| First Author | Mallis RJ | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 27 | Pages | 8373-8 |
| PubMed ID | 26056289 | Mgi Jnum | J:223762 |
| Mgi Id | MGI:5660166 | Doi | 10.1073/pnas.1504971112 |
| Citation | Mallis RJ, et al. (2015) Pre-TCR ligand binding impacts thymocyte development before alphabetaTCR expression. Proc Natl Acad Sci U S A 112(27):8373-8 |
| abstractText | 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 alphabetaT-cell receptors (alphabetaTCRs) recognizing peptides bound to MHC molecules (pMHC). Here, we show that the pre-TCR (preTCR), a pTalpha-beta heterodimer appearing before alphabetaTCR 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 beta-subunit binds pMHC using Vbeta complementarity-determining regions as well as an exposed hydrophobic Vbeta patch characteristic of the preTCR. Force-regulated single bonds akin to those of alphabetaTCRs but with more promiscuous ligand specificity trigger calcium flux. Thus, thymic development involves sequential beta- and then, alphabeta-repertoire tuning, whereby preTCR interactions with self pMHC modulate early thymocyte expansion, with implications for beta-selection, immunodominant peptide recognition, and germ line-encoded MHC interaction. |
