Abstract

Iron deficiency is the most common micronutrient deficiency worldwide, causes anaemia, stunts growth, and imparts a significant burden of global disease, but its influence on immunity remains unclear. Hepcidin is the iron regulatory hormone that controls iron homeostasis, but hepcidin is also an acute-phase protein. When induced by inflammation, hepcidin rapidly and profoundly decreases serum iron levels (hypoferraemia), and this protects against some infections by iron-requiring pathogens, for example malaria and Vibrio vulnificus. However emerging evidence shows that T- and B-lymphocytes are highly iron-requiring too, and so we hypothesized that hypoferraemia could have detrimental effects on adaptive immunity. We will present data supporting this concept, showing that hepcidin-mediated control of iron distribution profoundly influences the magnitude and quality of responses to immunization and infection. Adaptive immunity requires adequate serum iron to support the metabolically intense demands of lymphocyte responses, and so in this regard is in conflict with innate immune activation that removes iron from serum. This trade-off is relevant for understanding immunity, infection and vaccination in the globally common contexts of iron deficiency and chronic inflammatory disorders. In addition, the findings provide proof-of-principle to allow therapeutic control of immune responses via hepcidin-mediated manipulation of iron.