CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8 T cell formation.

Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8 tissue-resident memory T (T) cell development. T cells depended on mitochondrial translation and respiration.

Metabolic rewiring and communication in cancer immunity.

The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity.

Strengthening bonds via RyR2 inhibition helps immune suppression.

Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates Treg contact-dependent suppressive function is not fully resolved. In this issue of the JCI, Wang and colleagues revealed that Foxp3-mediated inhibition of ryanodine receptor 2 (RyR2) led to strong Treg-DC interactions and enhanced immunosuppression.

Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer.

CD8 cytotoxic T cells (CTLs) orchestrate antitumour immunity and exhibit inherent heterogeneity, with precursor exhausted T (T) cells but not terminally exhausted T (T) cells capable of responding to existing immunotherapies. The gene regulatory network that underlies CTL differentiation and whether T cell responses can be functionally reinvigorated are incompletely understood. Here we systematically mapped causal gene regulatory networks using single-cell CRISPR screens in vivo and discovered checkpoints for CTL differentiation.

CXCR6 orchestrates brain CD8 T cell residency and limits mouse Alzheimer's disease pathology.

Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8 T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8 T cells restrict AD pathologies, including β-amyloid deposition and cognitive decline.

SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.

Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours. DC functions are orchestrated by pattern recognition receptors, although other signals involved remain incompletely defined.

PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis.

Phosphatase and tensin homologue (PTEN) is frequently mutated in human cancer, but its roles in lymphopoiesis and tissue homeostasis remain poorly defined. Here we show that PTEN orchestrates a two-step developmental process linking antigen receptor and IL-23-Stat3 signalling to type-17 innate-like T cell generation. Loss of PTEN leads to pronounced accumulation of mature IL-17-producing innate-like T cells in the thymus.

Lipid metabolism in T cell signaling and function.

T cells orchestrate adaptive immunity against pathogens and other immune challenges, but their dysfunction can also mediate the pathogenesis of cancer and autoimmunity. Metabolic adaptation in response to immunological and microenvironmental signals contributes to T cell function and fate decision. Lipid metabolism has emerged as a key regulator of T cell responses, with selective lipid metabolites serving as metabolic rheostats to integrate environmental cues and interplay with intracellular signaling processes.

Metabolic adaptation of lymphocytes in immunity and disease.

Adaptive immune responses mediated by T cells and B cells are crucial for protective immunity against pathogens and tumors. Differentiation and function of immune cells require dynamic reprogramming of cellular metabolism. Metabolic inputs, pathways, and enzymes display remarkable flexibility and heterogeneity, especially in vivo.

Metabolic Control of Memory T-Cell Generation and Stemness.

The formation of long-lived memory T cells is a critical feature of the adaptive immune response. T cells undergo metabolic reprogramming to establish a functional memory population. While initial studies characterized key metabolic pathways necessary for memory T-cell development, recent findings highlight that metabolic regulation of memory T-cell subsets is diverse.

T cell metabolism in homeostasis and cancer immunity.

T cells shape immune responses in cancer, autoimmunity and infection, in which CD4 T helper (Th) and CD8 T cells mediate effector responses that are suppressed by regulatory T (T) cells. The balance between effector T cell and T cell function orchestrates immune homeostasis and functional programming, with important contributions to the onset and progression of cancer. Cellular metabolism is dynamically rewired in T cells in response to environmental cues and dictates various aspects of T cell function.

Lipid signalling enforces functional specialization of T cells in tumours.

Regulatory T cells (T cells) are essential for immune tolerance, but also drive immunosuppression in the tumour microenvironment. Therapeutic targeting of T cells in cancer will therefore require the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in T cells unleashes effective antitumour immune responses without autoimmune toxicity.

Protein Prenylation Drives Discrete Signaling Programs for the Differentiation and Maintenance of Effector T Cells.

Effector regulatory T (eT) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling mechanisms that promote the differentiation and maintenance of eT cells remain unclear. Here, we show that isoprenoid-dependent posttranslational lipid modifications dictate eT cell accumulation and function by intersecting with TCR-induced intracellular signaling.

Preventing Ubiquitination Improves CAR T Cell Therapy via 'CAR Merry-Go-Around'.

Chimeric antigen receptor (CAR) T cells are potent drivers of antitumor immunity, but promoting durable CAR T cell responses remains challenging. In this issue of Immunity, Li et al. (2020) show that blockade of CAR ubiquitination induces CAR recycling to the cell surface, leading to increased CAR T cell cytotoxicity and longevity by amplifying 41BB-dependent signaling and mitochondrial metabolism.

Hippo/Mst signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions.

Invariant natural killer T (iNKT) cells acquire effector functions during development by mechanisms that remain poorly understood. Here, we show that the Hippo kinases Mst1 and Mst2 act as molecular rheostats for the terminal maturation and effector differentiation programs of iNKT cells. Loss of Mst1 alone or together with Mst2 impedes iNKT cell development, associated with defective IL-15-dependent cell survival.

mTOR signaling at the crossroads of environmental signals and T-cell fate decisions.

The evolutionarily conserved serine/threonine kinase mTOR (mechanistic target of rapamycin) forms the distinct protein complexes mTORC1 and mTORC2 and integrates signals from the environment to coordinate downstream signaling events and various cellular processes. T cells rely on mTOR activity for their development and to establish their homeostasis and functional fitness. Here, we review recent progress in our understanding of the upstream signaling and downstream targets of mTOR.

Signaling networks in immunometabolism.

Adaptive immunity is essential for pathogen and tumor eradication, but may also trigger uncontrolled or pathological inflammation. T cell receptor, co-stimulatory and cytokine signals coordinately dictate specific signaling networks that trigger the activation and functional programming of T cells. In addition, cellular metabolism promotes T cell responses and is dynamically regulated through the interplay of serine/threonine kinases, immunological cues and nutrient signaling networks.

Homeostasis and transitional activation of regulatory T cells require c-Myc.

Regulatory T cell (T) activation and expansion occur during neonatal life and inflammation to establish immunosuppression, yet the mechanisms governing these events are incompletely understood. We report that the transcriptional regulator c-Myc (Myc) controls immune homeostasis through regulation of T accumulation and functional activation. Myc activity is enriched in T generated during neonatal life and responding to inflammation.

Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb.

Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes.

Metabolic coordination of T cell quiescence and activation.

Naive T cells are actively maintained in a quiescent state that promotes their survival and persistence. On antigen stimulation, T cells exit quiescence to initiate clonal expansion and effector differentiation. Initial studies focused on the immune receptors and transcriptional regulators involved in T cell quiescence and activation, but recent findings highlight cell metabolism as a crucial regulator of these processes.

Helper T cell differentiation.

CD4 T helper cells are key regulators of host health and disease. In the original model, specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs, but recent studies have revealed increasing complexities for CD4 T-cell differentiation. Here, we first discuss CD4 T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells.