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

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

Research output: Contribution to journalArticleResearchpeer-review

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 aco-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 - 2007
Externally publishedYes

Cite this