Insight into the basis of autonomous immunoreceptor activation

Expression of the pre-T cell receptor (pTCR) by immature thymocytes is crucial for T cell development. The pTCR comprises an invariant pre-Tα chain that pairs with a newly rearranged TCRβ chain and CD3 signaling components. Despite its similarity to the mature αβTCR, which binds to specific peptide-loaded major histocompatibility molecules, the pTCR functions in a ligand-independent manner. Precisely how pTCR functions autonomously has remained a source of intense debate. Recently, the structure of the extracellular domain of the pTCR has been determined, providing insight into the mechanism of pTCR autonomous signaling. In this review, we reflect on the current understanding of pTCR function and draw comparisons to the mechanisms employed by the mature αβTCR and the related pre-B cell receptor.