Iron controls the adaptive immune response
<p>Adaptive immune responses require dynamic cellular reconfigurations as antigen-specific lymphocytes proliferate, acquire effector functions and generate immunological memory. Several metabolic pathways are co-opted during this process, but specific metabolites identified as important substr...
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| Format: | Thesis |
| Language: | English |
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2019
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| _version_ | 1826316315338473472 |
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| author | Frost, J |
| author2 | Drakesmith, H |
| author_facet | Drakesmith, H Frost, J |
| author_sort | Frost, J |
| collection | OXFORD |
| description | <p>Adaptive immune responses require dynamic cellular reconfigurations as antigen-specific lymphocytes proliferate, acquire effector functions and generate immunological memory. Several metabolic pathways are co-opted during this process, but specific metabolites identified as important substrates are rarely systemically limiting. Iron deficiency affects a billion people worldwide and a mutation in transferrin receptor that disrupts the ability of lymphocytes to acquire iron causes immunodeficiency. However, to date if and how serum iron deficiency disrupts adaptive immunity has not been investigated. Here we demonstrate that genetic defects in iron homeostasis, such as the TfrcY20H/Y20H mutation and IRP1/2 deficiency, cell-intrinsically disrupt adaptive immunity. We find that T-cell metabolic activity including mitochondrial ATP generation is impaired by limiting iron acquisition in vitro, concomitant with reduced proliferation, suggesting that iron is a key ‘immunometabolite’. We then provide in vivo evidence that transient and physiological serum iron deficiency caused by increased activity of the iron regulatory hormone hepcidin profoundly reduces the magnitude of the primary antigen specific CD8, CD4 and B-cell responses to multiple immunisation platforms, and alters the differentiation trajectory of CD8 T-cells such that memory and secondary recall responses are impaired even after iron status has been normalised. Low serum iron levels also disrupt protective T- and B-cell responses to experimental influenza virus infection, increasing lung viral load, inflammation and neutrophil infiltration, and prolonging weight loss in infected animals. Overall, these findings reveal an unexpected sensitivity of adaptive immunity to serum iron availability and may have implications for control of infections and vaccination programmes in developing-world populations where iron deficiency is highly prevalent and the infectious burden is considerable.</p>
<p>More generally we suggest that manipulating iron availability may provide a tool to control the amplitude and quality of adaptive immune responses.</p> |
| first_indexed | 2024-03-07T07:30:02Z |
| format | Thesis |
| id | oxford-uuid:38257fec-43bd-4cbf-b84a-b11f866ce23f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:42:51Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:38257fec-43bd-4cbf-b84a-b11f866ce23f2024-12-07T13:59:28ZIron controls the adaptive immune responseThesishttp://purl.org/coar/resource_type/c_db06uuid:38257fec-43bd-4cbf-b84a-b11f866ce23fImmunologyIron homeostasisEnglishORA Deposit2019Frost, JDrakesmith, H<p>Adaptive immune responses require dynamic cellular reconfigurations as antigen-specific lymphocytes proliferate, acquire effector functions and generate immunological memory. Several metabolic pathways are co-opted during this process, but specific metabolites identified as important substrates are rarely systemically limiting. Iron deficiency affects a billion people worldwide and a mutation in transferrin receptor that disrupts the ability of lymphocytes to acquire iron causes immunodeficiency. However, to date if and how serum iron deficiency disrupts adaptive immunity has not been investigated. Here we demonstrate that genetic defects in iron homeostasis, such as the TfrcY20H/Y20H mutation and IRP1/2 deficiency, cell-intrinsically disrupt adaptive immunity. We find that T-cell metabolic activity including mitochondrial ATP generation is impaired by limiting iron acquisition in vitro, concomitant with reduced proliferation, suggesting that iron is a key ‘immunometabolite’. We then provide in vivo evidence that transient and physiological serum iron deficiency caused by increased activity of the iron regulatory hormone hepcidin profoundly reduces the magnitude of the primary antigen specific CD8, CD4 and B-cell responses to multiple immunisation platforms, and alters the differentiation trajectory of CD8 T-cells such that memory and secondary recall responses are impaired even after iron status has been normalised. Low serum iron levels also disrupt protective T- and B-cell responses to experimental influenza virus infection, increasing lung viral load, inflammation and neutrophil infiltration, and prolonging weight loss in infected animals. Overall, these findings reveal an unexpected sensitivity of adaptive immunity to serum iron availability and may have implications for control of infections and vaccination programmes in developing-world populations where iron deficiency is highly prevalent and the infectious burden is considerable.</p> <p>More generally we suggest that manipulating iron availability may provide a tool to control the amplitude and quality of adaptive immune responses.</p> |
| spellingShingle | Immunology Iron homeostasis Frost, J Iron controls the adaptive immune response |
| title | Iron controls the adaptive immune response |
| title_full | Iron controls the adaptive immune response |
| title_fullStr | Iron controls the adaptive immune response |
| title_full_unstemmed | Iron controls the adaptive immune response |
| title_short | Iron controls the adaptive immune response |
| title_sort | iron controls the adaptive immune response |
| topic | Immunology Iron homeostasis |
| work_keys_str_mv | AT frostj ironcontrolstheadaptiveimmuneresponse |