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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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 5

Analysis of mRNA levels for TAAs in activated T cells.

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Analysis of mRNA levels for TAAs in activated T cells. Quantitative mRNA...
Quantitative mRNA expression of 22 TAAs was performed using activated lymphocytes of 4 healthy donors using LightCycler technology, and the values are given as mean with SEM. For each donor, the TAA expression profile of nonactivated PBMCs and nonactivated enriched CD8+ T cells was compared with that of CD3/CD28-activated PBMCs and CD8+ T cells. Differences in mRNA levels detected in unstimulated versus stimulated cell populations were expressed as x-fold increases and are depicted on the x axis. The y axis represents the CP values, in order to demonstrate the overall prevalence of TAAs in activated cells. The CP value defines the cycle number in the logarithmic phase of the PCR where the product is the same in all the samples that are compared. Low CP values represent high levels of mRNA template, while high CP values indicate rare mRNA templates. An mRNA template with a CP value of less than 30 is considered rare. The housekeeping gene 18S rRNA was processed as an internal control for normalization of samples. The data were statistically analyzed as described in Methods.