Our Science – Ashwell Website
Jonathan D. Ashwell, M.D.
Physiologic and Pathologic Regulation of T Cell Signaling and Apoptosis
Signaling via the T cell receptor results in a large number of biochemical and biological outcomes: tyrosine kinase activation, cytokine production, proliferation, and apoptosis. Apoptosis is a means of eliminating unwanted cells. Many cells, including immature and mature lymphocytes, undergo apoptosis under the appropriate conditions. Inappropriate apoptosis has clearly been shown to result in both tumor formation and autoimmunity (lack of appropriate cell death) and has been implicated in the loss of CD4+ cells in AIDS (death of functionally useful cells). We are examining the mechanisms and biological relevance of apoptosis in a number of settings.
Molecules Involved in Apoptosis
IAP (Inhibitor of Apoptosis) proteins constitute a family of molecules that have one or more motifs (BIRs) that can bind and antagonize caspases. Three classic mammalian IAP molecules (XIAP, c-IAP1, and c-IAP2) also contain a C-terminal RING domain. We have shown that the RING domain confers ubiquitin protein ligase (E3) activity to these molecules, allowing them to ubiquitinate substrates and promote their degradation in proteasomes. In fact, these IAP molecules have autoubiquitinating activity, and in cells receiving an apoptotic stimulus they autoubiquitinate and are degraded, facilitating cell death. Furthermore, we have found that c-IAP1, a member of the TNF receptor (TNFR) signaling complex, ubiquitinates TRAF2 upon TNFR2 ligation, resulting in TRAF2 degradation, aborted signaling, and enhanced apoptosis. Therefore, IAPs have roles in regulating signaling pathways and can, in fact, have pro-apoptotic activity. We are currently studying how IAP E3 activity is regulated in cells, and what effect loss of IAP expression has in knockout animal models.
Signaling Molecules and Pathways
Several molecules and signaling pathways involved in T cell function and development are under investigation. (1) p38 is a MAP kinase (MAPK) involved in inflammatory processes. Like all MAPK, p38 is activated by Thr/Tyr dual phosphorylation via upstream MAP kinase kinases (MAPKK). We have found that T cells possess an alternative p38 activation pathway involving phosphorylation of a novel tyrosine residue in a MAPKK-independent manner. (2) GADD45a is a small adaptor protein involved in p38 and JNK activation. We have found that mice deficient in this protein develop autoimmunity. Current studies involve analysis of aberrant MAPK signaling in these animals and how it relates to their immune phenotype. (3) IL-7 is a cytokine found in the thymus and peripheral lymphoid organs that has anti-apoptotic and pro-proliferative activities. Expression of the IL-7 receptor (IL-7R) is tightly controlled during early T cell development for reasons that are not understood. We have generated IL-7R transgenic mice that express this receptor under the control of the CD2 promoter. These animals have an unexpected age-related decrease in thymic size, and studies on the mechanism for this, and what it tells us about the need for dynamic regulation of IL-7R expression, are ongoing.
This page was last updated on 6/7/2013.