| First Author | Xue SA | Year | 2008 |
| Journal | Immunology | Volume | 124 |
| Issue | 3 | Pages | 315-21 |
| PubMed ID | 18217949 | Mgi Jnum | J:138470 |
| Mgi Id | MGI:3805192 | Doi | 10.1111/j.1365-2567.2007.02793.x |
| Citation | Xue SA, et al. (2008) Generation and characterization of transgenic mice expressing a T-cell receptor specific for the tumour-associated antigen MDM2. Immunology 124(3):315-21 |
| abstractText | 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. |
