger
Slavoljub
S
Milosevic
Bernhard
B
Frankenberger
Wolfgang
W
Uckert
Dolores J
DJ
Schendel
D000818:Animals; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008214:Lymphocytes / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D008869:Microtubule-Associated Proteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D000077022:Survivin; D013601:T-Lymphocytes / Q000276:immunology; D019076:Transgenes
C107489:BIRC5 protein, human; D015789:HLA-A2 Antigen; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D011948:Receptors, Antigen, T-Cell; D000077022:Survivin