Fine-tuning T cell receptor signaling to control T cell development

• Signaling in thymocyte positive selection is qualitatively different from negative selection.
• Developmentally regulated molecules tune TCR signaling during positive selection.
• These include the adaptor Themis, the phosphatase SHP1 and regulators of Ca2+ signaling.
• Stage-specific expression of these molecules may govern positive selection.

T cell development from immature CD4+CD8+ double-positive (DP) thymocytes to the mature CD4 or CD8 single-positive (SP) stage requires proper T cell receptor (TCR) signaling. The current working model of thymocyte development is that the strength of the TCR-mediated signal – from little-or-none, through intermediate, to strong – received by the immature cells determines whether they will undergo death by neglect, positive selection, or negative selection, respectively. In recent years, several developmentally regulated, stage-specifically expressed proteins and miRNAs have been found that act like fine-tuners for signal transduction and propagation downstream of the TCR. This allows them to govern thymocyte positive selection. Here, we summarize recent findings on these molecules and suggest new concepts of TCR positive-selection signaling.