Thesis Defense - Edward Judokusumo
April 23, 2014, 1:00PM, BME Conference Room (ET351)
Advisor: Lance C. Kam, PhD
Mechanosensing in T cells
T cells are key players in adaptive immune response. Originating from the Thymus, they seek and eliminate infected cells in various locations of our body. It is not yet known how natural changes in physical environment could affect T cell function. The focus on this thesis is to address the functional impact of T cell activation based on substrate modulus and to probe the underlying mechanism behind it.
T cell response has been shown to be sensitive around external forces in the environment. It is not clear whether T cells could sense the physical environment and transmit that information to regulate cell function. We developed the use of substrate with varying modulus to analyze the functional impact of T cell activation. We demonstrate that naive T cells are capable in sensing and transmitting information from substrate modulus to regulation of IL-2 secretion, revealing functional impact of rigidity to T cell activation. The increased cytokine production is correlated with increasing substrate modulus and is associated with TCR/CD3 complex. Furthermore, we identified that T cell mechanosensing is mediated downstream of early TCR signaling molecules, SFK and Zap-70.
To understand mechanism of rigidity dependent activation of T cells, we developed a method of combining geometry sensing and substrate modulus to probe the scale on which rigidity sensing is regulated. T cells were able to generate contractility across the whole cell and sustained TCR triggering as a result. Tension generated across equilateral triangle geometry failed to sustain TCR triggering, indicating a global cell response. We postulated that cytoskeletal tension generated to sense geometry and substrate modulus is regulated through Rho-asscoiated kinase in T cells.