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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
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Abstract
Developing 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.
Notes
Zarin, 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.