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CTLA-4 promotes glucose uptake by tumour-infiltrating regulatory T cells, making them unstable.

Wang, Wilfahrt and colleagues show that phosphoethanolamine, a phospholipid intermediate, is enriched in tumour interstitial fluid and induces T cell dysfunction, in part by depleting diacylglycerol and dampening T cell receptor signalling.

Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1α-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion.

The tumour microenvironment is low in glucose and high in the alternative metabolite lactate, which regulatory T cells are shown here to use, maintaining their ability to suppress effector immune cells.

Here the authors show that high expression of MCT11 is key to the dysfunctionality associated with exhausted CD8⁺ T cells in tumors. By targeting MCT11, uptake of lactic acid, which is abundant in the tumor, is reduced, resulting in improved effector functions and tumor immunity.

IL-35 is an immunomodulatory cytokine, but the molecular details of its effects have remained obscure. Vignali and colleagues determine the IL-35 receptor and how its signaling pathway leads to its suppressive action.

In this Review, Wilfahrt and Delgoffe discuss how T cells integrate nutrient sensing with activating stimuli to shape their differentiation and sensitivity to metabolites.

Exhausted CD8⁺ T cells with diminished effector functions accumulate in tumors. Here, the authors show that hypoxia induces a suppressive phenotype in exhausted T cells and that interfering with hypoxia-mediated CD39 expression limits immunosuppression in the tumor and augments immunotherapy, resulting in arrest of tumor growth.

Regulatory T cells must limit activation of the metabolic checkpoint kinase mTOR to maintain their identity. The lipid ceramide serves a unique role in this process by inducing phosphatase PP2A–mediated inhibition of the mTORC1 complex.

Interferon-β (IFN-β) is widely used to treat multiple sclerosis (MS), but its mechanism of protection remains obscure. A new study shows that IFN-β induces FoxA1⁺ regulatory T cells, a new regulatory T cell population, which suppress conventional T cells via programmed cell death 1 ligand 1. This cell subset limits disease in a mouse model of MS and was found in patients with MS who responded to IFN-β therapy (pages 272–282).

Immunotherapeutic approaches to cancer can be affected by metabolic restrictions that limit the potency of anticancer T cell responses. In this Review, DePeaux and Delgoffe discuss the metabolic features of the tumour microenvironment that limit anticancer immune responses, as well as emerging therapeutic approaches to target these.

Germinal center B cells can undergo rapid proliferation. Shlomchik and colleagues show that germinal center B cells, unlike other rapidly proliferating cells, do not depend on glycolysis, but rather increase their peroxisome content and rewire their cellular metabolism to exclusively utilize fatty acid oxidation for their energetic needs.

Fibroblastic reticular cells support lymph-node function and adaptive immunity. McGeachy and colleagues show that the cytokine IL-17 is needed to trigger metabolic changes required for the proliferation and survival of these cells in reactive lymph nodes.

Neuropilin-1 (Nrp1) on regulatory T (T_reg) cells is shown to interact with semaphorin-4a (Sema4a) to promote a program of T_reg-cell stability and survival, in part through PTEN-mediated modulation of Akt signalling; Nrp1-deficient T_reg cells can maintain immune homeostasis but fail to suppress in inflammatory sites, such as tumours, providing an attractive immunotherapeutic target for the treatment of cancers.

Th17 cells can transdifferentiate into regulatory T (T_reg) cells. Here the authors characterize tumour-driven Th17-to-T_regcell transdifferentiation and identify potential cancer therapy targets.

The kinase mTOR has emerged as an important regulator of helper T cell differentiation. Powell and co-workers show that the mTOR complex mTORC1 selectively regulates T_H1 and T_H17 differentiation, whereas mTORC2 signaling is required for T_H2 differentiation.

Asymmetric division can generate effector and memory CD8⁺ T cell precursors. Powell and colleagues show asymmetric partitioning of mTORC1 activity upon CD8⁺ T cell division, which results in distinct metabolic programming of daughter T cells.