Regulation of CTLA-4 Function by PP2A
CTLA-4 is an inhibitory receptor on T cells. We have shown that a regulatory subunit of the phosphatase PP2A plays a critical role in modulating CTLA-4 function, and demonstrated that one can convert CTLA-4 from inhibitory to activating receptor by changing the level of PP2A association with CTLA-4. We are currently performing a structure:function analysis of the CTLA-4:PP2A association, as well as exploring functional implications of this regulatory mechanism. |
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Role of Lck in the regulation
of early TCR signaling
The src kinase Lck plays a critical role in the initiation of TCR signaling. However, we have revealed that this kinase is also responsible for triggering negative feedback loops on TCR signals, which become apparent under conditions of Lck-independent T cell activation. We are currently addressing the molecular basis of such a role and the implications of this loop during stages of T cell differentiation. |
Regulation of T cell activation by Phosphodiesterase 4B2 (PDE4B2)
PDE4B2 degrades cAMP to 5’AMP. We have identified PDE4B2 as a key enhancer of T cell activation. Such a role correlates with a regulated targeting of the molecule to the lipid rafts, and its dynamic redistribution from the immunological synapse to the antipodal pole of the T cell. Current work is aimed at defining the molecular mechanisms involved in targeting and redistribution of PDE4B2 during T cell activation. |
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Role of RIP2 in innate and adaptive immune responses during peritoneal dialysis-associated peritonitis
We are currently studying immune cell activation in vivo, during clinical immune responses to infection. We focus on the responses to peritoneal infection during peritoneal dialysis, one of the treatments for patients with end-stage renal disease. Under these conditions, we have characterized distinct stages of differentiation of immune cells. We are currently examining the role that the kinase RIP2 plays in the different stages of this immune response. |
In the next five years, we expect:
- To have a better understanding of the regulatory mechanisms triggered by early events of TCR-mediated signalling. More importantly, we will have a view of the molecular mechanisms that regulate signalosome assembly and triggering of the second wave of signalling encompassing events downstream of signalosome assembly and upstream of gene transcription.
- To develop and/or refine variant TCR ligands with partial agonist/antagonist properties through the identification of common features on activation of signalling cascades.
- To develop strategies for delivery of signal inhibitors into specific subcellular compartments.
- To discover the structural motifs determining the interaction of regulatory molecules with negative regulators of T cell activation. Initially this will relate to CTLA-4 but will expand to other novel negative regulators of T cell activation and/or homeostasis; and
- To develop an in vivo map of changes in gene expression and protein activation in human disease conditions. We are developing the tools for analysis of parameters of cell activation and inactivation in peritoneal dialysis-associated peritonitis.
Special thanks to our sponsors. Funding provided by:
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