Cell intrinsic heme synthesis is required for the proper activation of naive CD4+ T cells

Abstract

Understanding the biology of naive CD4+ T cell activation is crucial for comprehending acquired immunity and related disorders. It was identified that the uptake of iron, one of the major micronutrients in mammals, is enormously enhanced during their activation. However, little is known about how iron is utilized in this activation process. Here, we found that the synthesis of heme, one of the major iron-containing metabolites, is indispensable for their activation. Mechanistically, heme supports the interleukin 2-signal transducer and activator of transcription 5 (IL-2-STAT5) signaling to enhance metabolism required for their activation, including glycolysis, which might be achieved by inactivating the repressive transcription factor BACH2. Moreover, several murine autoimmune disorders, derived from CD4+ T cells, were ameliorated by heme synthesis inhibition. These findings will pave the way for understanding how T cell activation is controlled by micronutrients through "mitochondria-glycolysis crosstalk", providing an opportunity to target heme metabolism for the treatment of autoimmune disorders.

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