Genetically engineering glycolysis in T cells increases their antitumor function.

Background: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.

Metabolic modeling of single Th17 cells reveals regulators of autoimmunity.

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays.

Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response.

Virus-infected cells and cancers share metabolic commonalities that stem from their insatiable need to replicate while evading the host immune system. These similarities include hijacking signaling mechanisms that induce metabolic rewiring in the host to up-regulate nucleotide metabolism and, in parallel, suppress the immune response. In both cancer and viral infections, the host immune cells and, specifically, lymphocytes augment nucleotide synthesis to support their own proliferation and effector functions.

T Cell Activation Depends on Extracellular Alanine.

T cell stimulation is metabolically demanding. To exit quiescence, T cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T cell activation.

Adaptation of Human iPSC-Derived Cardiomyocytes to Tyrosine Kinase Inhibitors Reduces Acute Cardiotoxicity via Metabolic Reprogramming.

Tyrosine kinase inhibitors (TKIs) are widely used to treat solid tumors but can be cardiotoxic. The molecular basis for this toxicity and its relationship to therapeutic mechanisms remain unclear; we therefore undertook a systems-level analysis of human cardiomyocytes (CMs) exposed to four TKIs. CMs differentiated from human induced pluripotent stem cells (hiPSCs) were exposed to sunitinib, sorafenib, lapatinib, or erlotinib, and responses were assessed by functional assays, microscopy, RNA sequencing, and mass spectrometry (GEO: GSE114686; PRIDE: PXD012043).

Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice.

T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation.

Maintenance of CD4 T cell fitness through regulation of Foxo1.

Foxo transcription factors play an essential role in regulating specialized lymphocyte functions and in maintaining T cell quiescence. Here, we used a system in which Foxo1 transcription-factor activity, which is normally terminated upon cell activation, cannot be silenced, and we show that enforcing Foxo1 activity disrupts homeostasis of CD4 conventional and regulatory T cells. Despite limiting cell metabolism, continued Foxo1 activity is associated with increased activation of the kinase Akt and a cell-intrinsic proliferative advantage; however, survival and cell division are decreased in a competitive setting or growth-factor-limiting conditions.

Suppression by T cells leads to durable and selective inhibition of B cell effector function.

Follicular regulatory T cells (T cells) inhibit follicular helper T cell (T cell)-mediated antibody production. The mechanisms by which T cells exert their key immunoregulatory functions are largely unknown. Here we found that T cells induced a distinct suppressive state in T cells and B cells, in which effector transcriptional signatures were maintained but key effector molecules and metabolic pathways were suppressed.

Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation.

Naive T cell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naive CD4(+) T cell activation induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T cell activation.

Mitochondrial metabolism in T cell activation and senescence: a mini-review.

The aging immune system is unable to optimally respond to pathogens and generate long-term immunological memory against encountered antigens. Amongst the immune components most affected by aging are T lymphocytes. T lymphocytes are cells of the cell-mediated immune system, which can recognize microbial antigens and either directly kill infected cells or support the maturation and activation of other immune cells.

CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging.

The adaptive arm of the immune system has been suggested as an important factor in brain function. However, given the fact that interactions of neurons or glial cells with T lymphocytes rarely occur within the healthy CNS parenchyma, the underlying mechanism is still a mystery. Here we found that at the interface between the brain and blood circulation, the epithelial layers of the choroid plexus (CP) are constitutively populated with CD4(+) effector memory cells with a T-cell receptor repertoire specific to CNS antigens.

Brain homeostasis is maintained by "danger" signals stimulating a supportive immune response within the brain's borders.

An organism's behavior is determined by the way it senses and perceives the surrounding environment, and by its responses to these stimuli. The major factors known to affect the behavioral response to an event are genetic background, environmental factors, and past experiences, and their imprinting on the relevant brain circuits. Recently, circulating immune cells were introduced as novel players into this system.

Thymic involution, a co-morbidity factor in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating disease, characterized by extremely rapid loss of motor neurons. Our studies over the last decade have established CD4(+) T cells as important players in central nervous system maintenance and repair. Those results, together with recent findings that CD4(+) T cells play a protective role in mouse models of ALS, led us to the current hypothesis that in ALS, a rapid T-cell malfunction may develop in parallel to the motor neuron dysfunction.

Immune senescence and brain aging: can rejuvenation of immunity reverse memory loss?

The factors that determine brain aging remain a mystery. Do brain aging and memory loss reflect processes occurring only within the brain? Here, we present a novel view, linking aging of adaptive immunity to brain senescence and specifically to spatial memory deterioration. Inborn immune deficiency, in addition to sudden imposition of immune malfunction in young animals, results in cognitive impairment.