Anna V. Kellner

Thesis Proposal Presentation

Date: December 9th, 2019

Time: 9:00 am

Location: Atwood Chemistry Center, Room 360. Emory University Department of Chemistry

Committee Members:

Khalid Salaita, PhD (Emory University, Department of Chemistry) (Advisor)

Cheng Zhu, PhD (Georgia Tech/Emory, Department of Biomedical Engineering)

Susan Thomas, PhD (Georgia Tech, School of Mechanical Engineering)

Erik Dreaden, PhD (Georgia Tech/Emory, Department of Biomedical Engineering)

Curtis Henry, PhD (Emory University, Department of Pediatrics)

Title: Investigating the underlying mechanisms of T cell mechanical regulation using DNA mechanotechnology

Summary

T cells survey the body for antigens by probing their environment through physical interactions. During these physical interactions, molecular-level forces transmitted through the T cell receptor (TCR) help discriminate antigenic tissue from self tissue by strengthening and prolonging cognate TCR-antigen bonds, thus causing an enhanced activation signal. This proposal delves deeper into the intriguing regulatory role of molecular-level forces in T cell biology. The first aim explores the mechanism that plasma membrane cholesterol plays in regulating TCR mechanical forces. Preliminary data show that depleting plasma membrane cholesterol causes a significant increase in TCR mechanics. Therefore, we hypothesize that TCR mechanical sensitivity and specificity can be increased by decreasing plasma membrane cholesterol levels. The second aim explores the role of mechanical forces in programmed cell death-1 (PD1) receptor, a co-receptor to the TCR that dampens T cell activity and leads to T cell exhaustion. Preliminary data show that the PD1 receptor is capable of exerting pN mechanical forces on its ligand. Therefore, we hypothesize that mechanical forces are a crucial component of regulating PD1 signaling. Aims 1 and 2 will be accomplished by using DNA mechanotechnology developed in the Salaita Lab to map and manipulate receptor-level mechanical forces.