Access

Letter

Nature 450, 299-303 (8 November 2007) | doi:10.1038/nature06253; Received 30 June 2007; Accepted 11 September 2007

There is an Erratum (21 February 2008) associated with this document.

Open Innovation Challenges

naturejobs

More science jobs
Post a job for free

Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA

Di Yu1, Andy Hee-Meng Tan2, Xin Hu1, Vicki Athanasopoulos1,3, Nicholas Simpson1, Diego G. Silva1, Andreas Hutloff4, Keith M. Giles5, Peter J. Leedman5,6, Kong Peng Lam2, Christopher C. Goodnow1,7,8 & Carola G. Vinuesa1,8

  1. Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, 2601, Australia
  2. Laboratory of Molecular and Cellular Immunology, Biomedical Sciences Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
  3. ARC Centre for the Molecular Genetics of Development, Australian National University, Canberra, 2601, Australia
  4. Molecular Immunology, Robert Koch-Institute, 13353, Berlin, Germany
  5. Laboratory for Cancer Medicine, The University of Western Australia Centre for Medical Research, Western Australian Institute for Medical Research, Perth, 6000, Australia
  6. School of Medicine and Pharmacology, The University of Western Australia, Perth, 6000, Australia
  7. Australian Phenomics Facility, Canberra, 2601, Australia
  8. These authors contributed equally to this work.

Correspondence to: Carola G. Vinuesa1,8 Correspondence and requests for materials should be addressed to C.G.V. (Email: carola.vinuesa@anu.edu.au).

Top

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.