Poor dietary iron weakens lung memory T cells after flu infection

By Priyanjana Pramanik, MSc.Reviewed by Susha Cheriyedath, M.Sc.Dec 8 2025

Even when immune memory cells form in the lung after influenza infection, insufficient dietary iron leaves them less able to mount a strong antiviral response, revealing how nutrition can shape long-term immune protection

Study: Dietary iron deficiency impairs effector function of memory T cells following influenza infection. Image Credit: Corona Borealis Studio  / Shutterstock

Researchers in a recent study in The Journal of Immunology examined how dietary iron deficiency affects influenza-infected memory T cells. They investigated the impact on cell function, characteristics, and development.

They found that iron-deficient mice were more likely to develop anemia. While T cells were able to mount antigen-specific responses, the mice exhibited transient alterations in early activation during primary infection and impaired effector function during the memory phase, particularly in the lungs, with reduced production of key antiviral cytokines.

Iron Deficiency and Immune Vulnerability

T cells play a pivotal role in clearing infections and establishing long-lasting immune memory. Maintaining adequate iron levels is crucial for forming robust T cell responses because iron is required for essential processes such as cellular proliferation and activation.

Nutrition-Linked Risks for Weak Immunity

However, iron deficiency, often due to dietary insufficiency, especially during early life, but also influenced by other causes such as blood loss, has been linked with increased susceptibility to allergic diseases and infections, raising concerns that it may weaken immune responses.

Transferrin Receptor in T Cell Iron Uptake

Iron uptake in T cells relies heavily on the transferrin receptor, a protein that mediates iron uptake from transferrin into cells. Mutations in this receptor impair both T and B cell activity. Chemical iron chelation can selectively disrupt T helper cell subsets and reduce production of key cytokines such as IL-2, TNF-α, and IFN-γ.

Impact of Low Iron on Antigen-Specific Immunity

Importantly, lower circulating iron levels during infection can diminish the formation of antigen-specific T cells. Given that nutritional deficiency is the most common cause of iron depletion globally, it is crucial to determine how an iron-poor diet shapes the development, maintenance, and long-term functional programming of T cells after real infections.

Study Design Using Dietary Iron Manipulation

Using dietary iron manipulation combined with an influenza infection model, researchers examined how iron deficiency alters memory T cell development across tissues, with particular focus on the lungs.

Mouse Diet Conditions and Sampling Timeline

Female mice were fed either an iron-deficient or an iron-replete diet from weaning and housed under pathogen-free conditions. Groups were kept separate by diet and euthanized at defined time points: before infection, during acute influenza infection (days 5 and 7), and during memory formation (day 28). Researchers assessed anemia using hemoglobin measurements from tail-prick blood samples and quantified systemic iron levels by measuring non-heme iron in liver tissue using acid digestion and colorimetric assays.

Influenza Infection Model and Tissue Processing

For infection, mice were anesthetized and given a standardized intranasal dose of X31 (H3N2) influenza virus, with daily weight monitoring used to track illness severity. After euthanasia, spleens and lungs were processed into single-cell suspensions using mechanical dissociation, enzymatic digestion, and red blood cell lysis.

Flow Cytometry for T Cell Activation Profiles

Flow cytometry was conducted to characterize intracellular cytokine production, T cell phenotypes, and activation markers using extensive panels of fluorescent antibodies. Antigen-specific CD4⁺ and CD8⁺ T cells were identified with influenza peptide-loaded MHC tetramers. To assess memory T cell function, lung T cells were stimulated either polyclonally or with influenza-loaded bone-marrow–derived dendritic cells generated from iron-replete donors, thereby allowing evaluation of T cell functional capacity under experimentally optimised antigen-presenting conditions.

Verification of Iron Deficiency in Study Mice

From weaning, mice fed iron-deficient diets gained less weight, developed anemia, and showed markedly reduced liver iron, confirming successful induction of deficiency. Despite similar overall T cell numbers across dietary groups, iron-deficient mice displayed altered baseline T cell phenotypes. These included higher expression of the transferrin receptor, particularly on splenic CD44⁺ CD4⁺ and CD8⁺ cells, as well as shifts in regulatory and Th1-associated markers.

Primary Infection Effects on Lung T Cell Activation

During primary influenza infection, iron-deficient mice experienced greater early weight loss and slower recovery. Total lung T cell counts were comparable between groups, but deficient mice showed increased splenic T cell numbers at early time points. Influenza-specific T cell numbers were broadly similar overall, although iron-replete mice exhibited higher numbers of lung-localized antigen-specific T cells at day 7. Activation marker expression was comparable in the spleen but temporarily reduced in lung CD4⁺ influenza-specific T cells of iron-deficient mice, suggesting delayed local activation rather than impaired early antigen recognition.

Memory T Cell Deficits in Antiviral Cytokine Production

At the memory stage, both groups had similar total T cell counts, but iron-deficient mice generated more influenza-specific T cells in the lung. However, these cells, particularly CD8⁺ memory T cells, displayed impaired production of TNF-α and IFN-γ. Notably, this functional impairment in CD8⁺ cells persisted even when stimulated with iron-replete antigen-presenting cells, indicating a durable, cell-intrinsic alteration in effector capacity established during iron deficiency. In contrast, CD4⁺ memory T cell cytokine production was largely restored under optimised recall conditions.

Summary of Immune Impairments from Iron Deficiency

The study demonstrates that dietary iron deficiency disrupts early lung T cell activation during infection and compromises the effector function of memory T cells, particularly CD8⁺ memory cells, during recall responses. Iron-deficient mice experienced greater illness severity, delayed early lung immune responses, and ultimately developed memory T cells with a reduced capacity to produce key antiviral cytokines. These defects persisted despite optimal antigen presentation, supporting the presence of intrinsic functional reprogramming during periods of iron deficiency.

Tissue-Specific Vulnerability of Lung Immunity

The effects were most pronounced in the lungs, indicating tissue-specific vulnerability. This is especially relevant given the lung’s central role in influenza immunity and the importance of tissue-localised memory T cells in protection against reinfection.

Study Limitations in T Cell Localization Analysis

While the study benefited from tight dietary control and a well-established infection model, it could not fully disentangle T cell–intrinsic defects from potential contributions of the lung microenvironment. In addition, the study could not definitively distinguish circulating from tissue-resident memory T cell populations within the lung.

Implications for Early-Life Nutritional Immunity

In summary, maintaining sufficient dietary iron is essential for healthy memory T cell function and robust long-term antiviral immunity. These findings may have particular implications for early-life iron deficiency and for immune responses to respiratory infections and vaccines, highlighting iron status as a potentially modifiable determinant of immune protection.