Chenghao “Charles” Ge

PhD Proposal Presentation

Date: Wednesday December 3rd, 2014

Time: 2:00pm

Location: Klaus Advanced Computing Building, Room 1116 East

Thesis committee members:

Advisor: Cheng Zhu, Ph.D. (BME)

Krishnendu Roy, Ph.D. (BME)

Khalid Salaita, Ph.D. (BME)

Robert Dickson, Ph.D. (Chemistry)

Michelle Krogsgaard, Ph.D. (NYU)

Title: Force Regulation of T Cell Activation

Abstract:

T lymphocytes play a central role in cell-mediated immunity through a variety of effector and regulatory functions. While functioning normally, T cells help protect the body against foreign pathogens, such as bacteria, viruses, toxins, and cancer cells. In autoimmune disease, T cells respond to healthy body tissues in the same way they would treat foreign antigens, resulting in a hypersensitive reaction that destroys healthy tissues and compromises organ functions, such is the case of Type-1 diabetes. Understanding the mechanism of T cell antigen recognition and triggering is key to the regulation of T cell activity and it can lead to potential strategies for optimizing immunotherapies in treating autoimmune diseases. T cell receptors (TCR) recognize antigen presented in the form of peptide-major histocompatibility complex (pMHC) molecules found on the surface of antigen-presenting cells (APCs). TCR itself does not contain signaling units, and signaling components are located on the intracellular tails of the CD3 subunits of the TCR complex. Therefore, the signal from TCR-pMHC interaction has to be transmitted to the adjacent CD3 subunits before T cell triggering can take place, but the mechanism of which has yet to be determined. Prior studies have suggested that TCR-pMHC interactions formed between T cells and APCs are likely subjected to mechanical forces in the form of tension in bridging the contact surfaces, as well as actin-directed retrograde flows. More recently, a study has demonstrated that force can prolong lifetime of TCR bonds with agonist pMHCs, further highlighting the relevance and importance of force as a potential regulator of T cell response. These studies have provided the foundation to the central hypothesis of this study that T cell triggering and functions can be directly regulated through force-manipulation. To better understand the role of force in T cell activation, we propose (1) to investigate the kinetics of extracellular TCR-CD3 interaction and its role in T cell antigen recognition, (2) to investigate how force levels can affect T cell functions when antigens are presented on DNA-based force probes, and (3) to determine the effect of force manipulation on the first step of T cell intracellular signaling events. Monitoring changes in T cell functions and intracellular signaling molecules would provide conclusive evidence toward the force regulation model of T cell activation.