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Zarin P , Wong GW , Mohtashami M , Wiest DL , Zuniga-Pflucker JC
Enforcement of gammadelta-lineage commitment by the pre-T-cell receptor in precursors with weak gammadelta-TCR signals
Proc Natl Acad Sci U S A. 2014 Apr 15;111(15) :5658-63
PMID: 24706811 PMCID: PMC3992653 URL: https://www.ncbi.nlm.nih.gov/pubmed/24706811
AbstractDeveloping thymocytes bifurcate from a bipotent precursor into alphabeta- or gammadelta-lineage T cells. Considering this common origin and the fact that the T-cell receptor (TCR) beta-, gamma-, and delta-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 gammadelta-TCR. Here, we tested this scenario by defining the differentiation outcomes and criteria for lineage choice when both TCR-beta and gammadelta-TCR are simultaneously expressed in Rag2(-/-) DN cells via retroviral transduction. Our results showed that Rag2(-/-) DN cells expressing both TCRs developed along the gammadelta-lineage, down-regulated CD24 expression, and up-regulated CD73 expression, showed a gammadelta-biased gene-expression profile, and produced IFN-gamma in response to stimulation. However, in the absence of Inhibitor of DNA-binding 3 expression and strong gammadelta-TCR ligand, gammadelta-expressing cells showed a lower propensity to differentiate along the gammadelta-lineage. Importantly, differentiation along the gammadelta-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-gamma. These results confirm a requirement for a strong gammadelta-TCR ligand engagement to promote maturation along the gammadelta T-cell lineage, whereas additional signals from the pre-TCR can serve to enforce a gammadelta-lineage choice in the case of weaker gammadelta-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.
NotesZarin, Payam Wong, Gladys W Mohtashami, Mahmood Wiest, David L Zuniga-Pflucker, Juan Carlos eng MOP-42387/Canadian Institutes of Health Research/Canada Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5658-63. doi: 10.1073/pnas.1312872111. Epub 2014 Mar 31.