Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function

Zajac, Allan; Blattman, Joseph N.; Murali‐Krishna, Kaja; Sourdive, David; Suresh, M.; Altman, John D.; Ahmed, Rafi

doi:10.1084/jem.188.12.2205

Cited by 1,760 publications

(1,710 citation statements)

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“…Nonetheless, depending on the pathogen dose and the epitope being studied, a significant fraction of T-cells bypasses deletion. This applies in LCMV clone-13 infections to T-cells specific for the gp33 peptide while their np396-specific counterparts become deleted 12,14 . The latter is thought to result from a higher avidity of T-cells for the np396 than for the gp33 peptide 23 .…”

Section: Origin Of the T-cell Exhaustion Conceptmentioning

confidence: 99%

“…Starting from high levels, the virus titer usually strongly declines to levels that are undetectable in the blood within 4-8 weeks post infection and also decreases in infected organs with the kidneys being a major exception as they continue to contain high titers 14,54 . Though the precise protective mechanisms underlying the decline remain unclear, this observation signals that the presence of an exhausted T-cell phenotype does not preclude substantial virus control.…”

Section: Evidence That Functional T-cells Are Maintained In Chronic Imentioning

confidence: 99%

“…Interestingly, it has long ago been realized that the elimination of CD4 T-cells increases total virus load and decreases the number of pathogen-specific T-cells in chronic LCMV infections 14,54 . The precise mechanisms how CD4 T-cells enhance survival and effector function of CD8 T-cells remain unclear.…”

Section: Why Are Memory-like Cells Formed In Chronic Infections?mentioning

confidence: 99%

“…A different outcome arises when infections become chronic and when viruses persist at high levels over long periods as in Human-Immunodeficiency-Virus (HIV) or Human-Hepatitis-C Virus (HCV) infections. Such conditions induce T-cells lacking the typical polyfunctional phenotype and T-cells retain the expression of inhibitory receptors including PD-1, Lag-3, Tim-3, and CD160 [9][10][11][12][13][14][15][16][17] . Very similar phenotypes can be observed, when T-cells are long-term exposed to tumor-antigen [18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

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T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors. Daniel T. Utzschneider Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandDaniel Utzschneider is a PhD student of Dietmar Zehn. His research is focused on T-cell differentiation in chronic infection. Susanne G. Oberle Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandSusanne Oberle is a PhD student of Dietmar Zehn. Her research interests are focused on investigating T-cell responses in acute and chronic infections. and it provides a rational for emerging therapies that enhance T-cell activity in chronic infection and cancer by blocking inhibitory receptors. Christian Münz PhD

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Section: Origin Of the T-cell Exhaustion Conceptmentioning

confidence: 99%

Section: Evidence That Functional T-cells Are Maintained In Chronic Imentioning

confidence: 99%

Section: Why Are Memory-like Cells Formed In Chronic Infections?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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“…2012. 42: 2290-2304 HIGHLIGHTS 2291as well as the availability of T-cell help [10,20] and , the overall duration and amount of antigen exposure seems to be a critical parameter driving CD8 + T-cell exhaustion. Recent work has highlighted a negative correlation between viral load and CTL function in chronically infected humans and mice [24][25][26][27].…”

mentioning

confidence: 99%

Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

2012

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Chronic viral infections lead to CD8 + T-cell exhaustion, characterized by impaired cytokine secretion and loss of proliferative capacity. While viral load and T-cell dysfunction correlate, it is currently unclear whether the quality of a cell type presenting antigen determines the degree of T-cell exhaustion or if the overall amount of antigen recognized by T cells promotes exhaustion. We found that chronic lymphocytic choriomeningitis virus infection led to decreased CD8 + T-cell exhaustion in DC-MHC class I (MHCI) mice, in which CD8 IntroductionDuring highly replicative chronic viral infections such as HIV-1, hepatitis B or hepatitis C virus infection in humans, or lymphocytic choriomeningitis virus (LCMV) in mice, virus-specific CD8 + T cells initially expand and acquire effector functions early after infection but then gradually lose these functions [1][2][3][4][5][6][7][8] in a hierCorrespondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch archical manner: first the ability to produce IL-2 and to proliferate, then TNF-α secretion and last IFN-γ production become impaired [9][10][11][12]. This T-cell dysfunction, also termed CD8 + T-cell exhaustion, is well studied after infection of mice with a high dose of LCMV clone 13 or LCMV-Docile [13]. Infection of mice with a low dose of the same virus strains results in an acute resolved infection [13].Besides a role for immunoregulatory cytokines such as 15], , a role for inhibitory receptor expression (reviewed in [18]) and perhaps regulatory T cells [19] C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2290-2304 HIGHLIGHTS 2291as well as the availability of T-cell help [10,20] and , the overall duration and amount of antigen exposure seems to be a critical parameter driving CD8 + T-cell exhaustion. Recent work has highlighted a negative correlation between viral load and CTL function in chronically infected humans and mice [24][25][26][27]. Even though these studies indicate that high overall antigen levels correlate with T-cell exhaustion, it was never directly shown whether alterations of antigen levels can substantially influence T-cell function independently of the cell type presenting the antigen in vivo. Furthermore, as T-cell exhaustion and viral persistence mutually depend on each other and since alterations in one of the parameters affects the other one, it is often difficult to assign causal relationships, particularly in humans.Here, we made use of Tg(CD11c-β2m) × Tg(K14-β2m) × β2m −/− (DC-MHCI, where DC is defined as dendritic cell; MHCI is defined as MHC class I) mice to assess the role of antigen presenting cells versus antigen load in induction of CD8 + T-cell exhaustion upon chronic LCMV infection. DC-MHCI mice are β2m −/− mice that transgenically express β2m in DCs, keratinocytes, and thymic cortical epithelial cells, ensuring positive selection of CD8 + T cells in the thymus [28]. Thus, DC-MHCI mice can mount normal endogenous CD8 + T-cell responses, but peripheral CD8 + T cells can o...

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Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure

Boomer

Chang

et al. 2011

JAMA

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Context Severe sepsis is typically characterized by initial cytokine-mediated hyper-inflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. Objectives To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. Design, Setting, and Participants Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009–2011). Control spleens (n=29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n=20) were obtained from transplant donors or from lung cancer resections. Main Outcome Measures Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Results The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1–195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1–40 days). Compared with controls, anti-CD3/anti-CD28–stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327–7485) pg/mL vs 418 (95% CI, 98–738) pg/mL; interferon γ, 1374 (95% CI, 550–2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313–5070) vs 365 (95% CI, 87–642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P<.001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells. Conclusions Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent ...

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Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function

Cited by 1,760 publications

References 58 publications

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure

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Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function

Cited by 1,760 publications

References 58 publications

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Antigen amount dictates CD8+T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure

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Antigen amount dictates CD8⁺T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell