2022: Edward Jenkins
Edward Jenkins’ passion for unravelling the molecular mechanisms that govern T cell biology was established during his undergraduate studies and MPhil at Imperial College London and the University of Cambridge, respectively. Although his biology degree at Imperial College London provided a broad understanding of molecular processes across cell biology, he was most interested in the complexity of the immune systems and its interconnectedness throughout the body, which, properly harnessed, could improve lives.
He first got properly stuck into molecular immunology research with an MPhil at the University of Cambridge in the lab of Dr John James. His MPhil focused on using DNA nanotechnology to study T cell activation, and along the way, he became hooked on the academic freedom and creativity that comes with basic research.
In 2016, after being awarded the MRC WIMM prize studentship to read for a DPhil in Medical Sciences, he continued to explore his interest in T cells under the supervision of Professors Simon Davis and Christian Eggeling. Diving deeper into basic research, his DPhil was focused on using reconstituted systems, biophysical approaches, and microscopy, to study the mechanism by which T-cells effectively discriminate between self and non-self - a long-standing conundrum in T cell biology.
Key to addressing this question was the kinetic segregation receptor signaling model, as proposed by Professors Simon Davis and Anton Van der Merwe. This theory posits that the T-cell receptor (TCR) is regulated by a balancing act between activating kinases and large inhibitory phosphatases, with TCR signaling being initiated by the displacement of large inhibitory phosphatases away from the TCR (such as when a T-cell forms a close contact with a target cell). Based on this mechanism, modelling predicted two key parameters tuning T-cell signaling outcomes: (1) contact size, and (2) the dwell time of the TCR within phosphatase-depleted contacts. Examining these parameters formed the basis of his DPhil.
In order to study how T-cells discriminate between antigens in the initial close contacts, Edward established a second generation glass-supported lipid bilayers (SLBs) system, with the help of Markus Körbel from the Klenerman Lab at the University of Cambridge. Using the unique property of this system to image contacts, Edward was able to solve a 45-year mystery of why T-cells use membrane protrusions (microvilli) to scan other cells for antigens. He was also able to validate the contact size prediction of the KS model: simply put, microvilli ensure close contacts remain small, a necessity for discriminating between self and non-self. This is because the TCR can signal in large contacts independent of antigen, owing to reduced encounters with signal-blocking phosphatases.
Another important prediction of the KS model is that slowing the diffusion of the TCR (i.e., increasing its dwell-time in phosphatase-depleted contacts) is sufficient to initiate signaling. With the help of Kevin Chen (Klenerman Lab, University of Cambridge), Edward was able to validate this prediction, by using recombinant proteins and natural ligands to slow the TCR within close contacts. This was a transformative result for the field, given this data cannot be explained by other ligand-centric theories of TCR signaling. Part of these results will be published in Nature Communications, with further results currently in press at PNAS.
Working with Dr. Mafalda Santos and Dr. Erdinc Sezgin, Edward also developed a also developed a novel reconstituted system (giant unilamellar vesicles) to study immune cell interactions in 3D, overcome the limitations of 2D reconstituted systems (e.g., SLBs).
Since finishing his DPhil, Edward remains in the Davis lab, focussing on applying these approaches to understanding receptor signal integration at T cell contacts. More recently, he was awarded a Henry Welcome postdoctoral fellowship, to understand how T cells integrate information from their environment, using cutting-edge live 4D imaging and computer vision approaches to dissect intracellular signaling cascades. This will be supported by the laboratories of professors Michael Dustin, Gaudenz Danuser, Klaus Hahn and Kevin Dean.
Overall, Edward says he is grateful for the support received from his supervisor Simon Davis, members of the Davis lab, the Eggeling lab (MRC WIMM), the Klenerman Lab and Lee lab (both at the Department of Chemistry, University of Cambridge), the MRC WIMM Flow Cytometry Facility, the Wolfson Imaging Centre, and the MRC WIMM cafeteria staff. It has been both a joy and privilege to work at the MRC WIMM.