Elucidating the dynamic characteristics of antigen recognition

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Cells use surface receptors to sense their surroundings. Sensing relies on recognition of molecules by receptors. Effectiveness of recognition is routinely measured at steady state between single receptors and their bound molecules. However, new experiments showed that cells essential for the immune system may probe the binding quality of their antigen receptors in a highly dynamic and collective manner via tactile senses (i.e., neither at steady state nor using independent receptors). Curiously, by forming transient cell-cell contact, immune cells collect receptor-bound antigens into clusters and extract them using pulling forces generated inside the cell. The PI aims to investigate the functional impacts, design, and control of active, physical sensing of cells. Through a close synergy between theory and experiment, the proposed research will elucidate the physical principles behind the dynamic characteristics of antigen recognition, advance our understanding of information transfer via cell-cell interaction, and uncover adaptive benefit that active sensing might confer. Broader impacts of the project lie in a close integration of education and outreach activities with the research program, to engage students at all levels with the role of physics in cellular dynamics, function, and adaptation. The PI will develop web-based learning modules to deepen the understanding of membrane-mediated interactions and the origin of molecular cooperativity and antagonism. She will expand on a new course to teach the elements of information and control theory with applications to sensing and dynamic adaptation in biology. The PI will continue to provide authentic research experiences in her lab by serving as a faculty mentor through the Computational and Systems Biology program at UCLA. Diverse lymphocytes expressing unique surface receptors work collectively to recognize myriad and changing microscopic entities invading a living organism. Potent protection relies on positive selection of immune cells expressing high-affinity antigen receptors. However, this process of selection appears surprisingly ineffective and hits a modest ceiling of binding affinity much lower than expected. Experimental data have started to reveal that immune recognition is far beyond equilibrium receptor-antigen binding; instead, cells exert contractile forces to actively extract antigen from antigen-presenting cells. The PI hypothesizes that the apparent ineffectiveness of selection is not an artifact due to unavoidable randomness, but rather, can be a direct consequence of the non-equilibrium nature of antigen recognition. She proposes to explore an explanation by establishing a mapping from molecular recognition to organismal responses via cellular dynamics and active force usage. This project will focus on (a) determining how and why cells create and maintain a multifocal contact pattern during antigen recognition; (b) examining the capacity of physical extraction of antigen in achieving affinity discrimination over a broad dynamic range; and (c) identifying information bounds and discovering cellular strategies to optimize competing functions. Mathematical and computational modeling will be combined with in vitro and in vivo experiments to clarify the functional consequences of the nonequilibrium nature and dynamic characteristics of antigen recognition, and to access whether and how cells can utilize physically acquired information to guide adaptation. While the role of biochemical circuitry in achieving the remarkable specificity and sensitivity of immune recognition has been extensively explored, this research on physical dynamics of immune cells in native environment is complementary to most ongoing work in the field, and could uncover unexpected functional objectives of active sensing by cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.