Iron is essential for living cells. Uptake of iron-loaded transferrin by the transferrin receptor 1 (CD71, TFR) is a major but not sufficient mechanism and an alternative iron-loaded ligand for CD71 has been assumed. Here, we demonstrate that CD71 utilizes heme-albumin as cargo to transport iron into human cells. Binding and endocytosis of heme-albumin via CD71 was sufficient to promote proliferation of various cell types in the absence of transferrin. Growth and differentiation of cells induced by heme-albumin was dependent on heme-oxygenase 1 (HO-1) function and was accompanied with an increase of the intracellular labile iron pool (LIP). Import of heme-albumin via CD71 was further found to contribute to the efficacy of albumin-based drugs such as the chemotherapeutic Abraxane. Thus, heme-albumin/CD71 interaction is a novel route to transport nutrients or drugs into cells and adds to the emerging function of CD71 as a scavenger receptor.

Iron uptake via the transferrin receptor (CD71) is a pivotal mechanism for T cell proliferation. Yet, it is incompletely understood if targeting of CD71 also affects the differentiation and functional polarization of primary human T cells. In this study, we demonstrate that inhibition of iron ingestion with blocking mAbs against CD71 induces nonproliferating T cells, which release high amounts of IL-2. Targeting of CD71 with blocking or nonblocking mAbs did not alter major signaling pathways and the activation of the transcription factors NF-kB, NFAT, or AP-1 as analyzed in Jurkat T cells. Growth arrest in iron-deficient (Fe-def) T cells was prevented upon addition of exogenous iron in the form of ferric ammonium citrate but was not reversible by exogenous IL-2. Surprisingly, protein synthesis was found to be intact in Fe-def T cells as demonstrated by comparable levels of CD69 upregulation and cytokine production with iron-sufficient T cells upon stimulation with CD3 plus CD28 mAbs. Indeed, high amounts of IL-2 were detectable in the supernatant of Fe-def T cells, which was accompanied with a reduced cell surface expression of IL-2R. When we used such Fedef T cells in allogeneic MLRs, we observed that these cells acquired an accessory cell function and stimulated the proliferation of bystander T cells by providing IL-2. Thus, the results of our study demonstrate that iron deprivation causes nonproliferating, altruistic T cells that can help and stimulate other immune cells by providing cytokines such as IL-2. ImmunoHorizons, 2020, 4: 165-177.

Targeting of the pro-inflammatory cytokines interleukin 17A (IL-17A) or tumor necrosis factor alpha (TNFα) with monoclonal antibodies (mAbs) ixekizumab or adalimumab, respectively, are successful therapies in chronic plaque psoriasis. The effects of these treatments on immune cell populations in the skin are largely unknown. In this study, we compared the composition of cutaneous, lesional as well as non-lesional, and blood immune cells in ixekizumab or adalimumab treated patients with psoriasis. Our data reveal that both treatments efficiently down-regulate T-cells, macrophages and different subsets of dendritic cells (DCs) in lesional skin towards levels of healthy skin. In contrast to lesional skin, non-lesional areas in patients harbor only few or no detectable DCs compared to skin of healthy subjects. Neither the treatment with ixekizumab nor adalimumab reverted this DC imbalance in non-lesonal skin of psoriatic patients. Taken together, our study shows that anti-IL-17A as well as anti-TNFα therapy rebalances the immune cell repertoire of lesional skin in psoriatic patients, but fail to restore the disturbed immune cell repertoire in non-lesional skin during the induction phase of therapy.