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Chronic viral infections are often associated with impaired CD8 + T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8 + T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8 + T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8 + T cell signaling and function in vivo. Excess antigenic exposure, such as in cancers or chronic viral infection, can lead to T cell exhaustion. Here the authors show that despite high exposure to antigen in the context of chronic LCMV infection in mice, exhausted CD8 + T cells have low levels of TCR signalling that can be reactivated by PD-L1 blockade.

Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance. TIGIT is a lymphocyte co-inhibitory receptor that can limit type 1 and cytotoxic T cell responses and maintain immunological tolerance. Here the authors show that TIGIT also limits immune pathology during LCMV or influenza infections in mice by driving IL-10 expression without negatively affecting the viral load.

Trajectory inference refers to the task of reconstructing state sequences of dynamic processes from single-cell RNA sequencing (scRNAseq) data. This task frequently results in ambiguous results due to the noisiness of the data. While this issue has been alleviated by the incorporation of directional information from RNA velocity analyses, it remains difficult to resolve complex differentiation topologies, such as convergent trajectories. We introduce exploratory trajectory inference to address this challenge. This approach considers unsupervised clustering analysis of trajectory ensembles derived from simulation-based trajectory inference to deduce differentiation lineages in a data-driven fashion. We assess this approach to resolve the convergent differentiation trajectories in CD8 T-cell differentiation in chronic infections. We utilize an original scRNAseq time-series dataset of CD8 T cells collected during the time course of a chronic LCMV infection. Simulation-based trajectory inference identified a branch region early during chronic infection where cells separate into an exhausted and a memory-like lineage. Exploratory trajectory inference further allowed us to identify a convergent differentiation trajectory traversing memory-like states and ending in the exhausted population. Adoptive transfer experiments showed CD8 T cells with predicted memory-like fate differentiating into both memory-like and exhaustion states, confirming the convergent differentiation topology. We expect exploratory trajectory inference to be applicable in other scRNAseq-based studies aiming at comprehensive characterization of differentiation trajectories with bifurcating and convergent topologies.

Legionella pneumophila is a facultative intracellular bacterium that lives in aquatic environments where it parasitizes amoeba. However, upon inhalation of contaminated aerosols it can infect and replicate in human alveolar macrophages, which can result in Legionnaires' disease, a severe form of pneumonia. Upon experimental airway infection of mice, L. pneumophila is rapidly controlled by innate immune mechanisms. Here we identified, on a cell-type specific level, the key innate effector functions responsible for rapid control of infection. In addition to the well-characterized NLRC4-NAIP5 flagellin recognition pathway, tumor necrosis factor (TNF) and reactive oxygen species (ROS) are also essential for effective innate immune control of L. pneumophila. While ROS are essential for the bactericidal activity of neutrophils, alveolar macrophages (AM) rely on neutrophil and monocyte-derived TNF signaling via TNFR1 to restrict bacterial replication. This TNF-mediated antibacterial mechanism depends on the acidification of lysosomes and their fusion with L. pneumophila containing vacuoles (LCVs), as well as caspases with a minor contribution from cysteine-type cathepsins or calpains, and is independent of NLRC4, caspase-1, caspase-11 and NOX2. This study highlights the differential utilization of innate effector pathways to curtail intracellular bacterial replication in specific host cells upon L. pneumophila airway infection.

The molecular nanoscale organization of the surfaceome is a fundamental regulator of cellular signaling in health and disease. Technologies for mapping the spatial relationships of cell surface receptors and their extracellular signaling synapses would unlock theranostic opportunities to target protein communities and the possibility to engineer extracellular signaling. Here, we develop an optoproteomic technology termed LUX-MS that enables the targeted elucidation of acute protein interactions on and in between living cells using light-controlled singlet oxygen generators (SOG). By using SOG-coupled antibodies, small molecule drugs, biologics and intact viral particles, we demonstrate the ability of LUX-MS to decode ligand receptor interactions across organisms and to discover surfaceome receptor nanoscale organization with direct implications for drug action. Furthermore, by coupling SOG to antigens we achieved light-controlled molecular mapping of intercellular signaling within functional immune synapses between antigen-presenting cells and CD8 +  T cells providing insights into T cell activation with spatiotemporal specificity. LUX-MS based decoding of surfaceome signaling architectures thereby provides a molecular framework for the rational development of theranostic strategies. The spatial organization of cell surface receptors is critical for cell signaling and drug action. Here, the authors develop an optoproteomic method for mapping surface protein interactions, revealing cellular responses to antibodies, drugs and viral particles as well as immunosynapse signaling events.

Interleukin 2 (IL‐2) was one of the first cytokines to be discovered. However, the complex role of IL‐2 and its receptor in the regulation of immune responses is only now emerging. This review explores the various signals triggered by IL‐2 and discusses their translation into biological function. A model is outlined that accommodates the seemingly contradictory functions of IL‐2, and explains how one cytokine can be an essential T‐cell growth and differentiation factor and yet also be indispensable to maintain peripheral tolerance.

Cytomegalovirus-based vaccine vectors offer interesting opportunities for T cell-based vaccination purposes as CMV infection induces large numbers of functional effector-like cells that accumulate in peripheral tissues, a process termed memory inflation. Maintenance of high numbers of peripheral CD8 T cells requires continuous replenishment of the inflationary T cell pool. Here, we show that the inflationary T cell population contains a small subset of cells expressing the transcription factor Tcf1. These Tcf1 + cells resemble central memory T cells and are proliferation competent. Upon sensing viral reactivation events, Tcf1 + cells feed into the pool of peripheral Tcf1 − cells and depletion of Tcf1 + cells hampers memory inflation. TCR repertoires of Tcf1 + and Tcf1 − populations largely overlap, with the Tcf1 + population showing higher clonal diversity. These data show that Tcf1 + cells are necessary for sustaining the inflationary T cell response, and upholding this subset is likely critical for the success of CMV-based vaccination approaches. Upon infection with cytomegalovirus, CD8 + T cells undergo prolific expansion in a process known as memory inflation. Here the authors define a population of Tcf1 expressing cells within the inflationary pool that is critical in fuelling this process.

Key Points Cytomegalovirus (CMV) induces large populations of CD8 + T cells that retain effector functions, have an effector memory phenotype and home to peripheral organs. The phenomenon has been termed 'memory inflation' on the basis of longitudinal studies in mouse models. The CMV-specific T cell populations that undergo memory inflation are a subset of those that are primed, and they are maintained owing to persistence of the antigen. The viral peptides that drive these responses seem to be presented by non-professional antigen-presenting cells and are immunoproteasome independent. The expanded CD8 + T cell populations that are observed in CMV infection have a transcriptional profile that is different to that seen in 'exhausted' CD8 + T cells but is similar to that seen in T cells responding to other low-level persistent challenges, such as adenoviral vaccines, in both humans and mice. Using the adenoviral system, conventional T cell responses can acquire features of expanded CMV-specific T cell responses by modifying the peptide context. The CMV-induced CD8 + T cell responses are dependent on CD4 + T cell help and co-stimulatory signals. Such signals are probably required to support the recruitment of effector memory T cells from a pool of central memory T cells, although the precise nature and niche of the non-professional antigen-presenting cells involved are still ill-defined. In elderly populations, the marked expansion of CMV-specific T cells is associated with a failure to control the virus and increased levels of CMV-specific IgG, which are features that have been linked to adverse health outcomes in some large epidemiological studies. Although causal mechanisms have not been defined, local replication of CMV may influence vascular pathology through the activation of inflammatory pathways. Infection with cytomegalovirus induces an unusually high level of long-lasting memory T cells that have potent effector functions. Understanding how and why this occurs might help to improve responses to vaccination. Human cytomegalovirus (HCMV) establishes a latent infection that generally remains asymptomatic in immune-competent hosts for decades but can cause serious illness in immune-compromised individuals. The long-term control of CMV requires considerable effort from the host immune system and has a lasting impact on the profile of the immune system. One hallmark of CMV infection is the maintenance of large populations of CMV-specific memory CD8 + T cells — a phenomenon termed memory inflation — and emerging data suggest that memory inflation is associated with impaired immunity in the elderly. In this Review, we discuss the molecular triggers that promote memory inflation, the idea that memory inflation could be considered a natural pathway of T cell maturation that could be harnessed in vaccination, and the broader implications of CMV infection and the T cell responses it elicits.

Efficient immune responses rely on heterogeneity, which in CD8 + T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8 + T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8 + T cells reveals that virtual memory cells (T VM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8 + T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing. Asymmetrical cell division helps to maintain cellular heterogeneity in the T cell compartment. Here the authors examine the differential immune responses built by naive and virtual memory T cells from young and aged individuals, and explore the effect of mTOR inhibition on asymmetrical cell division and memory formation.

Foxp3 + regulatory T (Treg) cells are essential for maintaining peripheral tolerance and preventing autoimmunity. While genetic factors may predispose for autoimmunity, additional environmental triggers, such as viral infections, are usually required to initiate the onset of disease. Here, we show that viral infection with LCMV results in type I IFN-dependent Treg cell loss that is rapidly compensated by the conversion and expansion of Vβ5 + conventional T cells into iTreg cells. Using Vβ5-deficient mice, we show that these Vβ5 + iTreg cells are dispensable for limiting anti-viral immunity. Rather, the delayed replenishment of Treg cells in Vβ5-deficient mice compromises suppression of microbiota-dependent activation of CD8 + T cells, resulting in colitis. Importantly, recovery from clinical symptoms in IBD patients is marked by expansion of the corresponding Vβ2 + Treg population in humans. Collectively, we provide a link between a viral trigger and an impaired Treg cell compartment resulting in the initiation of immune pathology. Viral infection transiently depletes T regulatory cells (Treg). Here the authors identify a compensatory induced Treg population, which is required to rapidly replenish the Treg niche and suppress microbiota-driven, virus-induced colitis.