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

Yu Di Yu, Andy Hee Meng Tan, Xin Hu, Vicki Athanasopoulos, Nicholas Simpson, Diego G. Silva, Andreas Hutloff, Keith M. Giles, Peter J. Leedman, Kong Peng Lam, Christopher C. Goodnow, Carola G. Vinuesa*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    369 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), 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.

    Original languageEnglish
    Pages (from-to)299-303
    Number of pages5
    JournalNature
    Volume450
    Issue number7167
    DOIs
    Publication statusPublished - 8 Nov 2007

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