The structural basis for autonomous dimerization of the pre-T-cell antigen receptor

The pre-T-cell antigen receptor (pre-TCR), expressed by immature thymocytes, has a pivotal role in early T-cell development, including TCR beta-selection, survival and proliferation of CD4(-)CD8(-) double-negative thymocytes, and subsequent ab T-cell lineage differentiation(1-3). Whereas alpha beta TCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling(4), preTCR-induced signalling occurs by means of a ligand-independent dimerization event(5). The pre-TCR comprises an invariant a-chain (pre-T alpha) that pairs with any TCR beta-chain (TCR beta) following successful TCR beta-gene rearrangement(6). Here we provide the basis of pre-T alpha-TCR beta assembly and pre-TCR dimerization. The pre-T alpha chain comprised a single immunoglobulin-like domain that is structurally distinct from the constant (C) domain of the TCR alpha-chain(7); nevertheless, the mode of association between pre-T alpha and TCRb mirrored that mediated by the C alpha-C beta domains of the abTCR. The pre-TCR had a propensity to dimerize in solution, and the molecular envelope of the pre-TCR dimer correlated well with the observed head-to-tail pre-TCR dimer. This mode of pre-TCR dimerization enabled the pre-T alpha domain to interact with the variable (V) beta domain through residues that are highly conserved across the V beta and joining (J) beta gene families, thus mimicking the interactions at the core of the alpha beta TCR's V alpha-V beta interface. Disruption of this pre-T alpha-V beta dimer interface abrogated pre-TCR dimerization in solution and impaired pre-TCR expression on the cell surface. Accordingly, we provide a mechanism of pre-TCR self-association that allows the pre-T alpha chain to simultaneously 'sample' the correct folding of both the V and C domains of any TCR beta-chain, regardless of its ultimate specificity, which represents a critical checkpoint in T-cell development. This unusual dual-chaperone-like sensing function of pre-T alpha represents a unique mechanism in nature whereby developmental quality control regulates the expression and signalling of an integral membrane receptor complex