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CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor

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Item Type:Article
Title:CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor
Creators Name:Ghorashian, S. and Veliça, P. and Chua, I. and McNicol, A. and Carpenter, B. and Holler, A. and Nicholson, E. and Ahmadi, M. and Zech, M. and Xue, S. and Uckert, W. and Morris, E. and Chakraverty, R. and Stauss, H.J.
Abstract:Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR-engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8(+) T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR-engineered CD4(+) T cells provided help and restored cytotoxic function of CD8(+) T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4(+) T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I-restricted TCR responsible for Ag recognition and tolerance induction in CD8(+) T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I-restricted CD4(+) T cells may enhance the efficacy of therapeutic TCR-engineered CD8(+) T cells and can be readily generated with the same TCR.
Keywords:Adoptive Transfer, Autoantigens, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Communication, Gene Expression, Genetic Transduction, Immune Tolerance, Immunologic Cytotoxicity, Immunophenotyping, Neoplasm Antigens, Phenotype, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Transgenic Mice, T-Cell Antigen Receptors, Animals, Mice
Source:Journal of Immunology
ISSN:0022-1767
Publisher:American Association of Immunologists (U.S.A.)
Volume:194
Number:3
Page Range:1080-1089
Date:1 February 2015
Official Publication:https://doi.org/10.4049/jimmunol.1401703
PubMed:View item in PubMed

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