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Hepcidin-mediated hypoferremia disrupts immune responses to vaccination and infection
Background: 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.
Methods: 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.
Findings: 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.
Conclusions: 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