Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA.
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.
Yu
Di
D
Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, 2601, Australia.
Tan
Andy Hee-Meng
AH
Hu
Xin
X
Athanasopoulos
Vicki
V
Simpson
Nicholas
N
Silva
Diego G
DG
Hutloff
Andreas
A
Giles
Keith M
KM
Leedman
Peter J
PJ
Lam
Kong Peng
KP
Goodnow
Christopher C
CC
Vinuesa
Carola G
CG
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D035683:MicroRNAs; D012333:RNA, Messenger; D038621:Regulatory Sequences, Ribonucleic Acid; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases