T Cell Development, Antigen Recognition, and Activation
T cells are an important subset of the immune system that plays a pivotal role in regulating various diseases. T cells functions are influenced both by biochemical and biophysical properties at local microenvironment that influences receptor-ligand interactions. Our goal is to understand how these interactions mediated by mechanical properties translate into intracellular signaling, thereby affecting cellular function and fate.
Development of T cells takes place in the thymus as they go through selection to ensure they target disease-associated proteins. When the host is stricken with a disease, T cells arrive at the affected microenvironment where it scans to recognize the ligand to induce proper function to eradicate the pathogen and return to homeostasis. T cell receptor (TCR) on T cells recognize peptide major histocompatibility complex (pMHC) found on antigen presenting cells (APCs). Depending on the potency of the peptide, interaction initiates signal being transduced mechanically exerted by force from the TCR and its co-receptor (CD4 or CD8). The cues transmitted from these proteins along with the CD3 complex is translated into intracellular biochemical responses. In cancer and chronic diseases, APCs and cancer cells express inhibitory proteins PDL1 and once they come in contact with PD1 expressed on T cells, effect of the TCR-pMHC interaction is dampened.
To understand the mechanical properties between receptor-ligand interactions, we utilize 2D micropipette assays to characterize 2D affinity, off-rate, and bond lifetime under various forces. Additionally, we utilize fluorescence assays to coincide our 2D measurement in the form of calcium flux, FRET biosensor, and force-probe assays to visualize T cells exerting force real-time.