Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection

How specific nutrients influence adaptive immunity is of broad interest. Iron deficiency is the most common micronutrient deficiency worldwide and imparts a significant burden of global disease; however, its effects on immunity remain unclear. We used a hepcidin mimetic and several genetic models to examine the effect of low iron availability on T cells in vitro and on immune responses to vaccines and viral infection in mice. We examined humoral immunity in human patients with raised hepcidin and low serum iron caused by mutant TMPRSS6. We tested the effect of iron supplementation on vaccination-induced humoral immunity in piglets, a natural model of iron deficiency. We show that low serum iron (hypoferremia), caused by increased hepcidin, severely impairs effector and memory responses to immunizations. The intensified metabolism of activated lymphocytes requires the support of enhanced iron acquisition, which is facilitated by IRP1/2 and TFRC. Accordingly, providing extra iron improved the response to vaccination in hypoferremic mice and piglets, while conversely, hypoferremic humans with chronically increased hepcidin have reduced concentrations of antibodies specific for certain pathogens. Imposing hypoferremia blunted the T cell, B cell, and neutralizing antibody responses to influenza virus infection in mice, allowing the virus to persist and exacerbating lung inflammation and morbidity. Hypoferremia, a well-conserved physiological innate response to infection, can counteract the development of adaptive immunity. This nutrient trade-off is relevant for understanding and improving immune responses to infections and vaccines in the globally common contexts of iron deficiency and inflammatory disorders. Medical Research Council, UK [Display omitted] Low serum iron caused by hepcidin impairs primary and memory immune responsesActivated T-cells demand iron and iron scarcity inhibits mitochondrial metabolismPatients with mutant TMPRSS6 have high hepcidin and lower IgG against pathogensHigh hepcidin during viral infection inhibits T- and B-cells and inflames disease Iron deficiency is very common in humans and animals. Frost et al demonstrate that low concentrations of iron in serum, caused by the hormone hepcidin, inhibit the body’s response to vaccines and infections; conversely, increasing iron can boost immunity. Iron deficiency is very common in humans and animals. Frost et al. demonstrate that low concentrations of iron in serum, caused by the hormone