Exhausted Cytotoxic Control of Epstein-Barr Virus in Human Lupus

Larsen, Martin; Sauce, Delphine; Deback, Claire; Arnaud, Laurent; Mathian, Alexis; Miyara, Makoto; Boutolleau, David; Parizot, Christophe; Dorgham, Karim; Papagno, Laura; Appay, Victor; Amoura, Zahir; Gorochov, Guy

doi:10.1371/journal.ppat.1002328

Cited by 117 publications

(115 citation statements)

References 43 publications

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“…Consistent with the aforementioned immune control in the presence of phenotypically exhausted T-cells, there is evidence that PD-1 high CD8 + T-cells can express similar or even elevated levels of cytotoxic molecules compared to cells with a less pronounced exhausted phenotype 37,[42][43][44][45] .…”

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

confidence: 52%

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

confidence: 52%

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

et al. 2014

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“…[ [21][22][23] The pathophysiology of EBV reactivation remains uncertain. Recent data suggest that EBV could trigger inflammatory process through interleukin-6 modulation.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus reactivation in critically ill immunocompetent patients

et al. 2015

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O ver the past years, particular attention has been given to herpes virus reactivations among immunocompetent critically ill patients. Although the true pathogenicity of these reactivations is still debated, some authors have hypothesized that it could be related to specific immune failure caused by sepsis or multi-organ failure. Others have argued that it is only a marker of severity. There is increasing evidence that reactivation of cytomegalovirus (CMV) and herpes simplex virus (HSV) is associated with mortality or morbidity, mainly for ventilator-acquired pneumonia. [1,2] CMV seroprevalence ranges from 40% to 95% depending on several factors, including age and geographic area. HSV1 seroprevalence is around 65% among the French population. Epstein-Barr virus (EBV) reactivation has been well docu- Original Article Epstein-Barr Virus Reactivation in Critically IllImmunocompetent Patients Background: Herpes viruses can be reactivated among immunocompetent patients in intensive care unit (ICU). Cytomegalovirus (CMV) and herpes simplex virus (HSV) have been the most studied. We hypothesized that Epstein-Barr virus (EBV) could also be reactivated in immunocompetent patients during their stay in ICU and that this would be associated with morbidity and mortality. Methods:This prospective observational study included 90 patients with an ICU stay of ≥ 5 days. CMV and HSV were considered when clinically suspected and DNA was researched in blood or bronchoalveolar lavage (BAL). EBV DNA viral quantification was performed in the blood samples. Results:EBV DNA was detected in blood of 61 patients (median length for positivity of 7.5 days). CMV DNA was detected in blood of 16 patients (median length for positivity of 13.5 days) and BAL of 6 patients. HSV1 DNA was detected in the BAL of 28 patients (median length for positivity of 7.5 days). Nineteen patients had no viral reactivation, 1 experienced only CMV, 32 had only EBV, 5 had only HSV, 6 had EBV and CMV, 14 had EBV and HSV, and 9 patients reactivated three viruses. Mortality was higher among patients with EBV reactivation (33/61 vs. 7/25, p = 0.02). Length of stay (21 vs. 10 days, p < 0.001) and length of mechanical ventilation (15 vs. 7 days, p < 0.001) were higher among patients with EBV reactivation. Conclusions: This study shows that EBV DNA is detected in blood of diverse ICU patients with ≥ ≥ 5 days of stay and that it is associated with morbidity and mortality. Larger dynamic prospective studies are needed to correlate viral reactivation with immune system evolution during ICU stay and to determine the role of polyviral reactivations. (Biomed J 2015;38:70-76)

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“…A number of studies indicated defective in vitro CTL function in murine and human lupus (58)(59)(60)(61). Effective CTLs are particularly important in lupus patients in the setting of a concomitant viral infection.…”

Section: Discussionmentioning

confidence: 99%

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

Nguyen

Rus

Chen

et al. 2016

The Journal of Immunology

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IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell–mediated response, respectively. Induction of acute GVHD using IL-21R–deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell–driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production.

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Exhausted Cytotoxic Control of Epstein-Barr Virus in Human Lupus

Cited by 117 publications

References 43 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?

Epstein-Barr virus reactivation in critically ill immunocompetent patients

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model

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