期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.637809
关键词
iron; T helper cell; TIM-3; immune checkpoint inhibitors; interferon-gamma; intracellular bacteria; infection control
类别
资金
- Austrian Research Fund FWF [P33062]
- Christian Doppler Society
- ERA-NET grant by the FWF (EPICROSS) [I-3321]
- Austrian Cancer Society/Tirol [P17006]
- FWF doctoral college project [W1253 HOROS]
- Austrian Science Fund (FWF) [P33062] Funding Source: Austrian Science Fund (FWF)
Iron inhibits the differentiation of naive CD4(+) T cells to protective Th1 lymphocytes by increasing TIM-3 expression. Blocking TIM-3 could restore Th1 cell differentiation and improve bacterial control in iron-loaded mice infected with S. Typhimurium, suggesting TIM-3 as a novel drug target for chronic infections with intracellular pathogens in iron loading diseases.
Iron plays an important role in host-pathogen interactions, in being an essential element for both pathogen and host metabolism, but also by impacting immune cell differentiation and anti-microbial effector pathways. Iron has been implicated to affect the differentiation of T lymphocytes during inflammation, however, so far the underlying mechanism remained elusive. In order to study the role of iron in T cell differentiation we here investigated how dietary iron supplementation affects T cell function and outcome in a model of chronic infection with the intracellular bacterium Salmonella enterica serovar typhimurium (S. Typhimurium). Iron loading prior to infection fostered bacterial burden and, unexpectedly, reduced differentiation of CD4(+) T helper cells type 1 (Th1) and expression of interferon-gamma (IFN gamma), a key cytokine to control infections with intracellular pathogens. This effect could be traced back to iron-mediated induction of the negative immune checkpoint regulator T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), expressed on the surface of this T cell subset. In vitro experiments demonstrated that iron supplementation specifically upregulated mRNA and protein expression of TIM-3 in naive Th cells in a dose-depdendent manner and hindered priming of those T cells towards Th1 differentiation. Importantly, administration of TIM-3 blocking antibodies to iron-loaded mice infected with S. Typhimurium virtually restored Th1 cell differentiation and significantly improved bacterial control. Our data uncover a novel mechanism by which iron modulates CD4(+) cell differentiation and functionality and hence impacts infection control with intracellular pathogens. Specifically, iron inhibits the differentiation of naive CD4(+) T cells to protective IFN gamma producing Th1 lymphocytes via stimulation of TIM-3 expression. Finally, TIM-3 may serve as a novel drug target for the treatment of chronic infections with intracellular pathogens, specifically in iron loading diseases.
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