Biology subjects

Theurich, S.

Publications and source records attributed to Theurich, S..

3 recordsLinked to original sources

bioRxiv2024

L-Asparaginase treatment induces reversible immunoregulatory and immunosuppressive effects in non-malignant B cells in a model of T-cell dependent B cell activation

Metabolic reprogramming is critical for immune cell adaptation upon activation to exert full functionality with amino acids being a key metabolic factor. While L-asparagine is a non- essential amino acid it turns out to be conditionally essential in malignant B cells due to defective asparagine synthetase making L-asparaginase a commonly used chemotherapeutic agent. Off-target enzymatic activity including glutaminolysis impacting crucial immune function. However, its effects on healthy B cells remain unclear, therefore in this study, we explored how L-asparaginase modulates the biology and function of CD40-activated B cells, using an in-vitro model. B cells from healthy donors were treated with increasing L- asparaginase concentrations and analyzed for proliferation, immune phenotype, and metabolic changes. Results showed L-asparaginase reduced B cell proliferation and homotypic clustering without inducing apoptosis, instead impairing metabolic pathways, lowering glycolysis and oxidative phosphorylation, and reducing surface markers associated with antigen-presenting cell (APC) function. Functional assays confirmed that L-asparaginase- treated B cells had diminished ability to activate T cells. Supplementing with asparagine or glutamine restored B cell proliferation and function, with glutamine slightly more effective than asparagine. Interestingly, L-asparaginase induced a regulatory B cell phenotype, marked by CD24+CD38+CD27+ expression and increased interleukin-10 and TGF-beta, suggesting a potential immunosuppressive mechanism. These findings indicate that L-asparaginase not only affects malignant cells but also impacts the function of non-malignant B cells, proposing potential therapeutic applications in B cell-driven autoimmune disorders. Further studies are needed to explore its effects at lower, clinically relevant concentrations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/625617v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1ae8d10org.highwire.dtl.DTLVardef@af405borg.highwire.dtl.DTLVardef@1aa4c0eorg.highwire.dtl.DTLVardef@16750ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells

Functional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to self-renew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation of hypoxia inducible factor 1 alpha (HIF-1) in Tpex cells. HIF-1 mediates the transcriptional-glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and functional exhaustion. Finally, we show that enhancing respiration by limiting the glycolytic activity of CAR T cells is a feasible metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.

immunology↗

bioRxiv2021

P2Y6 receptor signaling in natural killer cells impairs insulin sensitivity in obesity

Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance and have previously been shown to up-regulate the expression of the P2Y purinoreceptor 6 (P2Y6R) upon high fat diet (HFD)-induced obesity. Here, we reveal that NK cell-specific inactivation of the P2Y6R gene improves insulin sensitivity in obese mice and reduces the expression of chemokines in adipose tissue infiltrating NK-cells. Obese mice lacking P2Y6R specifically in NK cells exhibited a reduction in adipose tissue inflammation, exhibited improved insulin-stimulated suppression of lipolysis in adipose tissue and a reduction in hepatic glucose production, leading to an overall improvement of systemic insulin sensitivity. In contrast, myeloid lineage specific P2Y6R inactivation does not affect energy or glucose homeostasis in obesity. Collectively, we show that P2Y6R signaling in NK cells contributes to the development of obesity-associated insulin resistance and thus might be a future target for the treatment of obesity-associated insulin resistance and type 2 diabetes.

immunology↗