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

D. Yu, A.H. Tan, X. Hu, V. Athanasopoulos, N. Simpson, D.G. Silva, A. Hutloff, K.M. Giles, Peter Leedman, K.P. Lam, C.C. Goodnow, C.G. Vinuesa

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    306 Citations (Scopus)

    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 39 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.
    Original languageEnglish
    Pages (from-to)299-303
    JournalNature
    Volume450
    Issue number8
    DOIs
    Publication statusPublished - 2007

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    Yu, D., Tan, A. H., Hu, X., Athanasopoulos, V., Simpson, N., Silva, D. G., Hutloff, A., Giles, K. M., Leedman, P., Lam, K. P., Goodnow, C. C., & Vinuesa, C. G. (2007). Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature, 450(8), 299-303. https://doi.org/10.1038/nature06253