MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors
Matthias Leisegang, Susanne Wilde, Stefani Spranger, Slavoljub Milosevic, Bernhard Frankenberger, Wolfgang Uckert, Dolores J. Schendel
Matthias Leisegang, Susanne Wilde, Stefani Spranger, Slavoljub Milosevic, Bernhard Frankenberger, Wolfgang Uckert, Dolores J. Schendel
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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.