title: Downmodulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific CD4(+) T cell responses.
abstract: 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.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Kyung Duk
authors.initials: KD
authors.lastname: Moon
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Vacchio
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Hathcock
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: hodesr@31.nia.nih.gov.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hodes
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D007376:Interleukin-2 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D007376:Interleukin-2; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2