UCLA

The immune system is a complex system of cells and molecules that work cooperatively to protect us against pathogenic organisms. It can perform complicated tasks such as pattern recognition, learning, and memory, all of which require dynamical coordination among a large number of components across multiple scales. Nevertheless, the multitude of different components makes it challenging to unveil the mechanistic principles that give rise to these remarkable functions.

My thesis focuses on how our immune system learns from infections and improves specificity of pathogens recognition on the fly. This process is known as affinity maturation, where the affinity of B cell receptor improves through Darwinian evolution. Although recent progresses in experiments revealed many details, what remains is a first-principle and quantitative understanding of how different elements come together to achieve the goal. Using statistical physics tools and computational modeling, I study various aspects of the maturation process, including molecular interactions, information extraction, and evolutionary dynamics.

To understand how B cells with different affinities are discriminated during affinity maturation, we investigate the process of antigen extraction, where B cells use cytoskeleton forces to extract antigen molecules from other presenting cell surface. We show this process allows a B cell to infer its receptor affinity by measuring the number of extracted antigens.Our model highlights the regulatory role of mechanical force: Application of a constant force with proper magnitude can enhance discrimination fidelity, and usage of a dynamical force that introduces negative feedback can improve discrimination robustness with respect to fluctuations in antigen concentration.

To illustrate how molecular interactions influence cellular evolution, we couple the physical theory of antigen extraction to a minimal model of affinity maturation and simulate ensembles of cell populations under different conditions. The multiscale model predicts that the affinity ceiling stems from the physical limit of antigen tether strength and identifies strategies to alleviate the constraint.

Lastly, we present a study on the long-term coevolution between evolving pathogen and adaptive immune response. Our work reveals that the asymmetric reaction range between immunogenicity (the ability of pathogens to induce an immune response) and antigenicity (the ability of pathogens to interact with antibodies) is critical in determining the dynamics of coevolution.