Iron plays a crucial role in the immune system, particularly in T-cell-mediated immunity, which is responsible for pathogen elimination and the creation of immune memory. Iron is necessary for cellular activation and proliferation, which are central to the protective responses of T-cells.
Researchers at Columbia University studied the impact of iron deficiency on T-cells in mice during and after influenza infection. Mice fed an iron-deficient diet experienced more severe illness, slower recovery, and more significant weight loss. While the number of antigen-specific T-cells increased, their ability to produce inflammatory cytokines such as IFNγ and TNFα was diminished. Moreover, antigen-specific T-cells exhibited reduced expression of markers needed to establish residency in tissues, essential for rapid response to reinfections at the same site. Thus, iron deficiency can weaken immune responses and impair immune memory formation.
Study Design
Two groups of mice were fed diets with different iron levels: one group received regular iron doses, while the other was given a diet low in iron. Mice with iron deficiency gained weight more slowly and developed anemia, confirmed by reduced hemoglobin levels and decreased iron content in the liver.
Iron Deficiency Affects T-Cells
While the total number of T-cells in the spleen remained unchanged, iron-deficient mice exhibited a reduction in the number of T-cells in lung tissue. Additionally, the proportion of naïve T-cells in the spleen was reduced in iron-deficient mice.
A notable finding was the increased expression of the transferrin receptor (CD71), which helps cells capture iron. In iron-deficient mice, transferrin receptor expression was significantly elevated on non-naïve CD4 and CD8 T-cells.
Iron Deficiency Weakens T-Cell Response to Influenza
During influenza infection, iron-deficient mice lost weight more rapidly and took longer to recover than mice with normal iron levels. Weight recovery in iron-sufficient mice coincided with the peak T-cell response.
An analysis of T-cell responses on days 5 and 7 of infection showed that, although the overall number of T-cells in the lungs remained the same, iron-deficient mice had an increased number of CD4 and CD8 T-cells in the spleen.
In iron-deficient mice, the early-stage infection saw a reduction in effector and memory T-cells in the lungs, as evidenced by decreased expression of the glycoprotein CD44—a marker for effector and memory responses.
Additionally, the scientists examined the markers CD25 and CD71, which directly correlate with T-cell activation and proliferation. In iron-deficient mice, the T-cell activation marker CD71 remained elevated at later stages of infection, indicating delayed immune response activation. Mice with normal iron levels developed effective T-cell responses more quickly, essential for clearing the virus. The lungs of iron-sufficient mice had a higher number of flu-specific CD8 T-cells.
Iron Deficiency Reduces Antiviral T-Cell Function
The researchers analyzed the T-cell response in mice that had recovered from influenza on day 28. The total number of CD4 and CD8 T-cells in the lungs and spleen was the same in iron-deficient and iron-sufficient mice. However, in the lung tissue of iron-deficient mice, there was an increased number of CD4 effector memory T-cells. These cells are known for their ability to remain in tissues and provide optimal protection during reinfections. These tissue-resident cells are called tissue-resident memory T-cells (TRM).
TRM expresses the markers CD69 and CD103. Using these markers, the researchers found a reduction in the proportion of CD8 TRM in the lungs of iron-deficient mice.
Furthermore, despite the accumulation of flu-specific CD4 and CD8 T-cells, iron-deficient mice exhibited a significantly reduced capacity to produce IFNγ. The ability to produce IFNγ and TNFα did not recover when T-cells were co-cultured with iron-rich dendritic cells, indicating an intrinsic defect in T-cells caused by iron deficiency, which hinders the formation of functional immune memory.
Conclusion
Iron deficiency affects the body’s ability to fight infections. In iron-deficient mice, there was reduced activity of T-cells, the key defenders of the body. Although the number of T-cells in the lungs increased, their ability to produce vital antiviral cytokines, such as IFNγ and TNFα, was significantly diminished. Iron deficiency causes immune cells to lose effectiveness in fighting infections and forming immune memory.
Iron deficiency is a widespread global issue associated with increased illness and reduced vaccination efficacy. Correcting iron levels could help improve vaccination outcomes and disease prognosis. However, excessive iron accumulation in the body may worsen viral infections—a topic discussed in the article “Iron Restriction Blocks Viral Replication.”
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Reference
Dietary iron deficiency impairs effector function of memory T cells following influenza infection
