MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors
Matthias Leisegang, … , Wolfgang Uckert, Dolores J. Schendel
Matthias Leisegang, … , Wolfgang Uckert, Dolores J. Schendel
Published October 11, 2010
Citation Information: J Clin Invest. 2010;120(11):3869-3877. https://doi.org/10.1172/JCI43437.
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Research Article Oncology

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

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.

Authors

Matthias Leisegang, Susanne Wilde, Stefani Spranger, Slavoljub Milosevic, Bernhard Frankenberger, Wolfgang Uckert, Dolores J. Schendel

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Figure 1

De novo priming of survivin-specific T cells with RNA-pulsed DCs.

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De novo priming of survivin-specific T cells with RNA-pulsed DCs. (A) Su...
(A) Survivin-multimer staining of bulk CD8+ T cell lines of HLA-A2+ and HLA-A2– donors after DC priming (Pre-sort) and after 26 days of expansion following multimer sorting (Post-expansion). CMV(pp65)-multimer served as a specificity control. Percentage double-positive cells are displayed in the upper-right quadrant. (B) Cytotoxic activity of multimer-sorted lines measured against T2 (HLA-A2+) cells pulsed with flu or survivin peptide (10–5 M) is presented as percent specific lysis. (C) Cytotoxic specificity of different T cell clones was measured against flu- and survivin-pulsed T2 cells (10–5 M) and presented as percent specific lysis. The x axis shows clone designation. (D) Cytotoxic activity of allorestricted survivin-specific T cell clones A71, A66, and A72 against Mel-1379 (HLA-A2– [A2–], survivin+ [S+]), T2 cells loaded with 10–5 M flu peptide (A2+, S–), and Mel-624.38 tumor cells (A2+, S+) at an E/T ratio of 5:1. Flu-pulsed T2 cells were used as survivin-negative control, since we identified no tumor cell lines that were survivin negative. (E) Functional avidity of CTLs (E/T, 10:1) was measured against T2 cells pulsed with graded amounts of survivin peptide. Relative values of half-maximal killing are depicted at the right. Flu-pulsed T2 cells (10–5 M) were not recognized (data not shown). Cytotoxicity data represent means of duplicates measured at each E/T ratio or peptide concentration.