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.
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.
T cell exhaustion Wherry, E John
Nature immunology,
06/2011, Letnik:
12, Številka:
6
Journal Article
Recenzirano
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.
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.
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
Combination therapies are becoming a focal point in cancer immunotherapy. In this issue of Cancer Cell, Johnston and colleagues identify the TIGIT/CD226 pathway, which provides significant interest ...for combination with PD-1 pathway blockade to improve anticancer CD8+ T cell responses, because it acts by a novel mechanism to regulate CD8+ T cell functions within the tumor microenvironment.
Combination therapies are becoming a focal point in cancer immunotherapy. In this issue of Cancer Cell, Johnston and colleagues identify the TIGIT/CD226 pathway, which provides significant interest for combination with PD-1 pathway blockade to improve anticancer CD8+ T cell responses, because it acts by a novel mechanism to regulate CD8+ T cell functions within the tumor microenvironment.
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
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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