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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.

Anandasabapathy and colleagues show that the inhibitory receptor PD-1 impacts the specification of tissue-resident memory T cells in the skin.

The JAK inhibitor ruxolitinib has been used for treatment of myeloproliferative neoplasms (MPN) and its association with clonal evolution requires further investigation. Here the authors report accumulation of RAS pathway mutations in ruxolitinib-treated myelofibrosis patients, stemming from RAS clonal selection induced by JAK2 inhibition.

In hematopoietic stem cell transplants, T cells mediate graft-versus-leukemia (GVL), but GVL can fail leading to leukemia relapse. Here the authors use a mouse model in which T cells target the minor histocompatibility antigen H60 to show how this can occur, characterize the CD8⁺ T cell response and demonstrate how anti-CD40 antibody therapy improves GVL.

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.

Here the authors present cyclic peptide-based AND-gated nanosensors to detect concomitant protease activity. These nanosensors improve detection specificity during immune checkpoint blockade therapy compared with off-tumour anti-viral immunity in a mouse model.

IL-35 is an immunomodulatory cytokine secreted by regulatory T cells. Vignali and colleagues demonstrate that IL-35 also mediates the induction of a unique regulatory population that may underpin infectious tolerance.

The use of functional genomics in primary immune cells has been limited by inefficient vector delivery and risk of perturbing cell states. Here the authors present CHimeric IMmune Editing (CHIME) for in vivo evaluation of gene function and pooled screening approaches.

Certain specific antigens have been shown to activate T cells in an MHC independent manner. Here the authors show a phycoerythrin reactive mouse TCR which recognises native protein and characterise the molecular nature of this interaction and that this specific TCR can be selected in the thymus.

Regulatory T cells obstruct effective anti-cancer immune responses. Vignali and colleagues demonstrate that IL-10 production and IL-35 production by tumor-infiltrating regulatory T cells mediate differential and non-redundant suppressive effects on tumor-reactive cytotoxic T cells.

In this Viewpoint article, several experts share their thoughts on the plasticity and stability of regulatory T cells, discussing the recent advances in our understanding of the transcriptional and epigenetic regulation of this important T cell subset, as well as the therapeutic implications of this research.

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.

Chronically infected mice upregulate expression of inhibitory molecules on exhausted T cells. Harty and colleagues report similar findings in human patients with malaria and show that blockade of the inhibitory receptors PD-L1 and LAG-3 restores antimalaria responses in mice.

GPCR kinases (GRKs) regulate GPCR interactions and thus functions. Here, the authors report a comprehensive panel of GRK knockout cells, used to assess the GRK-specific β-arrestin recruitment. Selective engagement of GRKs induces distinct GPCR–β-arrestin complexes.

A library of protease-cleavable sensors conjugated to antibodies against the programmed cell death protein 1 allows for the urinary detection of early antitumour responses to immune checkpoint blockade therapy and of resistance to it in mice.

The RNA binding protein MUSASHI-2 (MSI2) is a potential therapeutic target for acute myeloid leukemia. Here the authors identify a small molecule inhibitor of MSI2 and characterize its effects in a murine leukemia model.

The differentiation and function of regulatory T (Treg) cells are critically controlled by T cell receptor (TCR) signaling. Here the authors show that CARD11-BCL10-MALT1 (CBM) complexes are dispensable for effector Treg conversion under inflammatory conditions but are critical for mediating Treg suppressive activity in a MALT1 paracaspase-dependent manner.

Regulated trafficking of major histocompatibility complex class II and CD86 is a prerequisite of antigen presenting cell functionality. Authors show here that ubiquitin-like protein 3 is critically involved in the ubiquitination process that controls trafficking, with wide-ranging immunological consequences.

John Harty and colleagues report that, in mouse models of malaria, regulatory T cells expand, as in humans, and inhibit conventional T cells and germinal center B cells, thereby impairing protective responses against blood-stage disease. Timed blockade of the inhibitory receptor CTLA-4 cured infection in mice and promoted cross-protective blood-stage immunity against a different Plasmodium species.

Allogeneic chimeric antigen receptor (CAR) T cells are capable of inducing graft-versus-host disease (GVHD) in recipients, yet this is not commonly seen in the clinic. Marcel van den Brink, Michel Sadelain and colleagues show that alloreactive CAR T cells have reduced effector function due to signaling through the CAR and T cell receptor, resulting in reduced GVHD, while the graft-versus-leukemia effect is maintained by non-alloreactive CAR T cells.

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.

Relevant features of T cell repertoire in human cancer remain to be delineated. Here the authors show, by TCR sequencing in a large cohort of lung cancer patients, that while a majority of T cell clones are shared between tumor and adjacent lung tissue, less frequent tumor-unique T cell clones correlate with worse prognosis.

Luster and colleagues show that T_reg cells that reside in lung mucosa can respond to IL-33 upon allergen exposure and suppress innate cell responses. IL-33-activated ST2⁺ T_reg cells secrete IL-35, which suppresses IL-17 production by γδ T cells and lessens eosinophil recruitment into the lung.

Regulatory T cells (T_Reg cells) have a central role in immune regulation, but how do they work? In this Review, our current understanding of the suppressive mechanisms used by T_Reg cells is described and the relative contribution of these mechanisms to T_Reg-cell function is discussed.

Chronic infection can lead to T cell exhaustion. Wherry and colleagues demonstrate that a hierarchy of inhibitory receptors coregulate CD8⁺ T cell exhaustion during chronic viral infection.

Surprisingly, and somewhat counter-intuitively, partial T-cell immunodeficiencies are commonly associated with hyper-immune dysregulation. Here, the authors review the genetic basis of such immunodeficiencies and draw on mouse models to provide a potential explanation for the coexistence of immunodeficiency and autoimmunity.

Activated CD8⁺ T cells must 'choose' between the terminal effector cell fate or the memory precursor cell fate. Amsen and colleagues find that the cell surface receptor Notch controls this 'choice'.

Combined analysis of proton-proton collision data from the Large Hadron Collider at CERN by the CMS and LHCb collaborations leads to the observation of the extremely rare decay of the strange B meson into muons; the result is compatible with the standard model of particle physics, and does not show any signs of new physics, such as supersymmetry.

An extremely young star-forming region caught at gravitational collapse in a distant galaxy is shedding new light on the processes driving galaxy growth in the early Universe.

T regulatory (T_reg) cells in visceral adipose tissue express high levels of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ, and fat-specific adaptation of T_reg cells is dependent on PPAR-γ.