Transcription factor p73 regulates Th1 differentiation.
Alleles
Animals
Base Sequence
Binding Sites
Cell Differentiation
Colitis
/ pathology
DNA
/ metabolism
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental
/ pathology
Gene Deletion
Gene Expression Regulation
Interferon-gamma
/ metabolism
Mice
Mutant Proteins
/ chemistry
Protein Binding
Protein Domains
Severity of Illness Index
Th1 Cells
/ cytology
Tumor Protein p73
/ chemistry
Tumor Suppressor Protein p53
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 03 2020
19 03 2020
Historique:
received:
03
08
2018
accepted:
12
02
2020
entrez:
21
3
2020
pubmed:
21
3
2020
medline:
16
7
2020
Statut:
epublish
Résumé
Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases. To identify factors contributing to these response differences, here we analyze in vitro differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicates that the p53 family protein, p73, affects Th1 differentiation. In cells differentiated under Th1 conditions in vitro, p73 negatively regulates IFNγ production. p73 binds within, or upstream of, and modulates the expression of Th1 differentiation-related genes such as Ifng and Il12rb2. Furthermore, in mouse experimental autoimmune encephalitis, p73-deficient mice have increased IFNγ production and less disease severity, whereas in an adoptive transfer model of inflammatory bowel disease, transfer of p73-deficient naïve CD4
Identifiants
pubmed: 32193462
doi: 10.1038/s41467-020-15172-5
pii: 10.1038/s41467-020-15172-5
pmc: PMC7081339
doi:
Substances chimiques
Mutant Proteins
0
Tumor Protein p73
0
Tumor Suppressor Protein p53
0
Interferon-gamma
82115-62-6
DNA
9007-49-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1475Subventions
Organisme : NHLBI NIH HHS
ID : K22 HL125593
Pays : United States
Références
Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445–489 (2010).
doi: 10.1146/annurev-immunol-030409-101212
Yamane, H. & Paul, W. E. Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets. Immunol. Rev. 252, 12–23 (2013).
doi: 10.1111/imr.12032
Nakayamada, S., Takahashi, H., Kanno, Y. & O’Shea, J. J. Helper T cell diversity and plasticity. Curr. Opin. Immunol. 24, 297–302 (2012).
doi: 10.1016/j.coi.2012.01.014
Soong, L., Henard, C. A. & Melby, P. C. Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasis. Semin. Immunopathol. 34, 735–751 (2012).
doi: 10.1007/s00281-012-0350-8
Zheng, M., Dill, D. & Peltz, G. A better prognosis for genetic association studies in mice. Trends Genet. 28, 62–69 (2012).
doi: 10.1016/j.tig.2011.10.006
Wang, J., Liao, G., Usuka, J. & Peltz, G. Computational genetics: from mouse to human. Trends Genet. 21, 526–532 (2005).
doi: 10.1016/j.tig.2005.06.010
Levrero, M. et al. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J. Cell Sci. 113(Pt 10), 1661–1670 (2000).
Allocati, N., Di Ilio, C. & De Laurenzi, V. p63/p73 in the control of cell cycle and cell death. Exp. Cell Res. 318, 1285–1290 (2012).
Nicolai, S. et al. DNA repair and aging: the impact of the p53 family. Aging (Albany NY) 7, 1050–1065 (2015).
doi: 10.18632/aging.100858
Yoon, M. K., Ha, J. H., Lee, M. S. & Chi, S. W. Structure and apoptotic function of p73. BMB Rep. 48, 81–90 (2015).
doi: 10.5483/BMBRep.2015.48.2.255
Napoli, M. & Flores, E. R. The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy. Br. J. Cancer 116, 149–155 (2017).
Ozaki, T., Kubo, N. & Nakagawara, A. p73-binding partners and their functional significance. Int. J. Proteomics 2010, 283863 (2010).
doi: 10.1155/2010/283863
Slade, N. & Horvat, A. Targeting p73–a potential approach in cancer treatment. Curr. Pharm. Des. 17, 591–602 (2011).
doi: 10.2174/138161211795222621
Rufini, A. et al. p73 in cancer. Genes Cancer 2, 491–502 (2011).
Alexandrova, E. M. & Moll, U. M. Role of p53 family members p73 and p63 in human hematological malignancies. Leuk. Lymphoma 53, 2116–2129 (2012).
Yang, A. et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404, 99–103 (2000).
doi: 10.1038/35003607
Zheng, M. et al. The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans. PLoS Med. 12, e1001782 (2015).
doi: 10.1371/journal.pmed.1001782
Liao, G. et al. In silico genetics: identification of a functional element regulating H2-Ealpha gene expression. Science 306, 690–695 (2004).
doi: 10.1126/science.1100636
Yang, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28, 29–39 (2008).
doi: 10.1016/j.immuni.2007.11.016
Maas, A. M., Bretz, A. C., Mack, E. & Stiewe, T. Targeting p73 in cancer. Cancer Lett. 332, 229–236 (2013).
doi: 10.1016/j.canlet.2011.07.030
Oestreich, K. J. & Weinmann, A. S. Transcriptional mechanisms that regulate T helper 1 cell differentiation. Curr. Opin. Immunol. 24, 191–195 (2012).
doi: 10.1016/j.coi.2011.12.004
Soond, S. M. et al. STAT1 regulates p73-mediated Bax gene expression. FEBS Lett. 581, 1217–1226 (2007).
doi: 10.1016/j.febslet.2007.02.049
Ethayathulla, A. S. et al. Structure of p73 DNA-binding domain tetramer modulates p73 transactivation. Proc. Natl Acad. Sci. USA 109, 6066–6071 (2012).
Lokshin, M., Li, Y., Gaiddon, C. & Prives, C. p53 and p73 display common and distinct requirements for sequence specific binding to DNA. Nucleic Acids Res. 35, 340–352 (2007).
Legroux, L. & Arbour, N. Multiple sclerosis and T lymphocytes: an entangled story. J. Neuroimmune Pharmacol. 10, 528–546 (2015).
doi: 10.1007/s11481-015-9614-0
Senoo, M., Manis, J. P., Alt, F. W. & McKeon, F. p63 and p73 are not required for the development and p53-dependent apoptosis of T cells. Cancer Cell 6, 85–89 (2004).
Nemajerova, A., Palacios, G., Nowak, N. J., Matsui, S. & Petrenko, O. Targeted deletion of p73 in mice reveals its role in T cell development and lymphomagenesis. PLoS ONE 4, e7784 (2009).
doi: 10.1371/journal.pone.0007784
Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).
doi: 10.1038/nature06005
Strober, W., Fuss, I. J. & Blumberg, R. S. The immunology of mucosal models of inflammation. Annu. Rev. Immunol. 20, 495–549 (2002).
doi: 10.1146/annurev.immunol.20.100301.064816
Liao, W., Lin, J. X. & Leonard, W. J. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr. Opin. Immunol. 23, 598–604 (2011).
doi: 10.1016/j.coi.2011.08.003
Liao, W., Lin, J. X., Wang, L., Li, P. & Leonard, W. J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat. Immunol. 12, 551–559 (2011).
doi: 10.1038/ni.2030
Zundler, S. & Neurath, M. F. Interleukin-12: functional activities and implications for disease. Cytokine Growth Factor Rev. 26, 559–568 (2015).
doi: 10.1016/j.cytogfr.2015.07.003
Arellano, G., Ottum, P. A., Reyes, L. I., Burgos, P. I. & Naves, R. Stage-specific role of interferon-gamma in experimental autoimmune encephalomyelitis and multiple sclerosis. Front. Immunol. 6, 492 (2015).
doi: 10.3389/fimmu.2015.00492
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
doi: 10.1038/nature05911
Peltz, G. et al. Next-generation computational genetic analysis: multiple complement alleles control survival after Candida albicans infection. Infect. Immun. 79, 4472–4479 (2011).
doi: 10.1128/IAI.05666-11
Du, N. et al. EGR2 is critical for peripheral naive T-cell differentiation and the T-cell response to influenza. Proc. Natl Acad. Sci. USA 111, 16484–16489 (2014).
doi: 10.1073/pnas.1417215111
Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011).
doi: 10.1186/1471-2105-12-323
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
doi: 10.1093/bioinformatics/btp616
Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).
doi: 10.1186/gb-2009-10-3-r25
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
doi: 10.1186/gb-2008-9-9-r137
Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).
doi: 10.1038/nbt.1754
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
doi: 10.1016/j.molcel.2010.05.004
Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).
doi: 10.1084/jem.190.7.995
Valatas, V. et al. Host-dependent control of early regulatory and effector T-cell differentiation underlies the genetic susceptibility of RAG2-deficient mouse strains to transfer colitis. Mucosal Immunol. 6, 601–611 (2013).
doi: 10.1038/mi.2012.102