Biology subjects

Sugiura, A.

Publications and source records attributed to Sugiura, A..

8 recordsLinked to original sources

bioRxiv2024

Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism

SummaryWe show that the mitochondrial fatty acid synthesis gene Mecr shapes CD4+ T cell metabolism and function. It may be targeted in inflammatory diseases and provides rationale to consider the immunological state of patients with mitochondrial disease. Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.

immunology↗

bioRxiv2023

Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation

Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4+ T cell subset requirements for specific AA remains uncertain. Here we tested CD4+ T cell AA demands with in vitro and multiple in vivo CRISPR screens and identify subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion over time in vitro and in vivo lung inflammation, SLC38A1 was critical for Th1 but not Th17 cell-driven Experimental Autoimmune Encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing intracellular glutamine and disrupting hexosamine biosynthesis and redox regulation. Similarly, pharmacological inhibition of SLC38 transporters delayed EAE but did not affect lung inflammation. Subset- and tissue-specific dependencies of CD4+ T cells on AA transporters may guide selective immunotherapies. HIGHLIGHTSO_LIT cells dynamically regulate glutamine amino acid transporters when activated C_LIO_LISLC38A1 supports Th1 cell mTORC1 and proliferation by redox and hexosamine pathways C_LIO_LITargeting SLC38A1 does not affect lung inflammation but delays IBD and EAE C_LIO_LINutrient transporter needs of T cell subsets vary based on disease and tissue site C_LI

immunology↗

bioRxiv2023

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Females have increased prevalence of many Th17-mediated diseases. While androgen signaling decreases Th17-mediated inflammation, the mechanisms are not fully understood. Th17 cells rely on glutaminolysis; however, it remains unclear whether androgen receptor (AR) signaling in males modifies glutamine metabolism to suppress Th17-mediated inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis. Using allergen-induced airway inflammation models, we determined females, but not males, had a critical reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake by reducing expression of glutamine transporters. These findings were confirmed in circulating human Th17 cells with minimal reliance on glutamine uptake in male compared to female Th17 cells. We found that AR signaling attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for design and implementation of Th17 or glutaminolysis targeted therapeutics. HighlightsO_LIHuman male CD4+ T cells have decreased expression of metabolic enzymes and decreased reliance on glutaminolysis compared to female CD4+ T cells. C_LIO_LIAndrogen signaling decreased mitochondrial metabolism in Th17 cells and decreased airway inflammation. C_LIO_LIAndrogen signaling decreased glutamine uptake and utilization in Th17 cells. C_LI

immunology↗

bioRxiv2023

Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities

Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and the de novo hexosamine synthesis enzyme, Gfpt1, are critical for T cell expansion and function. Interestingly, Gfpt1-deficient TH1 cells were more affected than TH17 cells, which had increased Nagk for salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factor Bcl11b promotes CD4+ T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders. HIGHLIGHTSO_LIInborn errors of immunity and metabolism have greater overlap than previously known C_LIO_LIGfpt1 deficiency causes an IEM but also selectively regulates T cell subset fate C_LIO_LILoss of Bcl11b causes a T cell deficiency IEI but also harms mitochondrial function C_LIO_LIMany IEM may have immune defects and IEI may be driven by metabolic mechanisms C_LI

immunology↗

bioRxiv2022

Subset-specific mitochondrial and DNA damage shapes T cell responses to fever and inflammation

Heat is a cardinal feature of inflammation. Despite temperature variability and dependence of enzymes and complexes, how heat and fever affect immune cells remains uncertain. We found that heat broadly increased inflammatory activity of CD4+ T cell subsets and decreased Treg suppressive function. Th1 cells, however, also selectively developed mitochondrial dysfunction with high levels of ROS production and DNA damage. This led Th1 cells to undergo Tp53-dependent death, which was required to minimize the accumulation of mutations in heat and inflammation. Th1 cells with similar DNA damage signatures were also detected in Crohns disease and rheumatoid arthritis. Fever and inflammation-associated heat thus selectively induce mitochondrial stress and DNA damage in activated Th1 cells that requires p53 to maintain genomic integrity of the T cell repertoire. One Sentence SummaryFever temperatures augment CD4+ T cell-mediated inflammation but induce differential metabolic stress and DNA damage in T cell subsets, with Th1 cells selectively sensitive and dependent on p53 to induce apoptosis and maintain genomic integrity.

immunology↗

bioRxiv2021

Dysregulated Transferrin Receptor Disrupts T Cell Iron Homeostasis to Drive Inflammation in Systemic Lupus Erythematosus

T cells in systemic lupus erythematosus (SLE) exhibit mitochondrial abnormalities including elevated oxidative stress. Because excess iron can promote these phenotypes, we tested iron regulation of SLE T cells. A CRISPR screen identified Transferrin Receptor (CD71) as important for Th1 cells but detrimental for induced regulatory T cells (iTreg). Activated T cells induce CD71 to increase iron uptake, but this was exaggerated in T cells from SLE-prone mice which accumulated iron. Treatment of T cells from SLE-prone mice with CD71 blocking antibody reduced intracellular iron and mTORC1 signaling and restored mitochondrial physiology. While Th1 cells were inhibited, CD71 blockade enhanced iTreg. In vivo this treatment reduced pathology and increased IL-10 in SLE-prone mice. Importantly, disease severity correlated with CD71 expression on SLE patient T cells and blocking CD71 enhanced IL-10 secretion. Excess T cell iron uptake thus contributes to T cell dysfunction and can be targeted to correct SLE-associated pathology.

immunology↗

bioRxiv2021

MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function

Antigenic stimulation promotes T cells metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2) is highly expressed in inflammatory diseases and induced in activated T cells to promote proliferation and produce inflammatory cytokines. In pathogenic Th17 cells, MTHFD2 also prevented aberrant upregulation of FoxP3 and suppressive capacity. Conversely, MTHFD2-deficiency enhanced lineage stability of regulatory T (Treg) cells. Mechanistically, MTHFD2 maintained cellular 10-formyltetrahydrofolate for de novo purine synthesis and MTHFD2 inhibition led to accumulation of the intermediate 5-aminoimidazole carboxamide ribonucleotide that was associated with decreased mTORC1 signaling. MTHFD2 was also required for proper histone de-methylation in Th17 cells. Importantly, inhibiting MTHFD2 in vivo reduced disease severity in Experimental Autoimmune Encephalomyelitis and Delayed-Type Hypersensitivity. MTHFD2 induction is thus a metabolic checkpoint for pathogenic effector cells that suppresses anti-inflammatory Treg cells and is a potential therapeutic target within 1C metabolism.

immunology↗

bioRxiv2019

Motivated for near impossibility: How task type and reward modulates intrinsic motivation and the striatal activation for an extremely difficult task.

Economic and decision-making theories suppose that people would disengage from a task with near zero success probability, because this implicates little normative utility values. However, humans are often motivated for an extremely challenging task, even without any extrinsic incentives. The current study aimed to address the nature of this challenge-based motivation and its neural correlates. We found that, when participants played a skill-based task without extrinsic incentives, their task enjoyment increased as the chance of success decreased, even if the task was almost impossible to achieve. However, such challenge-based motivation was not observed when participants were rewarded for the task or the reward was determined in a probabilistic manner. The activation in the ventral striatum/pallidum tracked the pattern of task enjoyment. These results suggest that people are intrinsically motivated to challenge a nearly impossible task, but only when the task requires certain skills and extrinsic rewards are unavailable.

neuroscience↗