Trx1/TrxR1 system regulates post-selected DP thymocytes survival by modulating ASK1-JNK/p38 MAPK activities

A key process in the development of T lymphocyte in the thymus is T-cell receptor (TCR) selection. It is controlled by complex signaling pathways that contain redox-sensitive molecules. However, the redox status early after TCR selection and how redox regulators promote the survival of post-selected DP thymocytes has not been directly addressed. The present study demonstrated that the transition from pre- to post-selected double-positive (DP) stages was accompanied with an increase of reactive oxygen species (ROS) and a transient surge in the expression of a variety of redox regulators. Among them, the thioredoxin (Trx)1/thioredoxin reductase (TrxR)1 system was found to be critically involved in the regulation of cell survival of DP thymocytes, especially that of post-selected CD69(+) subset, as its inhibition caused a specific reduction of these cells both in vitro and in vivo, most likely owing to increased apoptosis. Suppression of the glutathione-dependent redox system, on the other hand, showed no obvious impact. Biochemically, treatment of DP thymcoytes with TrxR1 inhibitor alone or in conjunction with anti-CD3 resulted in enhanced phosphorylation of redox-sensitive ASK-1, JNK and p38 MAPK, and upregulated expression of Bim. Taken together, the data presented here suggest that the timely upregulation of Trx1/TrxR1 and the active control of intracellular redox status is critical for the survival of thymocytes during and short after positive selection.