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

ABSTRACT: Developing thymocytes bifurcate from a bipotent precursor into ??- or ??-lineage T cells. Considering this common origin and the fact that the T-cell receptor (TCR) ?-, ?-, 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-? 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.

SUBMITTER: Zarin P 

PROVIDER: S-EPMC3992653 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature