Roquin represses autoimmunity by limiting inducible t-cell co-stimulator messenger rna

ABSTRACT Immune responses are normally targeted against microbial pathogens and not self-antigens by mechanisms that are only partly understood. Here we define a newly discovered pathway

that prevents autoimmunity by limiting the levels on T lymphocytes of a co-stimulatory receptor, the inducible T-cell co-stimulator (ICOS). In _sanroque_ mice homozygous for an M199R

mutation in the ROQ domain of Roquin (also known as Rc3h1)1, increased Icos expression on T cells causes the accumulation of lymphocytes that is associated with a lupus-like autoimmune

syndrome. Roquin normally limits Icos expression by promoting the degradation of _Icos_ messenger RNA. A conserved segment in the unusually long _ICOS_ 3′ untranslated mRNA is essential for

regulation by Roquin. This segment comprises a 47-base-pair minimal region complementary to T-cell-expressed microRNAs including miR-101, the repressive activity of which is disrupted by

base-pair inversions predicted to abrogate miR-101 binding. These findings illuminate a critical post-transcriptional pathway within T cells that regulates lymphocyte accumulation and

autoimmunity, and highlights the therapeutic potential of partially antagonising the ICOS pathway. Access through your institution Buy or subscribe This is a preview of subscription content,

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PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS We thank R. Parker and J. Liu for the MS2–YFP–NLS plasmids; R. Kroczek and Millennium Pharmaceuticals for _Icos_-/- mice;

Q.-J. Li, M. Davis and C.-Z. Chen for advice with the miRNA experiments; and the ACRF Biomolecular Resource Facility for real-time RT–PCR. This work was supported by the NHMRC, and by a

Senior Viertel Medical Research Fellowship to C.G.V. AUTHOR CONTRIBUTIONS D.Y., C.C.G. and C.G.V. designed the study; D.Y., A.H.T. and X.H. performed experiments and analyzed the data; V.A.,

N.S., K.M.G. and D.G.S. helped with experiments; A.H., P.J.L. and K.P.L. provided expertise and advice; and D.Y., C.C.G. and C.G.V. wrote the manuscript. AUTHOR INFORMATION Author notes *

Christopher C. Goodnow and Carola G. Vinuesa: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Division of Immunology and Genetics, John Curtin School of Medical

Research, The Australian National University, Canberra, 2601, Australia, Di Yu, Xin Hu, Vicki Athanasopoulos, Nicholas Simpson, Diego G. Silva, Christopher C. Goodnow & Carola G. Vinuesa

* Laboratory of Molecular and Cellular Immunology, Biomedical Sciences Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore , Andy Hee-Meng Tan &

 Kong Peng Lam * ARC Centre for the Molecular Genetics of Development, Australian National University, Canberra, 2601, Australia , Vicki Athanasopoulos * Molecular Immunology, Robert

Koch-Institute, 13353, Berlin, Germany , Andreas Hutloff * Laboratory for Cancer Medicine, The University of Western Australia Centre for Medical Research, Western Australian Institute for

Medical Research, Perth, 6000, Australia , Keith M. Giles & Peter J. Leedman * School of Medicine and Pharmacology, The University of Western Australia, Perth, 6000, Australia , Peter J.

Leedman * Australian Phenomics Facility, Canberra, 2601, Australia , Christopher C. Goodnow Authors * Di Yu View author publications You can also search for this author inPubMed Google

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search for this author inPubMed Google Scholar * Diego G. Silva View author publications You can also search for this author inPubMed Google Scholar * Andreas Hutloff View author

publications You can also search for this author inPubMed Google Scholar * Keith M. Giles View author publications You can also search for this author inPubMed Google Scholar * Peter J.

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this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Carola G. Vinuesa. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests.

SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary Figures 1-12 with Legends and Supplementary Table 1. (PDF 555 kb) RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Di Yu, Tan, AM., Hu, X. _et al._ Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. _Nature_ 450,

299–303 (2007). https://doi.org/10.1038/nature06253 Download citation * Received: 30 June 2007 * Accepted: 11 September 2007 * Issue Date: 08 November 2007 * DOI:

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