An essential role of iron in Tfh cell development and effector function

Abstract Background: T follicular helper CD4+ cells (Tfh) are essential for maintenance of systemic lupus erythematosus (SLE) as they help germinal center B cells generate high affinity auto-antibodies. The activation of STAT3 is critical for generation of Tfh cells as it promotes the transcription of BCL6 (the essential transcription factor for Tfh cell differentiation). It is recognized that activated, proliferating SLE CD4+ T cells, contain more iron than controls. Iron binds CDK1 to accentuate JAK1 phosphorylation and activation of STAT3 in proliferating cells. Whether increased iron content of SLE CD4+ T cells augments JAK1-STAT3 signaling and their differentiation into Tfh cells has not been investigated. Experiments: RNAseq and qPCR was used to compare iron regulatory pathways in purified Tfh cells from WT and SLE-prone mice. Labile iron (bio-active) content was measured in freshly isolated Tfh cells. The effect of iron chelator on in vitro Tfh differentiation and effector function was evaluated. Results: Compared to WT, SLE Tfh cells displayed significant increase in genes associated with iron uptake and transmembrane iron transport. Labile iron content and CDK1 gene expression were elevated in SLE Tfh cells. Iron chelation attenuated STAT3 activation, BCL6 expression and IL-21 production in in vitro generated Tfh cells. Conclusion: Our novel data identify an essential role of iron in Tfh cell differentiation and effector function. Increased iron and CDK1 may amplify JAK1-STAT3 signaling and potentiate Tfh cell differentiation. This can be blocked by restricting free iron availability. Understanding this aspect of Tfh cell biology in SLE may support strategies that control labile iron as potential adjunct therapy. Supported by grants from Vifor Pharma (P0213104, P0226952) to Yogesh Scindia NIH (R01AI135128) to Borna Mehrad NIH (R01AI128901) to Laurence Morel