SUMMARY

T cells, an essential adaptive immune system component, primarily elicit responses to antigen by sensing exogenous peptide antigens presented Major Histocompatibility Complex (pMHC) on Antigen Presenting Cells (APCs) through their T Cell Receptor (TCR). Many aspects of the antigen recognition mechanism remain elusive. Affinity/kinetic based mechanisms have been controversial in explaining triggering, as mathematical models of the current signaling mechanism fail to demonstrate TCR sensitivity and specificity through biophysical measurements alone. Additionally, the inability of soluble, antigenic pMHCs to produce a response demonstrates that binding alone cannot trigger signaling. Recent studies have demonstrated that mechanical force in the TCR triggering mechanism may play a significant role in explaining these observations. Additionally, TCRs have been shown to have transient quantifiable “memory” of antigens in the micropipette assay. This memory mechanism likely is involved in signaling dynamics and may be related to the antigen recognition mechanism, as serial triggering of multiple receptors has been shown to be crucial to T cell activation. This project aims to develop and perform experiments using a Horizontal Atomic Force Microscopy technique and the micropipette assay along with computational simulations to provide insight into the role of mechanical forces in the TCR triggering and memory.