Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4(+) T cell responses

Immunity. 2014 May 15;40(5):681-91. doi: 10.1016/j.immuni.2014.04.006. Epub 2014 May 1.


Antigen specificity is critical in immune response and requires integration of antigen-specific signals with antigen-nonspecific signals such as those provided by cytokines. The mechanism integrating these pathways is incompletely understood. We report here that antigen-specific proliferative responses of CD4(+) T cells required downmodulation of tumor suppressor p53. In the absence of T cell receptor (TCR) signal, IL-2 induced sustained increase in p53 protein, which prevented proliferative responses despite strong signaling through the IL-2 receptor. In contrast, TCR signaling resulted in early termination of p53 protein expression by decreasing p53 mRNA as well as strong transcriptional induction of the p53-regulating protein Mdm2. Downmodulation of p53 in response to antigen stimulation was in fact critical for antigen-specific T cell proliferation, and preventing p53 degradation by inhibiting Mdm2 resulted in sustained p53 protein and prevented antigen-specific T cell proliferation. It is thus termination of p53 by TCR signaling that allows proliferative responses, enforcing antigen specificity.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Specificity / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Cycle / genetics
  • Cell Cycle / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Interleukin-2 / immunology*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • RNA, Messenger / biosynthesis
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Interleukin-2 / immunology
  • Signal Transduction / immunology
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics*


  • Interleukin-2
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-2
  • Tumor Suppressor Protein p53
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2