T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORα and RORγ

Abstract

T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.

Immunometabolism: Is it under the eye of the clock?

“…Il-6 and Tnf˛ RNA. Lower NF-B activation [147] Cry1 (AP-Tg) Global • Elevated glucose levels in serum and urine [161] • Common symptoms of diabetes mellitus, polydipsia and polyuria [161] Per2 Global • Reduced levels of triacylglycerol and non-sterified fatty acids [139] • Enhanced adipocyte differentiation [139] • Increased plasma insulin and impaired gluconeogenesis [142,143] • Protected from sepsis-induced death [144] • Lower IL-1␤ and IFNϒ in serum [144] • Lower Tlr9 expression [82] Per3 Global • Enhanced adipogenesis [139] • Increased adipose tissue and decreased muscle tissue mass [139] Rev-erb˛ Global • Increased adiposity and mild hyperglycemia [119] • Altered lipid and glucose metabolism [119] • Increase in G6Pase and PEPCK [120] • Increased IL-6 in serum [124] ROR˛ sg/sg Global • Reduced adiposity and protection from obesity [128] • Lower serum and liver triglyceride levels [128] • Impaired Th17 cell development [133] • Highly susceptible to LPS induced sepsis [136] ROR Global • Enhanced production of insulin sensitive adipocytes.…”

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

“…STAT3 is also required for full generation of the Th17 lineage [9]. The upregulation of RORγt depends on STAT3 [9], and the selective deletion of STAT3 in T cells partially abrogates the development of Th17 cells because it also abrogates the expression of RORα and RORγt [8].…”

“…The orphan receptor RORγt is a thymusspecific isoform of RORγ [7]. A related nuclear receptor, RORα, was shown to act in synergy with RORγt to promote the differentiation of Th17 cells [8]. STAT3 is also required for full generation of the Th17 lineage [9].…”

“…STAT3 is also required for full generation of the Th17 lineage [9]. The upregulation of RORγt depends on STAT3 [9], and the selective deletion of STAT3 in T cells partially abrogates the development of Th17 cells because it also abrogates the expression of RORα and RORγt [8].IL-6 is an important cytokine in the differentiation of Th17 cells. IL-6, together with TGF-β, is required to induce IL-17 expression in naïve CD4 + T cells, which are characterized by the expression of RORγt [5,10,11].…”

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

“…Pro-inflammatory Th17 cells produce IL-17 to recruit neutrophils and induce the production of pro-inflammatory factors in immune cells [7,8]. In contrast to their Th17 counterpart, Treg cells suppress inflammatory responses and regulate the function of other T cell populations [3,[9][10][11].…”