Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling.

T helper 9 (Th9) cells are interleukin 9 (IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation. Th9 cells differentiate from naïve CD4 T cells in the presence of IL-4 and transforming growth factor-beta (TGF-β); however, our understanding of the molecular basis of their differentiation remains incomplete. Previously, we reported that the differentiation of another subset of TGF-β-driven T helper cells, Th17 cells, is highly dependent on de novo lipid biosynthesis.

The integration of metabolic and proteomic data uncovers an augmentation of the sphingolipid biosynthesis pathway during T-cell differentiation.

Recent studies have highlighted the significance of cellular metabolism in the initiation of clonal expansion and effector differentiation of T cells. Upon exposure to antigens, naïve CD4 T cells undergo metabolic reprogramming to meet their metabolic requirements. However, only few studies have simultaneously evaluated the changes in protein and metabolite levels during T cell differentiation.

ACC1-mediated fatty acid biosynthesis intrinsically controls thymic iNKT cell development.

To meet the energetic requirements associated with activation, proliferation, and survival, T cells switch their metabolic signatures from energetically quiescent to activated. However, little is known about the role of metabolic pathway controlling the development of invariant natural killer T (iNKT) cells. In the present study, we found that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for the fatty acid biosynthesis pathway, plays an essential role in the development of iNKT cells in the thymus.

1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in T17 cells.

Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (T17) cells. However, the exact enzymes and lipid metabolites involved, as well as their link to promoting the core gene transcriptional signature required for the differentiation of T17 cells, remain largely unknown. From a pooled CRISPR-based screen and unbiased lipidomics analyses, we identified that 1-oleoyl-lysophosphatidylethanolamine could act as a lipid modulator of retinoid-related orphan receptor gamma t (RORγt) activity in T17 cells.

Characterization of proteogenomic signatures of differentiation of CD4+ T cell subsets.

Functionally distinct CD4+ helper T (Th) cell subsets, including Th1, Th2, Th17, and regulatory T cells (Treg), play a pivotal role in the regulation of acquired immunity. Although the key proteins involved in the regulation of Th cell differentiation have already been identified how the proteogenomic landscape changes during the Th cell activation remains unclear. To address this issue, we characterized proteogenomic signatures of differentiation to each Th cell subsets by RNA sequencing and liquid chromatography-assisted mass spectrometry, which enabled us to simultaneously quantify more than 10,000 protein-coding transcripts and 8,000 proteins in a single-shot.

SCD2-mediated cooperative activation of IRF3-IRF9 regulatory circuit controls type I interferon transcriptome in CD4 T cells.

Type I interferons (type I-IFN) are critical for the host defense to viral infection, and at the same time, the dysregulation of type I-IFN responses leads to autoinflammation or autoimmunity. Recently, we reported that the decrease in monounsaturated fatty acid caused by the genetic deletion of is essential for the activation of type I-IFN signaling in CD4 Th1 cells. Although interferon regulatory factor (IRF) is a family of homologous proteins that control the transcription of type I-IFN and interferon stimulated genes (ISGs), the member of the IRF family that is responsible for the type I-IFN responses induced by targeting of SCD2 remains unclear.

ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice.

T cells possess distinguishing effector functions and drive inflammatory disorders. We have previously identified IL-5-producing Th2 cells as the pathogenic population predominantly involved in the pathology of allergic inflammation. However, the cell-intrinsic signaling pathways that control the pathogenic Th2 cell function are still unclear.

Acsbg1-dependent mitochondrial fitness is a metabolic checkpoint for tissue T cell homeostasis.

Regulatory T (T) cells are critical for immunological tolerance and immune homeostasis. T cells strongly rely on mitochondrial metabolism and show a lower level of glycolysis. However, little is known about the role of lipid metabolism in the regulation of T cell homeostasis.

SCD2-mediated monounsaturated fatty acid metabolism regulates cGAS-STING-dependent type I IFN responses in CD4 T cells.

Host lipid metabolism and viral responses are intimately connected. However, the process by which the acquired immune systems adapts lipid metabolism to meet demands, and whether or not the metabolic rewiring confers a selective advantage to host immunity, remains unclear. Here we show that viral infection attenuates the expression of genes related to lipid metabolism in murine CD4 T cells, which in turn increases the expression of antiviral genes.

ACC1 determines memory potential of individual CD4 T cells by regulating de novo fatty acid biosynthesis.

Immunological memory is central to adaptive immunity and protection from disease. Changing metabolic demands as antigen-specific T cells transition from effector to memory cells have been well documented, but the cell-specific pathways and molecules that govern this transition are poorly defined. Here we show that genetic deletion of ACC1, a rate-limiting enzyme in fatty acid biosynthesis, enhances the formation of CD4 T memory cells.

DUSP10 constrains innate IL-33-mediated cytokine production in ST2 memory-type pathogenic Th2 cells.

ST2 memory-type Th2 cells are identified as a pathogenic subpopulation in eosinophilic airway inflammation. These ST2 pathogenic Th2 cells produce large amount of IL-5 upon T cell receptor stimulation, but not in response to IL-33 treatment. By contrast, IL-33 alone induces cytokine production in ST2 group 2 innate lymphoid cells (ILC2).

Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells.

To fulfil the bioenergetic requirements for increased cell size and clonal expansion, activated T cells reprogramme their metabolic signatures from energetically quiescent to activated. However, the molecular mechanisms and essential components controlling metabolic reprogramming in T cells are not well understood. Here, we show that the mTORC1-PPARγ pathway is crucial for the fatty acid uptake programme in activated CD4 T cells.

Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1.

Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo.

The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway.

Memory CD4(+) T helper (Th) cells provide long-term protection against pathogens and are essential for the development of vaccines; however, some antigen-specific memory Th cells also drive immune-related pathology, including asthma. The mechanisms regulating the pathogenicity of memory Th cells remain poorly understood. We found that interleukin-33 (IL-33)-ST2 signals selectively licensed memory Th2 cells to induce allergic airway inflammation via production of IL-5 and that the p38 MAP kinase pathway was a central downstream target of IL-33-ST2 in memory Th2 cells.