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Differential Developmental Regulation and Functional Effects on Pre-TCR Surface Expression of Human pT^a and pT^b Spliced Isoforms¹

Almudena R. Ramiro^*, María N. Navarro^*, Aura Carreira^*, Yolanda R. Carrasco^*, Virginia G. de Yébenes^*, Graciela Carrillo^*, José L. San Millán, Bent Rubin and María L. Toribio^2,*

^* Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain; Genetics Unit, Hospital Ramón y Cajal, Madrid, Spain; and Centre National de la Recherche Scientifique, Centre Hospitalier Universitaire Purpan, Toulouse, France

Functional rearrangement at the TCR locus leads to surface expression on developing pre-T cells of a pre-TCR complex composed of the TCR-chain paired with the invariant pre-TCR (pT) chain and associated with CD3 components. Pre-TCR signaling triggers the expansion and further differentiation of pre-T cells into TCR mature T cells, a process known as selection. Besides the conventional pT transcript (termed pT^a), a second, alternative spliced, isoform of the pT gene (pT^b) has been described, whose developmental relevance remains unknown. In this study, phenotypic, biochemical, and functional evidence is provided that only pT^a is capable of inducing surface expression of a CD3-associated pre-TCR complex, which seems spontaneously recruited into lipid rafts, while pT^b pairs with and retains TCR intracellularly. In addition, by using real-time quantitative RT-PCR approaches, we show that expression of pT^a and pT^b mRNA spliced products is differentially regulated along human intrathymic development, so that pT^b transcriptional onset is developmentally delayed, but selection results in simultaneous shutdown of both isoforms, with a relative increase of pT^b transcripts in -selected vs nonselected pre-T cells in vivo. Relative increase of pT^b is also shown to occur upon pre-T cell activation in vitro. Taken together, our data illustrate that transcriptional regulation of pT limits developmental expression of human pre-TCR to intrathymic stages surrounding selection, and are compatible with a role for pT^b in forming an intracellular TCR-pT^b complex that may be responsible for limiting surface expression of a pT^a-containing pre-TCR and/or may be competent to signal from a subcellular compartment.

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