Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

TRIM28 prevents autoinflammatory T cell development in vivo

Nature Immunology volume 13, pages 596–603 (2012)Cite this article

Subjects

Abstract

TRIM28 is a component of heterochromatin complexes whose function in the immune system is unknown. By studying mice with conditional T cell–specific deletion of TRIM28 (CKO mice), we found that TRIM28 was phosphorylated after stimulation via the T cell antigen receptor (TCR) and was involved in the global regulation of CD4+ T cells. The CKO mice had a spontaneous autoimmune phenotype that was due in part to early lymphopenia associated with a defect in the production of interleukin 2 (IL-2) as well as incomplete cell-cycle progression of their T cells. In addition, CKO T cells showed derepression of the cytokine TGF-β3, which resulted in an altered cytokine balance; this caused the accumulation of autoreactive cells of the TH17 subset of helper T cells and of Foxp3+ T cells. Notably, CKO Foxp3+ T cells were unable to prevent the autoimmune phenotype in vivo. Our results show critical roles for TRIM28 in both T cell activation and T cell tolerance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: TRIM28 is regulated by TCR signaling and regulates IL-2 production.
Figure 2: CKO mice show mild T lymphopenia, defective IL-2 production and defective cell-cycle progression.
Figure 3: Accumulation of autoreactive TH17 cells in TRIM28-deficient mice.
Figure 4: TRIM28 deficiency exacerbates EAE, with enhanced induction of TH17 cells.
Figure 5: Aberrant induction of Foxp3+ T cells in TRIM28-deficient mice.
Figure 6: Cell-extrinsic promotion of TH17 cells and Foxp3+ T cells by TRIM28-deficient T cells.
Figure 7: Deregulation of TGF-β expression in TRIM28 deficiency.
Figure 8: Functional involvement of TGF-β production in TRIM28 deficiency.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Cantrell, D. T cell antigen receptor signal transduction pathways. Annu. Rev. Immunol. 14, 259–274 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  Google Scholar 

  3. Jordan, M.S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306 (2001).

    Article  CAS  Google Scholar 

  4. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 3, 756–763 (2002).

    Article  CAS  Google Scholar 

  5. Marks, B.R. et al. Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation. Nat. Immunol. 10, 1125–1132 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  Google Scholar 

  7. Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  Google Scholar 

  9. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000–1007 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

    Article  CAS  Google Scholar 

  11. Lee, Y.K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Reymond, A. et al. The tripartite motif family identifies cell compartments. EMBO J. 20, 2140–2151 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Le Douarin, B. et al. A possible involvement of TIF1α and TIF1β in the epigenetic control of transcription by nuclear receptors. EMBO J. 15, 6701–6715 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Friedman, J.R. et al. KAP-1, a novel corepressor for the highly conserved KRAB repression domain. Genes Dev. 10, 2067–2078 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Moosmann, P., Georgiev, O., Le Douarin, B., Bourquin, J.P. & Schaffner, W. Transcriptional repression by RING finger protein TIF1β that interacts with the KRAB repressor domain of KOX1. Nucleic Acids Res. 24, 4859–4867 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Nielsen, A.L. et al. Interaction with members of the heterochromatin protein 1 (HP1) family and histone deacetylation are differentially involved in transcriptional silencing by members of the TIF1 family. EMBO J. 18, 6385–6395 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Schultz, D.C., Ayyanathan, K., Negorev, D., Maul, G.G. & Rauscher, F.J. 3rd SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 919–932 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Wolf, D. & Goff, S.P. TRIM28 mediates primer binding site-targeted silencing of murine leukemia virus in embryonic cells. Cell 131, 46–57 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Rowe, H.M. et al. KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463, 237–240 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. White, D.E. et al. KAP1, a novel substrate for PIKK family members, colocalizes with numerous damage response factors at DNA lesions. Cancer Res. 66, 11594–11599 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Noon, A.T. et al. 53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair. Nat. Cell Biol. 12, 177–184 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Ziv, Y. et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat. Cell Biol. 8, 870–876 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Gack, M.U. et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Tsuchida, T. et al. The Ubiquitin Ligase TRIM56 Regulates Innate Immune Responses to Intracellular Double-Stranded DNA. Immunity 33, 765–776 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Okazaki, I.M. et al. Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation. Proc. Natl. Acad. Sci. USA 108, 7920–7925 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Navarro, M.N., Goebel, J., Feijoo-Carnero, C., Morrice, N. & Cantrell, D.A. Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes. Nat. Immunol. 12, 352–361 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Chang, C.W. et al. Phosphorylation at Ser473 regulates heterochromatin protein 1 binding and corepressor function of TIF1β/KAP1. BMC Mol. Biol. 9, 61 (2008).

    Article  PubMed  Google Scholar 

  28. Stefanová, I., Dorfman, J.R. & Germain, R.N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429–434 (2002).

    Article  Google Scholar 

  29. Cammas, F. et al. Mice lacking the transcriptional corepressor TIF1β are defective in early postimplantation development. Development 127, 2955–2963 (2000).

    CAS  PubMed  Google Scholar 

  30. Takahama, Y. et al. Functional competence of T cells in the absence of glycosylphosphatidylinositol-anchored proteins caused by T cell-specific disruption of the Pig-a gene. Eur. J. Immunol. 28, 2159–2166 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Linton, P.J., Haynes, L., Tsui, L., Zhang, X. & Swain, S. From naive to effector–alterations with aging. Immunol. Rev. 160, 9–18 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Veldhoen, M., Hocking, R.J., Flavell, R.A. & Stockinger, B. Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat. Immunol. 7, 1151–1156 (2006).

    Article  CAS  Google Scholar 

  33. Nelson, B.H. IL-2, regulatory T cells, and tolerance. J. Immunol. 172, 3983–3988 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    Article  CAS  Google Scholar 

  35. Zhou, X. et al. Selective miRNA disruption in Treg cells leads to uncontrolled autoimmunity. J. Exp. Med. 205, 1983–1991 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Graycar, J.L. et al. Human transforming growth factor-β3: recombinant expression, purification, and biological activities in comparison with transforming growth factors-β1 and -β2. Mol. Endocrinol. 3, 1977–1986 (1989).

    Article  CAS  PubMed  Google Scholar 

  37. Webster, K.E. et al. In vivo expansion of Treg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med. 206, 751–760 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. King, C., Ilic, A., Koelsch, K. & Sarvetnick, N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 117, 265–277 (2004).

    Article  CAS  Google Scholar 

  39. Kench, J.A. et al. Aberrant wound healing and TGF-β production in the autoimmune-prone MRL/+ mouse. Clin. Immunol. 92, 300–310 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Lowrance, J.H., O'Sullivan, F.X., Caver, T.E., Waegell, W. & Gresham, H.D. Spontaneous elaboration of transforming growth factor β suppresses host defense against bacterial infection in autoimmune MRL/lpr mice. J. Exp. Med. 180, 1693–1703 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, Z., Kyttaris, V.C. & Tsokos, G.C. The role of IL-23/IL-17 axis in lupus nephritis. J. Immunol. 183, 3160–3169 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Caver, T.E., O'Sullivan, F.X., Gold, L.I. & Gresham, H.D. Intracellular demonstration of active TGFβ1 in B cells and plasma cells of autoimmune mice. IgG-bound TGFβ1 suppresses neutrophil function and host defense against Staphylococcus aureus infection. J. Clin. Invest. 98, 2496–2506 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Münoz-Valle, J.F. et al. The functional class evaluated in rheumatoid arthritis is associated with soluble TGF-β1 serum levels but not with G915C (Arg25Pro) TGF-β1 polymorphism. Rheumatol. Int. 32, 367–372 (2010).

    Article  PubMed  Google Scholar 

  44. Gutcher, I. et al. Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation. Immunity 34, 396–408 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Beyer, M. et al. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat. Immunol. 12, 898–907 (1038).

    Article  Google Scholar 

  46. Maloy, K.J. Induction and regulation of inflammatory bowel disease in immunodeficient mice by distinct CD4+ T-cell subsets. Methods Mol. Biol. 380, 327–335 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank X. Zhou, A. Shimizu, S. Bailey-Bucktrout, K. Ikuta, T. Eagar, K. Ogasawara and M. Aida for discussions; K. Yurimoto for assistance in mouse genotyping; P. Chambon and R. Losson (Institut de Génétique et de Biologie Moléculaire et Cellulaire, France) for mice with loxP-flanked Trim28 alleles; J. Takeda (Osaka University) for mice with Cre expression driven by the Lck promoter; J. Bluestone (University of California-San Francisco) for Foxp3-GFP-Cre–transgenic mice; S. Nagata (Kyoto University) for CD45.1+ mice; K. Kabashima (Kyoto University) for Rag2−/− mice; and J. Bluestone and N. Minato for critical reading of the manuscript. Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI Grant-in-Aid for Scientific Research Young Scientist (B) 21790465 and 23790534 to S.C.) and the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (T.H.).

Author information

Authors and Affiliations

  1. Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Shunsuke Chikuma & Tasuku Honjo

  2. Advanced Medicinal Research Laboratories, Tsukuba Research Institute, Ono Pharmaceutical, Tsukuba, Japan

    Naomasa Suita

  3. Division of Immune Regulation, Institute for Genome Research, The University of Tokushima, Tsukuba, Japan

    Il-Mi Okazaki

  4. Exploratory Research Laboratories, Tsukuba Research Institute, Ono Pharmaceutical, Tsukuba, Japan

    Shiro Shibayama

Authors
  1. Shunsuke Chikuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naomasa Suita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Il-Mi Okazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shiro Shibayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tasuku Honjo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.C. and T.H. designed the research; S.C. did experiments; S.C., N.S. and S.S. did microarrays and analyzed the data; I.-M.O. provided materials essential to the research; and S.C. and T.H. wrote the paper.

Corresponding author

Correspondence to Tasuku Honjo.

Ethics declarations

Competing interests

N.S. and S.S. are employees of Ono Pharmaceutical.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Table 1 (PDF 1084 kb)

Supplementary Table 2

Microarray comparison of Trim28 regulated genes. (XLS 244 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chikuma, S., Suita, N., Okazaki, IM. et al. TRIM28 prevents autoinflammatory T cell development in vivo. Nat Immunol 13, 596–603 (2012). https://doi.org/10.1038/ni.2293

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2293

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing