Jingxia Wu

Fatty acid (FA) oxidation plays an important role in T cell responses. However, whether DGAT1-mediated FA esterification to triacylglycerol also regulates T cell function remains unclear. Here we uncover a sexually dimorphic requirement for DGAT1 expression in CD8⁺ tumour-infiltrating lymphocyte function. In female mice, T cell-specific Dgat1 deficiency improves mitochondrial metabolic fitness and expands the pool of progenitor exhausted CD8⁺ T (T_ex) cells to sustain antitumour responses. In male mice, however, Dgat1 deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8⁺ T_ex cell death. We show that these effects are mediated by androgen receptor (AR) signalling. Deletion of Ar, overexpression of glutathione peroxidase 4, or inhibition of ER stress-induced cell death rescues Dgat1-deficient CD8⁺ T cell survival and promotes antitumour responses in male mice. Overall, this study suggests that DGAT1 detoxifies AR signalling in male mice to protect against ER stress-induced cell death and maintain T cell stemness, and uncovers sex-specific metabolic adaptations in the tumour microenvironment.

Regulatory T cells (Tregs) are fundamental to immune homeostasis, maintaining peripheral tolerance and preventing pathological autoimmunity across vertebrate species. The recent publication, “Beyond FoxP3: Identification of a Chicken Regulatory T Cell Signature,” in the European Journal of Immunology by Naumann et al., addresses a critical gap in comparative immunology by providing a comprehensive phenotypic and transcriptional characterization of chicken Treg cells. This commentary will situate the study within the historical context of Treg research, underscore the specific challenges in avian Treg characterization, and highlight the work's transformative implications for both basic immunology and applied poultry science.

This comprehensive review explores the atypical metabolic roles of metabolites, extending beyond their conventional functions in energy production and biosynthesis. It systematically discusses how metabolites serve as substrates for post-translational protein modifications (PTMs), including lactylation, acetylation, and palmitoylation, detailing their metabolic origins, enzymatic regulation, and impacts on development, homeostasis, and diseases. Additionally, the review highlights how metabolites and metabolic enzymes act as signaling molecules to modulate intracellular and intercellular signal transduction, influencing processes like cell differentiation, survival, and proliferation. Unlike previous reviews, this work integrates PTM mechanisms with metabolic signaling networks, aiming to inspire research on metabolic regulation in health and disease, and to identify novel therapeutic targets.

CD4 ⁺ regulatory T (T _reg ) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences T _reg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed T _reg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible T _reg cell differentiation in vitro in a PD-1–dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for T _reg cell differentiation and limits antitumor immunity.

T cells are an important component of adaptive immunity and protect the host from infectious diseases and cancers. However, uncontrolled T cell immunity may cause autoimmune disorders. In both situations, antigen-specific T cells undergo clonal expansion upon the engagement and activation of antigens. Cellular metabolism is reprogrammed to meet the increase in bioenergetic and biosynthetic demands associated with effector T cell expansion. Metabolites not only serve as building blocks or energy sources to fuel cell growth and expansion but also regulate a broad spectrum of cellular signals that instruct the differentiation of multiple T cell subsets. The realm of immunometabolism research is undergoing swift advancements. Encapsulating all the recent progress within this concise review in not possible. Instead, our objective is to provide a succinct introduction to this swiftly progressing research, concentrating on the metabolic intricacies of three pivotal nutrient classes—lipids, glucose, and amino acids—in T cells. We shed light on recent investigations elucidating the roles of these three groups of metabolites in mediating the metabolic and immune functions of T cells. Moreover, we delve into the prospect of “editing” metabolic pathways within T cells using pharmacological or genetic approaches, with the aim of synergizing this approach with existing immunotherapies and enhancing the efficacy of antitumor and antiinfection immune responses.

The malate shuttle is traditionally understood to maintain NAD⁺/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8⁺ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD⁺/NADH ratio and limited antiviral CD8⁺ T cell responses to chronic infection; however, increasing the NAD⁺/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8⁺ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8⁺ T cells is not to maintain the NAD⁺/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8⁺ T cells during chronic infection.