A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function.
<h4>Background</h4>Most tumor-associated antigens (TAA) currently used for immunotherapy of cancer are also expressed in normal tissues, which may induce tolerance and impair T cell-mediated immunity. However, there is limited information about how physiological expression in normal tiss...
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Public Library of Science (PLoS)
2007-04-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000353&type=printable |
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| author | Gavin M Bendle Shao-An Xue Angelika Holler Hans J Stauss |
| author_facet | Gavin M Bendle Shao-An Xue Angelika Holler Hans J Stauss |
| author_sort | Gavin M Bendle |
| collection | DOAJ |
| description | <h4>Background</h4>Most tumor-associated antigens (TAA) currently used for immunotherapy of cancer are also expressed in normal tissues, which may induce tolerance and impair T cell-mediated immunity. However, there is limited information about how physiological expression in normal tissues alters the function of TAA-specific T cells.<h4>Methodology/principal findings</h4>We used a T cell receptor transgenic model to study how MDM2 expression in normal tissues affects the function of T cells specific for this TAA that is found at high levels in many different types of tumors. We found that some MDM2-specific T cells escaped thymic deletion and persisted in the peripheral T cell pool. When stimulated with antigen, these T cells readily initiated cell division but failed to proliferate and expand, which was associated with a high rate of apoptosis. Both IL-2 and IL-15 efficiently rescued T cell survival and antigen-specific T cell proliferation, while IL-7 and IL-21 were ineffective. Antigen-stimulated T cells showed impaired expression of the effector molecules CD43, granzyme-B and IFN-gamma, a defect that was completely restored when T cells were stimulated in the presence of IL-2. In contrast, IL-15 and IL-21 only restored the expression of CD43 and granzyme-B, but not IFN-gamma production. Finally, peptide titration experiments with IL-2 rescued T cells indicated that they were of lower avidity than non-tolerant control T cells expressing the same TCR.<h4>Conclusions/significance</h4>These data indicate that cytokines can rescue the antigen-specific proliferation and effector function of MDM2-specific T cells, although this does not lead to the recovery of high avidity T cell function. This study sheds light on possible limitations of immunotherapy approaches that target widely expressed TAA, such as MDM2. |
| format | Article |
| id | doaj-art-61e8c3d9adfd4ab79995e7f84fbc53ab |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2007-04-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-61e8c3d9adfd4ab79995e7f84fbc53ab2025-08-20T02:17:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032007-04-0124e35310.1371/journal.pone.0000353A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function.Gavin M BendleShao-An XueAngelika HollerHans J Stauss<h4>Background</h4>Most tumor-associated antigens (TAA) currently used for immunotherapy of cancer are also expressed in normal tissues, which may induce tolerance and impair T cell-mediated immunity. However, there is limited information about how physiological expression in normal tissues alters the function of TAA-specific T cells.<h4>Methodology/principal findings</h4>We used a T cell receptor transgenic model to study how MDM2 expression in normal tissues affects the function of T cells specific for this TAA that is found at high levels in many different types of tumors. We found that some MDM2-specific T cells escaped thymic deletion and persisted in the peripheral T cell pool. When stimulated with antigen, these T cells readily initiated cell division but failed to proliferate and expand, which was associated with a high rate of apoptosis. Both IL-2 and IL-15 efficiently rescued T cell survival and antigen-specific T cell proliferation, while IL-7 and IL-21 were ineffective. Antigen-stimulated T cells showed impaired expression of the effector molecules CD43, granzyme-B and IFN-gamma, a defect that was completely restored when T cells were stimulated in the presence of IL-2. In contrast, IL-15 and IL-21 only restored the expression of CD43 and granzyme-B, but not IFN-gamma production. Finally, peptide titration experiments with IL-2 rescued T cells indicated that they were of lower avidity than non-tolerant control T cells expressing the same TCR.<h4>Conclusions/significance</h4>These data indicate that cytokines can rescue the antigen-specific proliferation and effector function of MDM2-specific T cells, although this does not lead to the recovery of high avidity T cell function. This study sheds light on possible limitations of immunotherapy approaches that target widely expressed TAA, such as MDM2.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000353&type=printable |
| spellingShingle | Gavin M Bendle Shao-An Xue Angelika Holler Hans J Stauss A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function. PLoS ONE |
| title | A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function. |
| title_full | A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function. |
| title_fullStr | A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function. |
| title_full_unstemmed | A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function. |
| title_short | A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function. |
| title_sort | study of t cell tolerance to the tumor associated antigen mdm2 cytokines can restore antigen responsiveness but not high avidity t cell function |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0000353&type=printable |
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