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.
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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.).
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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.
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N.S. and S.S. are employees of Ono Pharmaceutical.
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Supplementary Figures 1–8 and Table 1 (PDF 1084 kb)
Supplementary Table 2
Microarray comparison of Trim28 regulated genes. (XLS 244 kb)
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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
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DOI: https://doi.org/10.1038/ni.2293
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