A study of T cell tolerance to the tumor-associated antigen MDM2: cytokines can restore antigen responsiveness, but not high avidity T cell function.
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.


RESULTS
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.


CONCLUSIONS
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.
Bendle
Gavin M
GM
Centre de Recherche Public-Santé, Luxembourg.
Xue
Shao-An
SA
Holler
Angelika
A
Stauss
Hans J
HJ
D000818:Animals; D000915:Antibody Affinity; D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000502:physiology*; D017931:DNA Primers; D005434:Flow Cytometry; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D051736:Proto-Oncogene Proteins c-mdm2 / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
D016207:Cytokines; D017931:DNA Primers; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2