Understanding and engineering the control circuits of the immune system

Synopsis

The immune system mounts effective responses tailored to counter diverse pathogenic threats.  These remarkable functional capabilities stem from the ability of immune cells to sense molecular signals emanating from pathogens, and to transition into functional cell states in appropriate numbers and proportions in response.  While we have increasingly detailed blueprints of the signaling and gene regulatory circuits controlling immune cell responses, we lack a first-principles physics-based understanding of how these circuits are designed to allow for robust, optimal response dynamics.  In this presentation, I will discuss two recent studies from my lab, where we combine quantitative single cell experiments with mathematical modeling to understand immune cell control circuit dynamics and design.  In our first study, we seek to understand how T cells selectively recognize peptide antigens from pathogens while ignoring self-antigens with slightly lower affinity, even when present at much higher levels.  We find that antigen recognition by the T cell receptor (TCR)-signaling circuit induces nucleation of liquid condensates of signaling components that are critical for downstream responses.  Importantly, these signaling-dependent condensate dynamics enable the generation of selective all-or-none responses to high-affinity antigen. Our second study seeks to understand how naïve T cells responding to an acute infection generates long-lived memory cells to protect against secondary challenge, in numbers that can scale with infection severity.  We find that such scalable memory formation occurs robustly when T cells can flexibly choose between whether to lose or gain memory potential at multiple junctures.  This flexibility arises from a stochastic, epigenetic switch that reversibly silences the memory regulator Tcf7 in responses to antigen signals.  Insights from these studies lay the groundwork for rational engineering of immune cell control circuits for next-generation cellular therapeutics.