Basic knowledge is lacking to understand immunological tipping points, where the same stimulus can cause paradoxical immune responses. For example, immune activation after injury or infection is required for downstream tissue repair and pathogen removal, but may also cause tissue damage; immune tolerance or rejection may occur after similar type of tissue transplant, but it is difficult to predict the outcome a priori; inflammation is needed to form blood vessels connecting mother and embryo upon implantation, but too much inflammation can lead to immune disorders during pregnancy. In contrast to these critical clinical complications caused by immune overactivation, cancer cells can bias the tipping point towards the opposite direction to suppress the immune response, but the underlying mechanism still remains unclear. Driven by a series of recent breakthroughs made in our laboratories, we propose to establish planarian flatworms as a novel ideal model to delineate these paradoxical effects: with their simple immune system, we will quantify and manipulate immune cell behaviors both directly in live animals and in engineered ex vivo reconstituted cell systems; with their unsurpassed regenerative ability, we will test the response of immune cells to immunological challenges during allogeneic tissue transplantation. Integrating quantitative experiments, genetic manipulation, and mathematical modeling, we will connect gene functions, cell feedback circuits, and organismal phenotypes, to provide for the first time a multi-scale systems-level mechanism by which the immunological tipping point balances the system sensitivity and robustness. This mechanistic and predictive understanding will also allow synthetically rebuilding immune cell circuits ex vivo for bioengineering and therapeutic purposes. Our work will establish a mechanistic footing to understand more complex immune systems, and can help optimize outcomes in cancer immunotherapy, tissue transplantation, autoimmune diseases, and pregnancy disorders. This work is only achievable through a unique international collaboration that bridge several distinct fields: cellular immunology, functional genomics, and quantitative biology.