Biology subjects

Zimmermann, V. S.

Publications and source records attributed to Zimmermann, V. S..

3 recordsLinked to original sources

bioRxiv2025

Intrathymic progenitor cell transplantation restores T cell development through ILC3-TEC crosstalk

T cell deficiencies are commonly treated by intravenous hematopoietic stem/progenitor cell (HSPC) transplantation. However, this approach often leads to delayed and incomplete T cell reconstitution, partly due to impaired thymic function. In contrast, intrathymic delivery of HSPCs enables rapid, thymus-autonomous T cell development. Using a ZAP-70-deficient mouse model of severe immunodeficiency, we show that intrathymic transplantation of wild-type HSPCs results in robust thymic engraftment, with mature T cells and FOXP3+ regulatory T cells (Treg) detectable within four weeks. This reconstitution parallels the regeneration of a functional thymic medulla and the emergence of mature medullary thymic epithelial cells (mTECs). Importantly, we identify an early wave of donor-derived ROR{gamma}T+ ILC3s that correlates with medullary regeneration. While dispensable for steady-state thymopoiesis, ILC3s accelerate medulla formation and support optimal T cell differentiation in this immunodeficient setting. These findings uncover a critical role for ILC3-TEC crosstalk in thymic repair and highlight intrathymic HSPC transplantation as a strategy to enhance immune reconstitution in immunodeficient hosts.

immunology↗

bioRxiv2022

Arginine-dependent hypusination of the eukaryotic translation initiation factor (eIF)5A drives erythroid lineage differentiation

Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. We discovered that SLC7A1/CAT1-dependent arginine uptake and its catabolism to spermidine control the erythroid specification of HSPCs via activation of eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on the metabolism of spermidine to hypusine and inhibiting hypusine synthesis abrogates erythropoiesis and diverts EPO-stimulated HSPCs to a myeloid fate. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and induction of mitochondrial function partially rescues erythropoiesis in the absence of hypusine. Within the hypusine network, ribosomal proteins are highly enriched and we identify defective eIF5A hypusination in erythroid pathologies caused by abnormal ribosome biogenesis. Thus, eIF5A-dependent protein synthesis is critical in the branching of erythro-myeloid differentiation and attenuated eIF5A activity characterizes ribosomal protein-linked disorders of ineffective erythropoiesis.

physiology↗

bioRxiv2020

Alpha-ketoglutarate inhibits Regulatory T cell differentiation by coupling lipidome remodelling to mitochondrial metabolism

The differentiation of CD4 T cells to a specific effector fate is metabolically regulated, integrating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) with transcriptional and epigenetic changes. OXPHOS is tightly coordinated with the tricarboxylic acid (TCA) cycle but the precise role of TCA intermediates in CD4 T cell differentiation remain unclear. Here we demonstrate that -ketoglutarate (KG) inhibited regulatory T cell (Treg) generation while conversely, increasing Th1 polarization. In accord with these data, KG promoted the effector profile of Treg-polarized chimeric antigen receptor-engineered T cells against the ErbB2 tumor antigen. Mechanistically, KG significantly altered transcripts of genes involved in lipid-related processes, inducing a robust lipidome-wide remodelling and decreased membrane fluidity. A massive increase in storage and mitochondria lipids was associated with expression of mitochondrial genes and a significantly augmented OXPHOS. Notably, inhibition of succinate dehydrogenase activity, the bridge between the TCA cycle and the electron transport chain, enforced Treg generation. Thus, our study identifies novel connections between KG, lipidome remodelling and OXPHOS in CD4 T cell fate decisions.

immunology↗