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

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.

Pathophysiology of T follicular helper cells in humans and mice

“…These findings suggest that excessive T FH cells in GCs corrupt positive selection, such as diminished competition for T cell help, and a lower threshold for selection allows the emergence of self-reactive clones. Excessive expression of ICOS 89 and, more prominently, of IFN-γ 84 was found to be an important contributor to Roquin san -mediated T FH cell accumulation. Of note, IFN-γ signaling blockade has been found not only to alleviate T FH and GC B cell accumulation but also to virtually prevent all clinical manifestations associated with Roquin san -mediated disease, unlike SAP deficiency, which did not correct the splenomegaly or hypergammaglobulinemia 88 , or ICOS deficiency, which did not eliminate autoantibody formation 84 .…”

Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling

“…Roquin-1 and its paralog Roquin-2 are functionally interchangeable (72). To degrade mRNAs, Roquins recruit an mRNA deadenylase complex via their C-terminal part (71) and regulate the half-life of key cytokines, chemokines, and costimulatory proteins such as ICOS, OX40, and TNF (71, 73, 74). Similar to Regnase-1 deficient mice, Roquin mutant mice (expressing a Roquin mutant that cannot bind CDEs), develop autoimmunity (73).…”

MicroRNA Regulation of T-Lymphocyte Immunity: Modulation of Molecular Networks Responsible for T-Cell Activation, Differentiation, and Development

“…The same region contains a predicted binding site for miR-101 and disruption of this site within the ICOS 3’UTR of human T cells reverses its repression by Roquin, suggesting that Roquin-mediated repression of ICOS requires miR-101. 65 In mouse embryonic fibroblasts, Roquin recruits mRNA to P-bodies and stress granules, subcellular structures where RNA decapping enzymes and nucleases are located, by interacting with P-body proteins. 66 However, this mRNA recruitment occurs in a miRNA-independent manner in fibroblasts, because Dicer depletion in these cells does not reduce the ability of Roquin to destabilize ICOS mRNA.…”

“…In summary, miR-101 appears to negatively regulate ICOS expression in CD4 T cells and this has possible implications in systemic lupus erythematosus (SLE), where ICOS overexpression has been shown to contribute to the disease. 65 …”