In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called ...'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Costimulatory and inhibitory receptors play a key role in regulating immune responses to infections. Recent translation of knowledge about inhibitory receptors such as CTLA-4 and PD-1 into the cancer ...clinic highlights the opportunities to manipulate these pathways to treat human disease. Studies in infectious disease have provided key insights into the specific roles of these pathways and the effects of their manipulation. Here, recent studies are discussed that have addressed how major inhibitory and costimulatory pathways play a role in regulating immune responses during acute and chronic infections. Mechanistic insights from studies of infectious disease provide opportunities to further expand our toolkit to treat cancer and chronic infections in the clinic.
Costimulatory and inhibitory receptors play key roles in regulating immune responses to infection. Attanasio and Wherry reviews how insights from these infectious systems have provided insights into the biology of pathways such as PD-1 and how these insights inform clinical therapeutic targeting of these pathways in infectious disease and cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
T cell exhaustion Wherry, E John
Nature immunology,
06/2011, Volume:
12, Issue:
6
Journal Article
Peer reviewed
T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a ...transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged and T cell exhaustion has been defined in many experimental and clinical settings. Although the pathways involved remain to be fully defined, advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Improving efficacy of immune checkpoint blockade for cancer can be facilitated by combining these agents with each other and/or with other conventional or targeted therapies. Interferon and innate ...immune signaling pathways in immune and tumor cells have emerged as intriguing determinants of response and resistance, often in complex and seemingly paradoxical ways.
Improving efficacy of immune checkpoint blockade for cancer can be facilitated by combining these agents with each other and/or with other conventional or targeted therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate ...protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity.
► Commensal bacteria augment immunity against systemic or mucosal viral infection ► Commensal-depleted mice exhibit impaired innate and adaptive antiviral immunity ► Expression of antiviral genes is reduced in macrophages from antibiotic-treated mice ► Commensal-derived signals tune the activation threshold of the innate immune system
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exhausted CD8+ T cells function poorly and are negatively regulated by inhibitory receptors. Transcriptional profiling has identified gene expression changes associated with exhaustion. However, the ...transcriptional pathways critical to the differences between exhausted and functional memory CD8+ T cells are unclear. We thus defined transcriptional coexpression networks to define pathways centrally involved in exhaustion versus memory. These studies revealed differences between exhausted and memory CD8+ T cells including the following: lack of coordinated transcriptional modules of quiescence during exhaustion, centrally connected hub genes, pathways such as transcription factors, genes involved in regulation of immune responses, and DNA repair genes, as well as differential connectivity for genes including T-bet, Eomes, and other transcription factors. These data identify pathways involved in CD8+ T cell exhaustion, and highlight the context-dependent nature of transcription factors in exhaustion versus memory.
► Network analysis reveals pathways and hub genes in memory versus exhausted CD8 T cells ► Memory and exhausted CD8 T cells have partially nonoverlapping modules and hubs ► Distinct modules include chromatin, cell cycle, DNA repair, and immune regulation ► Transcription factors have distinct connections in exhausted versus memory CD8 T cells
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T ...cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8(+) T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8(+) TEX cells. These results demonstrate that CD8(+) T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.
Highlights • T cell exhaustion is present in both chronic infections and cancer. • PD-1 regulates T cell exhaustion and PD-1 blockade enhances tumor and viral immunity. • Molecular pathways of ...exhaustion may reveal biomarkers and immunotherapy targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector ...functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.
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