Pre-TCR ligand binding impacts thymocyte development before ??TCR expression.

ABSTRACT: Adaptive cellular immunity requires accurate self- vs. nonself-discrimination to protect against infections and tumorous transformations while at the same time excluding autoimmunity. This vital capability is programmed in the thymus through selection of ??T-cell receptors (??TCRs) recognizing peptides bound to MHC molecules (pMHC). Here, we show that the pre-TCR (preTCR), a pT?-? heterodimer appearing before ??TCR expression, directs a previously unappreciated initial phase of repertoire selection. Contrasting with the ligand-independent model of preTCR function, we reveal through NMR and bioforce-probe analyses that the ?-subunit binds pMHC using V? complementarity-determining regions as well as an exposed hydrophobic V? patch characteristic of the preTCR. Force-regulated single bonds akin to those of ??TCRs but with more promiscuous ligand specificity trigger calcium flux. Thus, thymic development involves sequential ?- and then, ??-repertoire tuning, whereby preTCR interactions with self pMHC modulate early thymocyte expansion, with implications for ?-selection, immunodominant peptide recognition, and germ line-encoded MHC interaction.

SUBMITTER: Mallis RJ 

PROVIDER: S-EPMC4500245 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature