Transferrin Receptor 1 is Required for CD4+ T Cell Iron-Dependent Response During Acute Toxoplasma gondii Infection

Elemental iron is an essential nutrient involved in many biological processes including infection and immunity. How iron impacts Toxoplasma gondii (T. gondii) in vivo and development of immunity during infection is unclear. We found that although iron is required for parasite proliferation in vitro, paradoxically, iron restriction in vivo increased parasite burdens during acute and persistent infection stages and decreased survival of mice. Iron restriction lowered IL-12 and IFN{gamma} in spleen and serum, but ratios of myeloid cells and the number and function of Natural Killer cells were unchanged. Iron restriction significantly impaired the development of CD4+ and CD8+ T cell responses to T. gondii during replicating type II and attenuated vaccine strain cps1-1 infection. Low iron conditions reduced the percent and absolute numbers of antigen experienced CD11a+CD49d+, functional IFN{gamma}+, and CD62L-KLRG1+ effector T cells. Iron restriction also decreased vaccine efficacy of cps1-1 strain against secondary lethal challenge. Antigen experienced CD4+ and CD8+ T cells both upregulated their iron transporter Transferrin receptor 1 (CD71) during infection regardless of iron restriction. Mice whose CD4+ T cells were deficient in CD71 had reduced CD4+ T cell antigen experience and polyfunctionality, yet CD8+ T cell responses remained intact, and their long term survival was not affected compared to wild type litter mate controls. This study highlights that iron acquisition by T cells is required for activation and vaccine induced long-term protection against T. gondii. Understanding how iron affects multiple immune compartments will be essential to define iron regulation of immunity to T. gondii.