Role of an IL-15-driven feedback loop in antigen-independent cytotoxic T cell response

Interleukin (IL)-15, a cytokine produced by myeloid, epithelial, and stromal cells, plays a key role in the long-term maintenance of memory T cells by driving their proliferation. IL-15 signaling can also induce a cytotoxic T cell response involving the production of granzymes as well as secretion of interferon (IFN)-γ by memory T cells. Here, we present a mathematical model of a cellular circuit involving memory T cells and myeloid cells (such as monocytes) that incorporates IL-15 and IFN-γ-mediated signaling, and show that the circuit can exhibit bistable behavior, including a state characterized by high memory T cell count, activation, and cytotoxicity. The existence of bistability is dependent on the strength of an IL-15 and IFN-γ-driven positive feedback loop. Close to the bifurcation point, the system exhibits very slow relaxation towards baseline after an immune perturbation such as infection, indicating a mechanism for T cell-driven, antigen-agnostic immune memory post-infection. Analysis of multiple datasets profiling the immune state indicates a role for this IL-15 / IFN-γ-driven cellular circuit in vaccination response as well as in multiple autoimmune disorders. Overall, we describe a plausible mechanism for antigen-independent memory T cell activation and response across contexts.