RORγT, a thymus-specific isoform of the orphan nuclear receptor RORγ/TOR, is up-regulated by signaling through the pre-T cell receptor and binds to the TEA promoter

Abstract

TEA (T early alpha) is a genetic element located upstream of the TCR-Jα cluster. Thymocytes from mice carrying a targeted deletion of TEA do not rearrange their TCRα locus on a window spanning the first nine Jα segments. This led us to the hypothesis of TEA having a 'rearrangement focusing' activity on the 5' side of the TCR-Jα region. We analyzed DNAsel and 'phylogenetic' footprints within the TEA promoter in an attempt to identify trans-acting factors that could account for its regulatory function on DNA accessibility. One of these footprints corresponded to a putative DNA-binding site for an orphan nuclear receptor of the ROR/RZR family. The RORγT cDNA clone was isolated from a thymus library using a probe corresponding to the DNA-binding domain of RORγ/TOR. RORγT is a thymus-specific isoform of RORγ, expressed almost exclusively in immature double-positive thymocytes. RORγT binds, to the TEA promoter in vitro. Lastly, the expression of RORγT is stimulated in two situations that mimic activation through the pre-TCR and in which the thymocytes have their TCR-α locus in an 'open', yet unrearranged DNA configuration. We propose that the expression of RORγT may be part of the pre-TCR activation cascade leading to the maturation of α/β T cells and may participate in the regulation of DNA accessibility in the TCR-Jα locus.