María N. Navarro

Serine-threonine kinases in TCR signaling

T lymphocyte proliferation and differentiation are controlled by signaling pathways initiated by the T cell antigen receptor. Here we explore how key serine-threonine kinases and their substrates mediate T cell signaling and coordinate T cell metabolism to meet the metabolic demands of participating in an immune response.

Regulation of surface expression of the human pre-T cell receptor complex

Considerable progress has recently been made in defining the role that pre-antigen receptor complexes, namely the pre-T and pre-B cell receptors, play in lymphocyte development. It is now established that these receptors direct, in a similar way, the survival, expansion, clonality and further differentiation of pre-T and pre-B lymphocytes, respectively. However, less is known about the mechanisms which ensure that only minute amounts of pre-TCR and pre-BCR reach the plasma membrane of developing lymphocytes. In this review, we discuss the implications of recent experimental approaches which address the developmental regulation of human pre-TCR expression and the molecular mechanisms that control surface pre-TCR expression levels.

Differential Developmental Regulation and Functional Effects on Pre-TCR Surface Expression of Human pTαa and pTαb Spliced Isoforms

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