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Immunol."],"abstract":"<jats:p>Iron plays an important role in host\u2013pathogen 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 <jats:italic>Salmonella enterica serovar typhimurium<\/jats:italic> (<jats:italic>S. Typhimurium<\/jats:italic>). Iron loading prior to infection fostered bacterial burden and, unexpectedly, reduced differentiation of CD4<jats:sup>+<\/jats:sup> T helper cells type 1 (Th1) and expression of interferon-gamma (IFN\u03b3), 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. <jats:italic>In vitro<\/jats:italic> experiments demonstrated that iron supplementation specifically upregulated mRNA and protein expression of TIM-3 in na\u00efve 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 <jats:italic>S. Typhimurium<\/jats:italic> virtually restored Th1 cell differentiation and significantly improved bacterial control. Our data uncover a novel mechanism by which iron modulates CD4<jats:sup>+<\/jats:sup> cell differentiation and functionality and hence impacts infection control with intracellular pathogens. Specifically, iron inhibits the differentiation of naive CD4<jats:sup>+<\/jats:sup> T cells to protective IFN\u03b3 producing Th1 lymphocytes <jats:italic>via<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fimmu.2021.637809","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T05:25:33Z","timestamp":1621833933000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Regulation of Th1 T Cell Differentiation by Iron via Upregulation of T Cell Immunoglobulin and Mucin Containing Protein-3 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