A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity

Abstract

Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

“…When analyzing the CD4 + T‐cell compartment in secondary lymphoid organs of Pou2af1 −/− mice immunized with SRBCs, we observed a strong reduction in the frequency of Tfh cells and changes to the expression of CXCR5 and costimulatory molecules as compared to heterozygous littermates or wild‐type mice. Tfh cells are typically identified as CD4 + T cells expressing CXCR5 in combination with ICOS, PD1, or BTLA (Chtanova et al , 2004; Vinuesa et al , 2005; Rasheed et al , 2006). These costimulatory molecules, however, identified overlapping but not identical populations of CD4 + CXCR5 + T cells and the relative size of these populations proved to be organ‐dependent.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…The presence of high numbers of Tfh cells results in a reduction in the selection threshold and enables survival of lower affinity and self‐reactive B cells, e.g. in sanroque mice homozygous for a loss of function mutation in Roquin, which results in high ICOS expression on Tfh cells and excessive Tfh cell accumulation, there is spontaneous B‐cell activation, GC formation, and autoantibody production, and the animals develop a lupus‐like phenotype 212, 213. Likewise increased numbers of circulating CXCR5 +  CD4 + T cells, frequencies of which correlate with autoantibody titers, are observed in patients with SLE and other autoimmune diseases including Sjogren's syndrome and myasthenia gravis 162, 214…”

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…The sanroque mutation not only causes the formation of excessive T FH cells and GCs, but also disrupts a repressor of ICOS and results in aberrant production of IL-21. 6 Using sanroque mice, Linterman et al 32 recently investigated the role of T FH cells in the development of murine lupus. They found that deletion of an allele of Bcl6 reduced the number of GC cells and ameliorated the SLE-like pathological reactions, suggesting that autoimmunity in sanroque mice is largely dependent on GC.…”

“…4,5 However, if T FH -cell function is not properly regulated, various pathologies ensue. [6][7][8][9][10][11] Here we present a review of the current literature pertaining to the role of T FH cells in the development of pathologies, such as autoimmunity, immunodeficiency and lymphoma, and the implications of these studies for development of therapies.…”