Hormonal rewiring of immunity upholds pathogen control and systemic nutrient homeostasis during dietary restriction

Food shortages and infectious diseases were constant threats throughout mammalian evolution and often occurred simultaneously. When food availability is reduced, it is unclear how the host adapts to fuel energy-demanding immune processes while preventing malnutrition. In the context of dietary restriction (DR), we found that glucocorticoids (GCs) are increased and promoted naïve T cell homing to the bone marrow niche, a site that supported their survival at steady-state. In response to a primary infection, DR-induced GCs dramatically rewired innate and adaptive immunity to simultaneously promote pathogen control and prevent hypoglycemia. This was achieved by dampening neutrophil glycolytic metabolism, which paradoxically enhanced their survival, function, and capacity to control pathogens. In parallel to enhancing neutrophils, DR-induced GCs restrained the generation of pathogen-specific effector T cells. This was essential for preventing hypoglycemia while combating a primary infection during DR. Although effector T cell responses were dampened, DR-induced GCs enriched for memory precursor effector cells to optimize memory T cell formation. Altogether, our work reveals a fundamental host adaptation strategy that upholds immediate and long-term pathogen control while maintaining systemic nutrient homeostasis in the setting of reduced food availability. These results redefine GCs as dominant optimizers of organismal fitness that align immunity and metabolic physiology with the nutritional status of the host.