NSF/NIH 2054354: DMS/NIGMS: An Experimental and Mathematical Framework for Understanding and Controlling Regulatory Delay in Self-Nonself Determination in the Immune System

Project Description:

Why is the fatality rate from COVID19 50 fold higher in elderly male patients? Why do some cancers recede while others grow? What causes allergies, arthritis, and chronic infection? The answer to these questions is the failure of the immune system to correctly differentiate self from nonself - resulting, e.g., in tolerance to cancer and suppression of collagen (arthritis). Immunotherapy is an attempt to reverse these immune decisions by amplifying either self or nonself signals - shifting the immune state toward a tolerogenic or immunogenic bias. And yet, how can we use immunotherapy effectively when we still do not have a clear understanding of how the self-nonself decision is made? While immunology has made great strides in identifying the mechanics of hundreds of regulatory (self) and helper/effector (nonself) pathways, this knowledge has not resulted in any certainty as to how the immune system as a whole decides whether a unknown antigen (Ag) is harmless or hostile. The picture became slightly clearer with the landmark studies in Johansen (2008) and Tam (2016) (JT), which used a novel experimental framework to isolate the effect of changes in Ag (vaccine schedule (VS)) and show that this factor alone can alter the self-nonself determination. Specifically, they concluded that if the Ag behaves like a threat, then it is treated like a threat. This definitive experimental evidence begs the question of HOW a decentralized network of immune cells and signals, with no central coordination or memory, differentiates threatening behaviour from harmless? Our hypothesis, based on circuit analogues, and supported by mathematical models, is that the delay between helper (Th) and regulatory T cell (Treg) response allows the immune system to respond to the rate of increase in Ag, and that it is this signal which triggers a broader immune response. The goal of this project, then, is to provide definitive experimental evidence verifying this hypothesis. Specifically, inspired by the work of JT, we propose an innovative in vivo experimental framework for isolating and controlling delay in immune response and use this framework to show that by changing this delay, we can alter the self-nonself determination.