Research
T Lymphocyte Activation and its Cross-Coupling with Apoptotic Pathway
The primary interests of our lab are on the regulation T lymphocyte activation, and the cross-talk between apoptotic messengers and activation signals. For T cell activation, we have previously characterized the contribution of ERK and p38 MAPK to different stages of T cell activation. Ongoing research is on the modulation of T cell activation signaling leading to immune tolerance and on the participation of cytoskeleton proteins ezrin and paxillin in T cell activation. We identified a new regulatory role of deltex in T cell tolerance. Deltex1 was up-regulated in anergy T cells. Overexpression of deltex1 suppressed T cell activation, and the impaired T cell activation by deltex could be partly attributed to a selective inhibition of JNK in T cells. Deltex1 interacted directly with MEKK1, and promoted the ubiquitination and degradation of MEKK1. Transgenic expression of deltex1 prevented T cell activation and resulted in T cell anergy. We are in the progress to delineate the exact contribution of deltex to immune tolerance in vivo. We also found phosphorylation of paxillin by JNK and p38 is essential for NFAT and full T cell activation, and is determining the molecular processes in between.
On the cross-talk between apoptotic messengers and activation signals, we have characterized antagonism of several apoptotic processes by mitogenic signals and Notch. We recently demonstrated that transactivation domain of Notch interacted directly with the RING region of XIAP to block the binding of E2 and prevent the ubiquitination of XIAP, revealing a novel mechanism for apoptosis suppression through increasing the stability of a key anti-apoptotic protein. Our current efforts are focused on how apoptosis-related molecules transmit activation signals, with specific emphasis on caspase-8/10, c-FLIP, and XIAP. We have identified new signaling pathway activated by pro-apoptotic molecules caspase-8 and -10. Caspase-8/10 are required for sustained calcium signals during T cell activation. We also identified that PI 3-K, activated during T cell stimulation, converts c-FLIP from an inhibitor to a constitutive signal mediator. In addition, XIAP transmits anti-apoptosisindependent signals contributing to cell activation. We are now working on the molecular mechanism how caspase-8/10 and c-FLIP are recruited to T cell receptor activation complex, and how XIAP interacts with signaling proteins.
