Related Experiment Video
Updated: Jun 7, 2026
Use of Single Chain MHC Technology to Investigate Co-agonism in Human CD8+ T Cell Activation
Published on: February 28, 2019
MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors
Matthias Leisegang1, Susanne Wilde, Stefani Spranger
1Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
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.
Insights
Survivin-targeted T cell therapy faces a challenge: survivin expression in T cells causes self-destruction (fratricide) in an HLA-A2 restricted manner, limiting its use in cancer immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Medicine
Background:
- Survivin, an apoptosis inhibitor, is highly expressed in numerous tumors, presenting a potential target for immunotherapy.
- Adoptive T cell therapy using T cells engineered with specific T cell receptors (TCRs) is a promising cancer treatment strategy.
Purpose of the Study:
- To investigate survivin as a target antigen for adoptive T cell therapy using survivin-specific transgenic T cell receptors (Tg-TCRs).
- To assess the efficacy and potential limitations of survivin-targeted T cell therapy.
Main Methods:
- Isolation of HLA-A2-allorestricted survivin-specific T cells with high functional avidity.
- Generation of lymphocytes expressing survivin-specific Tg-TCRs.
- Evaluation of T cell recognition of tumor cells and self-lymphocytes.
Main Results:
- Survivin-specific Tg-TCR-expressing lymphocytes recognized and killed HLA-A2+ survivin+ tumor cells.
- HLA-A2+ lymphocytes expressing Tg-TCRs underwent significant apoptosis due to HLA-A2-restricted fratricide, caused by survivin expression in lymphocytes.
- Survivin-specific Tg-TCR-expressing lymphocytes also eliminated other T cell clones from HLA-A2+ donors, but not HLA-A2- donors.
Conclusions:
- Survivin-specific TCR gene therapy is limited by self-MHC-restricted fratricide and may be restricted to HLA-A2-mismatched stem cell transplantation.
- Targeting self-proteins like survivin, which are also expressed in activated lymphocytes, raises concerns for cancer vaccine development due to potential self-destruction of therapeutic T cells and bystander T cells.
More Related Videos
11:31Determining Optimal Cytotoxic Activity of Human Her2neu Specific CD8 T cells by Comparing the Cr51 Release Assay to the xCELLigence System
Published on: August 8, 2012
10:13Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
