T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ

Speaker：  鄭元鈞                            Time：13:10-14:00, Mar. 5, 2008

Commentator： 楊倍昌 教授                                Place：Room 601

Abstract

            Th17 cell, a new Th cell subset, can regulate neutrolphil recruitment and is associated with autoimmune disease.  Previous study found that retinoid- related orphan nuclear receptor (RORγt) played a crucial role in Th17 cell differentiation.  RORγt deficiency could partially inhibit Th17 differentiation and protected mice from developing experimental autoimmune encephalomyelitis (EAE).  However, the effect of that was not complete.  Therefore, the authors considered that there might be other some other transcription factors involved in the differentiation of Th17 cell.  They analyzed gene expression of in vitro-differentiated Th1, Th2, and Th17 cells and then found that the expression of two ROR genes, Rora (encoding RORα) and Rorc (encoding RORγ), were elevated in Th17 cells.  As RORc gene , RORa gene expression was also upregulated during Th17 cell differentiation by TGF-β and IL-6 synergistically.  Furthermore, RORα or RORγ expression could upregulate most of Th17-specific genes and could promote Th17 cell differentiation possibly through chromatin remodeling of the conserved noncoding site 2 (CNS2) in the Il17- Il17f loci.  Next, they tested the RORα function by using staggerer (Rora^sg/sg) mice with a deficiency of RORα ligand-binding domain and Rag deficient (Rag^-/-) mice with staggerer mice bone marrow cells.  They found that RORαdeficiency selectively reduced Il17 and Il23r mRNA expression but not Il21, Il21, and Il17f.  Because expression and function of RORα were similar to that of RORγ, the authors further investigated why both receptors were coexpression in Th17 cells.  They found that combined expression of RORα and RORγ would greatly promoted Th17 development and antagonize Th1, Th2 or Treg program.  RORα and RORγ double deficiency would completely impaired Th17 differentiation and protect mice from EAE.  Therefore, these results reveled that not onlyRORγ but also RORα were the transcription factor for Th17 differentiation.  RORγ and RORα together could synergistically promote greater Th17 differentiation than RORγ or RORα alone.

Reference

1.         Mark S. Sundrud and Anjana Rao  Regulation of T helper 17 differentiation by orphan nuclear receptors: t’s not just RORγt Anymore  Immunity 28, January 2008

2.         Brigitta Stockinger and Marc Veldhoen  Differentiation and function of Th17 T cells Current Opinion in Immunology 2007, 19:281–286