T-cell receptor associated signals that modulate lymphocyte homeostasis

grantor: University of TorontoLymphocyte homeostasis is central to the normal functioning of immune responses. Failure of T-cells and B-cells in either recognizing pathogens, becoming activated, proliferating, destroying pathogens, shutting down, or eventually decreasing in numbers can lead to immune dysfunctions such as the absence of adaptive immune responses, the generation of autoimmune diseases, or the induction of lymphoproliferative diseases. Many cellular receptors function together to regulate lymphocyte homeostasis. Among these, the CD28 co-stimulatory receptor is crucial to T-cell activation and proliferation. Moreover, CD28 has also been reported to regulate T-cell survival, a role usually associated with members of the TNF receptor supergene family. Similarly, some TNFR superfamily members, in addition to their role in apoptosis, have also been shown to influence cellular activation and proliferation. In an attempt to try to understand how these receptors function together to regulate homeostasis, we have studied the activation of intracellular signaling pathways downstream of the CD28 and CD30 cellular receptors. The findings, presented in Chapter 2, demonstrate that CD28 activates the sphingomyelinase pathway, a pathway often associated with apoptosis, and that this activation can participate in CD28's co-stimulatory activity. Chapter 3 presents evidence that CD30 can interact with TRAF-1, -2, and -3 survival factors, and defines the binding specificities of these intracellular signaling effectors with various TNFR superfamily members. The fourth chapter of this thesis is aimed at studying the function of a lymphocyte cellular receptor called Toso. The study was done by generating and analyzing a Toso knockout mouse. This receptor is thought to inhibit lymphocyte apoptosis induced by Fas, however, our results have so far failed to confirm a critical role for Toso in regulating Fas-induced lymphocyte killing. It is our hope that such studies will, one day, further our knowledge of lymphocyte homeostasis enough as to allow the design of interventions aimed at regulating specific defects in immune responses.Ph.D