|Mentors:||Robert Mason, Ph.D., Nemours Biomedical Research
Robert Akins, Ph.D., Nemours Biomedical Research
Terri H. Finkel, M.D., Ph.D., Nemours Biomedical Research
At the interface between T cell and antigen presenting cell (APC), binding of peptide antigen presented by MHC (pMHC) to the T cell receptor (TCR) initiates TCR signaling. Despite its critical importance in T cell antigen recognition and T cell-mediated immune responses, how pMHC-TCR interaction triggers TCR signaling remains unclear. Classical models such as receptor conformational change or crosslinking have failed to explain TCR triggering due to its unique complexity. Considering the highly mobile nature of T cells and the potential role of mechanical stress sustained by the pMHC-TCR interaction at the dynamic T cell/APC interface, we proposed the novel “receptor deformation model” of TCR triggering, which, for the first time, explains all three aspects of the TCR triggering puzzle: mechanism, specificity and sensitivity. We hypothesize that TCR is triggered by conformational changes of the TCR-CD3 complex caused by a pulling force originating from the cytoskeleton and transferred through pMHC-TCR binding. Here, we propose to investigate the TCR triggering mechanism and test the receptor deformation model by characterizing pMHC-TCR interaction under mechanical stress for the first time using an innovative biophysical approach, atomic force microscopy. We will measure the mechanical strength of pMHC-TCR binding and correlate it with the potency of pMHC to trigger TCR. We will also test whether exerting pulling forces on TCRs initiates signals in T cells. In addition, we will ask whether force-induced fast dissociation of pMHC-TCR interaction is required for efficient TCR serial triggering. Finally, we will determine how the binding between peptide and MHC is impacted by disengaging forces. By using a highly innovative single molecule approach to tackle a long-standing and fundamental question in immunology, we believe the proposed research will break new ground and impact significantly on our understanding of the immune system and how to manipulate it to treat immune-mediated diseases in children.