a study of t cell tolerance to the tumor-associated antigen mdm2 cytokines can restore antigen responsiveness, but not high avidity t cell function研究肿瘤相关抗原的t细胞耐受mdm2细胞因子可以恢复抗原反应,但不是高活动性t细胞的功能.pdfVIP

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a study of t cell tolerance to the tumor-associated antigen mdm2 cytokines can restore antigen responsiveness, but not high avidity t cell function研究肿瘤相关抗原的t细胞耐受mdm2细胞因子可以恢复抗原反应,但不是高活动性t细胞的功能.pdf

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a study of t cell tolerance to the tumor-associated antigen mdm2 cytokines can restore antigen responsiveness, but not high avidity t cell function研究肿瘤相关抗原的t细胞耐受mdm2细胞因子可以恢复抗原反应,但不是高活动性t细胞的功能

A 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. Bendle., Shao-An Xue., Angelika Holler, Hans J. Stauss* 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-c, 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-c 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 limitati