The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions

Abstract

LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation. T cell–specific deletion of LRH-1 causes a drastic loss of mature peripheral T cells. LRH-1–depleted CD4+ T cells exert strongly reduced activation-induced proliferation in vitro and in vivo and fail to mount immune responses against model antigens and to induce experimental intestinal inflammation. Similarly, LRH-1–deficient cytotoxic CD8+ T cells fail to control viral infections. This study describes a novel and critical role of LRH-1 in T cell maturation, functions, and immopathologies and proposes LRH-1 as an emerging pharmacological target in the treatment of T cell–mediated inflammatory diseases.

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

“…Hence, to delineate the MoA by which BL001 conveyed these effects we initially focused on the autoimmune response. We show that, in the RIP-B7.1 mouse model, BL001 promoted the expansion of Th2 and Tregs, a process likely implicating the stimulation of the LRH-1/NR5A2-Fas/FasL signalling pathway [51,108]. Recently, Dirice and colleagues reported that the expansion of the beta-cell mass before the invasion of immune cells prevented the progression of T1DM in NOD mice through an increase Fig.…”

“…Contextually relevant, islet autoreactive CD8+ cytotoxic T-lymphocytes isolated from T1DM patients displayed persistent proliferation with a concomitant reduction in apoptosis susceptibility upon repeated antigen stimulation, an effect mediated by reduced Fas expression levels [107]. Genetic deletion of LRH-1/ NR5A2 blunted activation-induced proliferation of murine CD4+ effector T-cells as well as Tregs and impaired viral clearance from infected tissue [108]. Taken together these new data shed light on a fundamental role of LRH-1/NR5A2 in both macrophage and T-cell homeostasis and the immune response that can potentially be exploited for therapeutic benefits for AIDs such as T1DM.…”

Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis

“…While in the intestine LRH-1 activity has been associated with anti-inflammatory properties, for example, via the production of immunoregulatory glucocorticoids, more recent studies proposed a novel and more direct role of LRH-1 in the regulation of immune cell differentiation and effector functions [11][12][13] . Given that activated macrophages are a rich source of cytokines implicated in the initiation of inflammatory responses, we aimed to investigate the effect of pharmacological inhibition of LRH-1 in the activation-induced production of proinflammatory cytokines.…”

“…We previously have shown that immature and mature T cells express LRH-1, which is further induced upon T cell activation 12 . A more recent publication highlights the critical role of LRH-1 in T cell maturation and functions 13 . Specific depletion of LRH-1 in T cells strongly reduced their activation-induced proliferation, resulting in the impaired induction of T cell-regulated immune responses 13 .…”

“…A more recent publication highlights the critical role of LRH-1 in T cell maturation and functions 13 . Specific depletion of LRH-1 in T cells strongly reduced their activation-induced proliferation, resulting in the impaired induction of T cell-regulated immune responses 13 . Importantly, we identified the tumor necrosis factor (TNF) family member Fas ligand (FasL, CD95L) as an LRH-1-regulated target gene 12 .…”