The Experts below are selected from a list of 109836 Experts worldwide ranked by ideXlab platform
Nicholas W Haining - One of the best experts on this subject based on the ideXlab platform.
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defining t cell Exhaustion
2019Co-Authors: Christian U Blank, Rachel C Lynn, Nicholas W Haining, Werner Held, Patrick G Hogan, Axel Kallies, Enrico Lugli, Mary Philip, Anjana RaoAbstract:'T cell Exhaustion' is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours. Understanding the features of and pathways to Exhaustion has crucial implications for the success of checkpoint blockade and adoptive T cell transfer therapies. In this Viewpoint article, 18 experts in the field tell us what Exhaustion means to them, ranging from complete lack of effector function to altered functionality to prevent immunopathology, with potential differences between cancer and chronic infection. Their responses highlight the dichotomy between terminally differentiated exhausted T cells that are TCF1- and the self-renewing TCF1+ population from which they derive. These TCF1+ cells are considered by some to have stem cell-like properties akin to memory T cell populations, but the developmental relationships are unclear at present. Recent studies have also highlighted an important role for the transcriptional regulator TOX in driving the epigenetic enforcement of Exhaustion, but key questions remain about the potential to reverse the epigenetic programme of Exhaustion and how this might affect the persistence of T cell populations.
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coregulation of cd8 t cell Exhaustion by multiple inhibitory receptors during chronic viral infection
2009Co-Authors: Shawn D Blackburn, Haina Shin, Nicholas W Haining, Tao Zou, Creg J Workman, Antonio Polley, Michael R Betts, Gordon J Freeman, Dario A A VignaliAbstract: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.
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coregulation of cd8 t cell Exhaustion by multiple inhibitory receptors during chronic viral infection
2009Co-Authors: Shawn D Blackburn, Haina Shin, Nicholas W Haining, Tao Zou, Creg J Workman, Antonio Polley, Michael R Betts, Gordon J Freeman, Dario A A VignaliAbstract:T cell Exhaustion often occurs during chronic infection and prevents optimal viral control. The molecular pathways involved in T cell Exhaustion remain poorly understood. Here we show that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to seven inhibitory receptors. Coexpression of multiple distinct inhibitory receptors was associated with greater T cell Exhaustion and more severe infection. Regulation of T cell Exhaustion by various inhibitory pathways was nonredundant, as blockade of the T cell inhibitory receptors PD-1 and LAG-3 simultaneously and synergistically improved T cell responses and diminished viral load in vivo. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of coexpressed inhibitory receptors.
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molecular signature of cd8 t cell Exhaustion during chronic viral infection
2007Co-Authors: John E Wherry, Nicholas W Haining, Sang Jun Ha, Susan M Kaech, Surojit Sarkar, Vandana Kalia, Shruti Subramaniam, Joseph N Blattman, Daniel L Barber, Rafi AhmedAbstract:Chronic viral infections often result in T cell Exhaustion. To determine the molecular signature of Exhaustion, we compared the gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8 + T cells from chronic infection to functional LCMV-specific effector and memory CD8 + T cells generated after acute infection. These data showed that exhausted CD8 + T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and cytokine signaling pathways, (3) displayed altered expression of genes involved in chemotaxis, adhesion, and migration, (4) expressed a distinct set of transcription factors, and (5) had profound metabolic and bioenergetic deficiencies. T cell Exhaustion was progressive, and gene-expression profiling indicated that T cell Exhaustion and anergy were distinct processes. Thus, functional Exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections.
John E Wherry - One of the best experts on this subject based on the ideXlab platform.
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network analysis reveals centrally connected genes and pathways involved in cd8 t cell Exhaustion versus memory
2012Co-Authors: Travis A Doering, Jill M Angelosanto, Alison Crawford, Michael A Paley, Carly G K Ziegler, John E WherryAbstract:Summary 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.
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transcription factor t bet represses expression of the inhibitory receptor pd 1 and sustains virus specific cd8 t cell responses during chronic infection
2011Co-Authors: Kenneth J Oestreich, Andrew M Intlekofer, Jill M Angelosanto, Steven L Reiner, Alison Crawford, Michael A Paley, Jeremy M Boss, Amy S Weinmann, John E WherryAbstract:The transcriptional control of T cell Exhaustion remains unclear. Wherry and colleagues show that the transcription factor T-bet regulates CD8+ T cell Exhaustion and inhibitory receptor expression.
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a role for the transcriptional repressor blimp 1 in cd8 t cell Exhaustion during chronic viral infection
2009Co-Authors: Haina Shin, Shawn D Blackburn, Andrew M Intlekofer, Jill M Angelosanto, Steven L Reiner, John E WherryAbstract:Summary T cell Exhaustion is common during chronic infections and can prevent optimal immunity. Although recent studies have demonstrated the importance of inhibitory receptors and other pathways in T cell Exhaustion, the underlying transcriptional mechanisms are unknown. Here, we define a role for the transcription factor Blimp-1 in CD8 + T cell Exhaustion during chronic viral infection. Blimp-1 repressed key aspects of normal memory CD8 + T cell differentiation and promoted high expression of inhibitory receptors during chronic infection. These cardinal features of CD8 + T cell Exhaustion were corrected by conditionally deleting Blimp-1. Although high expression of Blimp-1 fostered aspects of CD8 + T cell Exhaustion, haploinsufficiency indicated that moderate Blimp-1 expression sustained some effector function during chronic viral infection. Thus, we identify Blimp-1 as a transcriptional regulator of CD8 + T cell Exhaustion during chronic viral infection and propose that Blimp-1 acts as a transcriptional rheostat balancing effector function and T cell Exhaustion.
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molecular signature of cd8 t cell Exhaustion during chronic viral infection
2007Co-Authors: John E Wherry, Nicholas W Haining, Sang Jun Ha, Susan M Kaech, Surojit Sarkar, Vandana Kalia, Shruti Subramaniam, Joseph N Blattman, Daniel L Barber, Rafi AhmedAbstract:Chronic viral infections often result in T cell Exhaustion. To determine the molecular signature of Exhaustion, we compared the gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8 + T cells from chronic infection to functional LCMV-specific effector and memory CD8 + T cells generated after acute infection. These data showed that exhausted CD8 + T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and cytokine signaling pathways, (3) displayed altered expression of genes involved in chemotaxis, adhesion, and migration, (4) expressed a distinct set of transcription factors, and (5) had profound metabolic and bioenergetic deficiencies. T cell Exhaustion was progressive, and gene-expression profiling indicated that T cell Exhaustion and anergy were distinct processes. Thus, functional Exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections.
Graham P. Bates - One of the best experts on this subject based on the ideXlab platform.
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the risk of heat Exhaustion at a deep underground metalliferous mine in relation to surface temperatures
2000Co-Authors: A M Donoghue, Graham P. BatesAbstract:The risk of heat Exhaustion at a deep underground metalliferous mine was assessed in relation to thermal conditions prevailing on the surface. For each day of a 1-year prospective case series of heat Exhaustion, surface 24-h mean wet and dry bulb temperatures were recorded. From this data, 24-h mean wet bulb globe temperatures were derived using certain assumptions. The three surface temperature variables were significantly higher on those days on which heat Exhaustion occurred, compared to those days on which it did not occur (P < 0.001). The relative risk of heat Exhaustion on days when the 24-h mean wet bulb globe temperature was in the range 26.0-28.0°C was 4.82 (95% confidence interval 2.12-10.96). Surface temperature data could be used at this mine to warn miners about the risk of heat Exhaustion.
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heat Exhaustion in a deep underground metalliferous mine
2000Co-Authors: Michael A Donoghue, Murray J Sinclair, Graham P. BatesAbstract:OBJECTIVES To examine the incidence, clinical state, personal risk factors, haematology, and biochemistry of heat Exhaustion occurring at a deep underground metalliferous mine. To describe the underground thermal conditions associated with the occurrence of heat Exhaustion. METHODS A 1 year prospective case series of acute heat Exhaustion was undertaken. A history was obtained with a structured questionnaire. Pulse rate, blood pressure, tympanic temperature, and specific gravity of urine were measured before treatment. Venous blood was analysed for haematological and biochemical variables, during the acute presentation and after recovery. Body mass index (BMI) and maximum O 2 consumption (V˙o 2 max) were measured after recovery. Psychrometric wet bulb temperature, dry bulb temperature, and air velocity were measured at the underground sites where heat Exhaustion had occurred. Air cooling power and psychrometric wet bulb globe temperature were derived from these data. RESULTS 106 Cases were studied. The incidence of heat Exhaustion during the year was 43.0 cases / million man-hours. In February it was 147 cases / million man-hours. The incidence rate ratio for mines operating below 1200 m compared with those operating above 1200 m was 3.17. Mean estimated fluid intake was 0.64 l/h (SD 0.29, range 0.08–1.50). The following data were increased in acute presentation compared with recovery (p value, % of acute cases above the normal clinical range): neutrophils (p 2 (SD 49, range 33–290) Mean psychrometric wet bulb globe temperature was 31.5°C (SD 2.0, range 25.2–35.3). Few cases ( 1.56 m/s, air cooling power >248 W/m 2 , or psychrometric wet bulb globe temperature CONCLUSION Heat Exhaustion in underground miners is associated with dehydration, neutrophil leukocytosis, eosinopenia, metabolic acidosis, increased glucose and ferritin, and a mild rise in creatine kinase, aspartate transaminase, and lactate dehydrogenase. Heat cramps are associated with dehydration but not hyponatraemia. The incidence of heat Exhaustion increases during summer and at depth. An increased fluid intake is required. Heat Exhaustion would be unlikely to occur if ventilation and refrigeration achieved air cooling power >250 W/m 2 at all underground work sites.
Dario A A Vignali - One of the best experts on this subject based on the ideXlab platform.
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coregulation of cd8 t cell Exhaustion by multiple inhibitory receptors during chronic viral infection
2009Co-Authors: Shawn D Blackburn, Haina Shin, Nicholas W Haining, Tao Zou, Creg J Workman, Antonio Polley, Michael R Betts, Gordon J Freeman, Dario A A VignaliAbstract: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.
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coregulation of cd8 t cell Exhaustion by multiple inhibitory receptors during chronic viral infection
2009Co-Authors: Shawn D Blackburn, Haina Shin, Nicholas W Haining, Tao Zou, Creg J Workman, Antonio Polley, Michael R Betts, Gordon J Freeman, Dario A A VignaliAbstract:T cell Exhaustion often occurs during chronic infection and prevents optimal viral control. The molecular pathways involved in T cell Exhaustion remain poorly understood. Here we show that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to seven inhibitory receptors. Coexpression of multiple distinct inhibitory receptors was associated with greater T cell Exhaustion and more severe infection. Regulation of T cell Exhaustion by various inhibitory pathways was nonredundant, as blockade of the T cell inhibitory receptors PD-1 and LAG-3 simultaneously and synergistically improved T cell responses and diminished viral load in vivo. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of coexpressed inhibitory receptors.
Pierre Tonnerre - One of the best experts on this subject based on the ideXlab platform.
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differentiation of exhausted cd8 t cells after termination of chronic antigen stimulation stops short of achieving functional t cell memory
2021Co-Authors: Pierre Tonnerre, David Wolski, Sonu Subudhi, Jihad Aljabban, Ruben C Hoogeveen, Marcos Damasio, Hannah K Drescher, Lea M Bartsch, Damien C TullyAbstract:T cell Exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell Exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the Exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts Exhaustion recovery, with antigen removal after long-term Exhaustion being insufficient for the development of functional T cell memory. Lauer and colleagues examine CD8+ T cells following cure of human hepatitis C virus (HCV) infection. CD8+ T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional Exhaustion that is maintained even after antigen stimulus is removed.
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differentiation of exhausted cd8 t cells after termination of chronic antigen stimulation stops short of achieving functional t cell memory
2021Co-Authors: Pierre Tonnerre, David Wolski, Sonu Subudhi, Jihad Aljabban, Ruben C Hoogeveen, Marcos Damasio, Hannah K Drescher, Lea M Bartsch, Damien C TullyAbstract:Abstract T cell Exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell Exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the Exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from Exhaustion, as antigen removal after long-term T cell Exhaustion is insufficient for the development of key T cell memory characteristics.
