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题名:A Study of T Cell Tolerance to the Tumor-Associated Antigen MDM2: Cytokines Can Restore Antigen Responsiveness, but Not High Avidity T Cell Function.
作者:Bendle GM, Xue SA, Holler A, Stauss HJ. Related Articles, Links
来源:PLoS ONE[IF=----]. 2007 Apr 4;2:e353.
URL :http://dx.doi.org/10.1371/journal.pone.0000353
日期:070415
摘要: Gavin M. Bendle, Shao-An Xue, Angelika Holler, and Hans J. Stauss*

Centre de Recherche Public-Sant, Luxembourg

* To whom correspondence should be addressed. E-mail: h.stauss@medsch.ucl.ac.uk
Conceived and designed the experiments: HS GB SX AH. Performed the experiments: GB SX AH. Analyzed the data: HS GB SX AH. Wrote the paper: HS GB.

Received March 7, 2007; Accepted March 13, 2007.

Abstract

Background
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.

Methodology/Principal Findings
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-, 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- 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.

Conclusions/Significance
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.

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