Redirection of T cells by delivering a transgenic mouse-derived MDM2 tumor antigen-specific TCR and its humanized derivative is governed by the CD8 coreceptor and affects natural human TCR expression.

Details

Serval ID
serval:BIB_02A56F3E95A5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Redirection of T cells by delivering a transgenic mouse-derived MDM2 tumor antigen-specific TCR and its humanized derivative is governed by the CD8 coreceptor and affects natural human TCR expression.
Journal
Immunologic Research
Author(s)
Voss R.H., Kuball J., Engel R., Guillaume P., Romero P., Huber C., Theobald M.
ISSN
0257-277X, 0257-277X[linking]
Publication state
Published
Issued date
2006
Volume
34
Number
1
Pages
67-87
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Retroviral transfer of T cell antigen receptor (TCR) genes selected by circumventing tolerance to broad tumor- and leukemia-associated antigens in human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic (Tg) mice allows the therapeutic reprogramming of human T lymphocytes. Using a human CD8 x A2.1/Kb mouse derived TCR specific for natural peptide-A2.1 (pA2.1) complexes comprising residues 81-88 of the human homolog of the murine double-minute 2 oncoprotein, MDM2(81-88), we found that the heterodimeric CD8 alpha beta coreceptor, but not normally expressed homodimeric CD8 alpha alpha, is required for tetramer binding and functional redirection of TCR- transduced human T cells. CD8+T cells that received a humanized derivative of the MDM2 TCR bound pA2.1 tetramers only in the presence of an anti-human-CD8 anti-body and required more peptide than wild-type (WT) MDM2 TCR+T cells to mount equivalent cytotoxicity. They were, however, sufficiently effective in recognizing malignant targets including fresh leukemia cells. Most efficient expression of transduced TCR in human T lymphocytes was governed by mouse as compared to human constant (C) alphabeta domains, as demonstrated with partially humanized and murinized TCR of primary mouse and human origin, respectively. We further observed a reciprocal relationship between the level of Tg WT mouse relative to natural human TCR expression, resulting in T cells with decreased normal human cell surface TCR. In contrast, natural human TCR display remained unaffected after delivery of the humanized MDM2 TCR. These results provide important insights into the molecular basis of TCR gene therapy of malignant disease.
Keywords
Animals, CD4-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/immunology, Cell Line, Tumor, Epitopes, T-Lymphocyte/immunology, Flow Cytometry, HLA-A2 Antigen/immunology, Humans, Mice, Mice, Transgenic, Proto-Oncogene Proteins c-mdm2/genetics, Proto-Oncogene Proteins c-mdm2/immunology, Receptors, Antigen, T-Cell, alpha-beta/immunology, Reverse Transcriptase Polymerase Chain Reaction, Self Tolerance/immunology
Pubmed
Web of science
Create date
28/01/2008 11:28
Last modification date
20/08/2019 12:24
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