Recent advances in the field of immunometabolism support the concept that fundamental processes in T cell biology, such as TCR-mediated activation and T helper lineage differentiation, are closely linked to changes in the cellular metabolic programs. Although the major task of the intermediate metabolism is to provide the cell with a constant supply of energy and molecular precursors for the production of biomolecules, the dynamic regulation of metabolic pathways also plays an active role in shaping T cell responses. Key metabolic processes such as glycolysis, fatty acid and mitochondrial metabolism are now recognized as crucial players in T cell activation and differentiation, and their modulation can differentially affect the development of T helper cell lineages. In this review, we describe the diverse metabolic processes that T cells engage during their life cycle from naïve towards effector and memory T cells. We consider in particular how the cellular metabolism may actively support the function of T cells in their different states. Moreover, we discuss how molecular regulators such as mTOR or AMPK link environmental changes to adaptations in the cellular metabolism and elucidate the consequences on T cell differentiation and function.

Neurotrophic factors produced by enteric glia in response to microbiota and alarmin cues regulate IL-22 production by group 3 innate lymphoid cells in the gut; disruption of this pathway leads to impaired clearance of Citrobacter rodentium and defects in epithelial integrity in a model of intestinal inflammation. Henrique Veiga-Fernandes and colleagues show that neurotrophic factors produced by enteric glial cells in response to microbiota-derived cues contribute to the interleukin-22 production and regulation of group 3 innate lymphoid cells in the gut. Disruption of this pathway leads to impaired clearance of Citrobacter rodentium and defects in epithelial integrity in a model of intestinal inflammation. Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers1. ILC3 development is thought to be programmed1, but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glial–ILC3–epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals.

While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity.

Regulatory T cells (Tregs) are associated with enhanced tumor progression and reduced therapy response rates. Therefore, overcoming the Treg‐mediated immunosuppressive barrier within the tumor to enhance antitumor immune responses is of central interest to advance cancer immunotherapy. To date, no tools exist that can be exploited to dampen Treg function and differentiation in vivo. Here, we show for the first time that the antibiotic thiostrepton exerts a potent inhibitory effect on Tregs. Mechanistically, thiostrepton disrupts Treg differentiation, reduces the expression of Treg activation markers, and inhibits Treg suppressive functions. Accordingly, using an MC38 tumor model, we demonstrate that thiostrepton treatment reduces the number of intratumoral Foxp3⁺ Treg cells and prevents tumor growth. These effects are conserved in human T cells, as thiostrepton also inhibits the differentiation of human Tregs. Our findings highlight thiostrepton as a promising Treg‐targeting immunomodulatory compound with the potential to enhance antitumor immune responses.