title: Tumor suppressor p53 inhibits systemic autoimmune diseases by inducing regulatory T cells.
abstract: The tumor suppressor p53 plays a central role in tumor suppression by inducing apoptosis, cell cycle arrest, senescence, and DNA repair. In addition to the antitumor functions of p53, accumulating evidence using systemic p53-deficient mice suggests that p53 suppresses autoimmunity. However, it remains unknown how p53 suppresses autoimmunity. In this study, we generated T cell-specific p53-deficient mice (CD4-Cre p53(fl/fl) mice, or p53 conditional knockout [cKO] mice) and found that aged p53-cKO mice spontaneously developed inflammatory lesions in various organs, including lung, liver, stomach, thyroid gland, submandibular gland, and kidney. Additionally, anti-nuclear Abs and autoantibodies against gastric parietal cells were detected in p53-cKO mice but not in control p53(fl/fl) mice (p53 wild-type mice). Importantly, the number of Foxp3(+)CD4(+) regulatory T cells (Tregs) in the spleen and lung as well as in vitro differentiation of induced Tregs was significantly reduced in p53-cKO mice as compared with that in p53 wild-type mice. Regarding the mechanisms underlying p53-mediated Treg induction, p53 enhanced the transcription of Foxp3 by binding to the promoter and the conserved noncoding DNA sequence-2 of the Foxp3 gene. Taken together, these results suggest that p53 expressed in T cells functions as a suppressor for autoimmunity by inducing Treg differentiation.
authors.affiliation: Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kawashima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takatori
authors.forename: Kotaro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Arifumi
authors.initials: A
authors.lastname: Iwata
authors.forename: Masaya
authors.initials: M
authors.lastname: Yokota
authors.forename: Akira
authors.initials: A
authors.lastname: Suto
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirose
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53