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.
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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.
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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
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DOI: https://doi.org/10.1038/nature06253
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