Biology subjects

Patente, T. A.

Publications and source records attributed to Patente, T. A..

6 recordsLinked to original sources

bioRxiv2026

O-GlcNAcylation and low glycolysis underpin Th2 polarization by dendritic cells

Activation of dendritic cells (DCs) is dependent on rewiring of their cellular metabolism. However, the metabolic requirements for DCs to prime T helper 2 (Th2) responses are still poorly understood. Using unbiased transcriptomics and non-targeted metabolomics we find that helminth antigen-conditioned human DCs suppress glycolysis while increasing hexosamine biosynthesis to fuel protein O-GlcNAcylation. Functionally, glycolytic inhibition of DCs selectively enhanced, while blocking O-GlcNAcylation impaired, Th2-priming capacity. In helminth infection and allergic challenge, Th2 responses were also attenuated in vivo in mice with specific deletion of O-GlcNAc Transferase (OGT) in CD11c-expressing cells. Mechanistically, through proteomic analysis and functional validation, we identified O-GlcNAcylation as a critical negative regulator of immune synapse formation by controlling cytoskeletal organization via Fascin-1 and Zyxin, thereby dampening TCR signalling to promote Th2 polarization. Altogether we reveal a novel metabolic program in DCs that governs Th2 polarization, that could potentially be harnessed to treat type 2 mediated inflammatory diseases.

immunology↗

bioRxiv2026

O-GlcNAcylation drives macrophage IL-4 responsiveness and tissue residency through metabolic and cell cycle calibration

The metabolic requirements for macrophage IL-4 polarization remain contentious, while immunometabolic studies of tissue resident macrophages are still sparse. Hexosamine biosynthesis has gained attention regarding its immune regulatory potential via downstream O-GlcNAcylation. Here we identify protein O-GlcNAcylation as a requirement for IL-4 polarization in vitro and proliferative expansion in vivo during cytokine challenge or infection. We further show that O-GlcNAcylation is critical for controlling tissue residency. By enforcing metabolic and cell cycle quiescence during differentiation, O-GlcNAcylation is needed for adult monocytes to establish a long-live residency program. In this context, its absence leads to perpetual DNA vulnerability and damage via reactive oxygen species, resulting in a senescent-like state poised for cell death. Conversely, long-lived populations instead require O-GlcNAcylation for self-renewal and inflammatory expansion. Our findings altogether suggest O-GlcNAcylation, fueled by hexosamine biosynthesis, serves as a central metabolic rheostat for resident macrophage formation and maintenance during homeostasis and disease.

immunology↗

bioRxiv2023

AMPK activation induces RALDHhigh tolerogenic dendritic cells through rewiring of glucose and lipid metabolism

It is well known that dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. The AMP-activated kinase (AMPK) is a central nutrient and energy sensor whose activation promotes catabolism while inhibiting ATP-consuming anabolic pathways. Yet the contribution of AMPK activation to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by a number of distinct metabolic changes, in particular increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity, and suggest that AMPK may serve as new target to direct DC-driven immune responses in therapeutic settings.

immunology↗

bioRxiv2022

Spectral flow cytometry reveals metabolic heterogeneity in tissue macrophages

Tissue-macrophage populations are constituted by a mosaic of phenotypes, yet new methods are needed to link metabolic status to the range of phenotypes in vivo. We therefore designed a high-dimensional panel for spectral flow cytometry to investigate the heterogeneity of tissue macrophage metabolism at steady-state, and their metabolic adaptation in response to infection. Distinct metabolic profiles were observed between tissue macrophages from different peripheral organs, as well as within populations from a specific site. As such, our data show multiple metabolic states in macrophages corresponding to relative stages of maturity in both the peritoneal cavity and small intestine. Immune perturbation with helminth infection further showed that peritoneal macrophages acquire an overall highly metabolically active profile, whereas responding intestinal macrophages displayed minimal changes in their metabolic phenotype. Thus, we demonstrate that high-dimensional, flow-based analysis is an exciting method to interrogate the metabolic heterogeneity and dynamics of tissue-macrophage populations.

immunology↗

bioRxiv2022

Fasciola hepatica Fatty Acid Binding Protein 1 modulates T cell polarization by promoting dendritic cell thrombospondin-1 secretion without affecting metabolic homeostasis in obese mice

BackgroundThe parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets. Methodology/Principal FindingsThe immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis. Conclusions/SignificanceWe show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.

immunology↗

bioRxiv2021

LKB1 signalling in dendritic cells controls whole-body metabolic homeostasis by limiting T helper 17 priming

Obesity-associated metaflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of dendritic cells (DCs). Here, we report that hepatic DCs from high-fat diet (HFD)-fed obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11c{Delta}LKB1) worsened HFD-driven hepatic steatosis, systemic insulin resistance and glucose intolerance. Loss of LKB1 in DCs was associated with increased cellular expression of Th17-polarizing cytokines and increased hepatic CD4+ IL-17A+ Th17 cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11c{Delta}LKB1 mice. Mechanistically, disrupted metabolic homeostasis was independent of the canonical LKB1-AMPK axis. Instead, we provide evidence for involvement of the AMPK-related salt-inducible kinase(s) in controlling Th17-polarizing cytokine expression in LKB1-deficient DCs. Altogether, our data reveal a key role for LKB1 signalling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 differentiation.

immunology↗