Generation and characterization of transgenic mice expressing a T-cell receptor specific for the tumour-associated antigen MDM2.
T-cell-based antigen-specific immunotherapy targeting tumour-associated antigens offers the potential for cancer immunotherapy. However, the majority of identified tumour-associated antigens are also expressed at low levels in normal tissues and mechanisms of tolerance induction are likely to affect the quality of T-cell responses to such antigens. In this study a T-cell receptor transgenic model was developed to determine the magnitude of T-cell tolerance to the tumour-associated antigen murine double minute-2 (MDM2), a widely expressed protein that is found at elevated levels in many tumours. The analysis of transgenic mice showed that thymic deletion was responsible for purging large numbers of MDM2-specific T cells from the repertoire. However, some T cells with specificity for MDM2 were able to escape thymic deletion and persisted in the peripheral T-cell pool. Functional analysis revealed that these T cells displayed defects in antigen-driven expansion. This functional impairment of the MDM2-specific T cells was maintained following adoptive transfer of the T cells into hosts that were unable to present the T-cell-receptor-recognized antigen. This study demonstrates that thymic deletion and the functional impairment of T cells present in the periphery both operate to establish T-cell tolerance to the tumour-associated antigen MDM2. Furthermore, the tolerant phenotype was stable and did not require continuous MDM2 peptide presentation in normal tissues.
Xue
Shao-An
SA
Department of Immunology & Molecular Pathology, University College London, Royal Free Hospital, London, UK.
Bendle
Gavin M
GM
Holler
Angelika
A
Stauss
Hans J
HJ
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology
D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2