Enforcement of gamma delta -lineage commitment by the pre-T-cell receptor in precursors with weak gamma delta -TCR signals

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 15; p. 5658
• Main Authors: Zarin, Payam, Wong, Gladys W, Mohtashami, Mahmood, Wiest, David L, Zuniga-Pfluecker, Juan Carlos
• Format: Journal Article
• Language: English
• Published: 15-04-2014
• ISSN: 0027-8424
• DOI: 10.1073/pnas.1312872111

Developing thymocytes bifurcate from a bipotent precursor into alpha beta - or ...-lineage T cells. Considering this common origin and the fact that the T-cell receptor (TCR) alpha -, ...-, and ...-chains simultaneously rearrange at the double negative (DN) stage of development, the possibility exists that a given DN cell can express and transmit signals through both the pre-TCR and ...-TCR. Here, we tested this scenario by defining the differentiation outcomes and criteria for lineage choice when both TCR- beta and ...-TCR are simultaneously expressed in Rag2... DN cells via retroviral transduction. Our results showed that Rag2... DN cells expressing both TCRs developed along the ...-lineage, down-regulated CD24 expression, and up-regulated CD73 expression, showed a ...-biased gene-expression profile, and produced IFN-... in response to stimulation. However, in the absence of Inhibitor of DNA-binding 3 expression and strong ...-TCR ligand, ...-expressing cells showed a lower propensity to differentiate along the ...-lineage. Importantly, differentiation along the ...-lineage was restored by pre-TCR coexpression, which induced greater down-regulation of CD24, higher levels of CD73, Nr4a2, and Rgs1, and recovery of functional competence to produce IFN-... These results confirm a requirement for a strong ...-TCR ligand engagement to promote maturation along the ... T-cell lineage, whereas additional signals from the pre-TCR can serve to enforce a ...-lineage choice in the case of weaker ...-TCR signals. Taken together, these findings further cement the view that the cumulative signal strength sensed by developing DN cells serves to dictate its lineage choice. (ProQuest: ... denotes formulae/symbols omitted.)