scholarly journals Critical Role for Alpha/Beta and Gamma Interferons in Persistence of Lymphocytic Choriomeningitis Virus by Clonal Exhaustion of Cytotoxic T Cells

2001 ◽  
Vol 75 (18) ◽  
pp. 8407-8423 ◽  
Author(s):  
Rong Ou ◽  
Shenghua Zhou ◽  
Lei Huang ◽  
Demetrius Moskophidis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Interferon Response ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Alpha Beta

ABSTRACT Under conditions of high antigenic load during infection with invasive lymphocytic choriomeningitis virus (LCMV) strains, virus can persist by selective clonal exhaustion of antigen-specific CD8+ T cells. In this work we studied the down-regulation of the virus-specific CD8+-T-cell response during a persistent infection of adult mice, with particular emphasis on the contribution of the interferon response in promoting host defense. Studies were conducted by infecting mice deficient in receptors for type I (alpha/beta interferon [IFN-α/β]), type II (IFN-γ), and both type I and II IFNs with LCMV isolates that vary in their capacity to induce T-cell exhaustion. The main conclusions of this study are as follows. (i) IFNs play a critical role in LCMV infection by reducing viral loads in the initial stages of infection and thus modifying both the extent of CD8+-T-cell exhaustion and the course of infection. The importance of IFNs in this context varies with the biological properties of the LCMV strain. (ii) An inverse correlation exists between antigen persistence and responsiveness of virus-specific CD8+ T cells. This results in distinct programs of activation or tolerance (functional unresponsiveness and/or physical elimination of antigen-specific cells) during acute and chronic virus infections, respectively. (iii) A successful immune response associated with definitive viral clearance requires an appropriate balance between cellular and humoral components of the immune system. We discuss the role of IFNs in influencing virus-specific T cells that determine the outcome of persistent infections.

scholarly journals Immune Exhaustion: Past Lessons and New Insights from Lymphocytic Choriomeningitis Virus

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 156 ◽  
Author(s):  
Shannon Kahan ◽  
Allan Zajac
Keyword(s):  
T Cells ◽  
T Cell ◽  
Experimental System ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Exhaustion ◽  
Chronic Infections ◽  
Cell Exhaustion ◽  
Adult Mice ◽  
Track Record

Lymphocytic choriomeningitis virus (LCMV) is a paradigm-forming experimental system with a remarkable track record of contributing to the discovery of many of the fundamental concepts of modern immunology. The ability of LCMV to establish a chronic infection in immunocompetent adult mice was instrumental for identifying T cell exhaustion and this system has been invaluable for uncovering the complexity, regulators, and consequences of this state. These findings have been directly relevant for understanding why ineffective T cell responses commonly arise during many chronic infections including HIV and HCV, as well as during tumor outgrowth. The principal feature of exhausted T cells is the inability to elaborate the array of effector functions necessary to contain the underlying infection or tumor. Using LCMV to determine how to prevent and reverse T cell exhaustion has highlighted the potential of checkpoint blockade therapies, most notably PD-1 inhibition strategies, for improving cellular immunity under conditions of antigen persistence. Here, we discuss the discovery, properties, and regulators of exhausted T cells and highlight how LCMV has been at the forefront of advancing our understanding of these ineffective responses.

scholarly journals Lymphocytic choriomeningitis virus Clone 13 infection causes either persistence or acute death dependent on IFN-1, cytotoxic T lymphocytes (CTLs), and host genetics

2018 ◽  
Vol 115 (33) ◽  
pp. E7814-E7823 ◽  
Author(s):  
Michael B. A. Oldstone ◽  
Brian C. Ware ◽  
Lucy E. Horton ◽  
Megan J. Welch ◽  
Roberto Aiolfi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
T Cell Exhaustion ◽  
Injury Death ◽  
Cell Exhaustion ◽  
Permeability Pulmonary Edema

Understanding of T cell exhaustion and successful therapy to restore T cell function was first described using Clone (Cl) 13 variant selected from the lymphocytic choriomeningitis virus (LCMV) Armstrong (ARM) 53b parental strain. T cell exhaustion plays a pivotal role in both persistent infections and cancers of mice and humans. C57BL/6, BALB, SWR/J, A/J, 129, C3H, and all but one collaborative cross (CC) mouse strain following Cl 13 infection have immunosuppressed T cell responses, high PD-1, and viral titers leading to persistent infection and normal life spans. In contrast, the profile of FVB/N, NZB, PL/J, SL/J, and CC NZO mice challenged with Cl 13 is a robust T cell response, high titers of virus, PD-1, and Lag3 markers on T cells. These mice all die 7 to 9 d after Cl 13 infection. Death is due to enhanced pulmonary endothelial vascular permeability, pulmonary edema, collapse of alveolar air spaces, and respiratory failure. Pathogenesis involves abundant levels of Cl 13 receptor alpha-dystroglycan on endothelial cells, with high viral replication in such cells leading to immunopathologic injury. Death is aborted by blockade of interferon-1 (IFN-1) signaling or deletion of CD8 T cells.

scholarly journals Farnesoid X Receptor in Mice Prevents Severe Liver Immunopathology During Lymphocytic Choriomeningitis Virus Infection

2017 ◽  
Vol 41 (1) ◽  
pp. 323-338 ◽  
Author(s):  
Nadine Honke ◽  
Namir Shaabani ◽  
Cornelia Hardt ◽  
Caroline Krings ◽  
Dieter Häussinger ◽  
...  
Keyword(s):  
T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Farnesoid X Receptor ◽  
Toxic Effects ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Lymphocytic Choriomeningitis Virus Infection

Background: Bile acids (BAs) are steroid molecules that are synthesized in the liver. In addition to their important role as a surfactant in solubilizing lipids and promoting the absorption of lipids in the gastrointestinal tract, they act as inflammagens. The role of BAs and their receptor farnesoid X receptor (FXR) during viral infection has not been studied in detail. Methods: By using FXR-deficient mice, we investigated the role of bile acid receptor FXR during infection with lymphocytic choriomeningitis virus (LCMV). The importance of FXR in inducing IFN-I and monocytes proliferation were investigated and viral titers and T cell exhaustion were analyzed at different time points. Results: This study shows that controlled levels of BAs activate FXR in hepatocytes and FXR in response upregulates the production of type I interferon. In turn, FXR maintains BAs within a balanced range to inhibit their toxic effects. The absence of FXR results in high levels of BAs, which inhibit the proliferation of monocytes and result in a defect in viral elimination, consequently leading to T cell exhaustion. Conclusion: We found that FXR contributes to IFN-I production in hepatocytes and balances BA levels to inhibit their toxic effects on monocytes.

scholarly journals IRF9 Prevents CD8+ T Cell Exhaustion in an Extrinsic Manner during Acute Lymphocytic Choriomeningitis Virus Infection

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Magdalena Huber ◽  
Tamara Suprunenko ◽  
Thomas Ashhurst ◽  
Felix Marbach ◽  
Hartmann Raifer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Viral Infection ◽  
Chronic Infection ◽  
Acute Infection ◽  
Lymphocytic Choriomeningitis ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Deficient Mice

ABSTRACT Effective CD8+ T cell responses play an important role in determining the course of a viral infection. Overwhelming antigen exposure can result in suboptimal CD8+ T cell responses, leading to chronic infection. This altered CD8+ T cell differentiation state, termed exhaustion, is characterized by reduced effector function, upregulation of inhibitory receptors, and altered expression of transcription factors. Prevention of overwhelming antigen exposure to limit CD8+ T cell exhaustion is of significant interest for the control of chronic infection. The transcription factor interferon regulatory factor 9 (IRF9) is a component of type I interferon (IFN-I) signaling downstream of the IFN-I receptor (IFNAR). Using acute infection of mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong, we show here that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and IFN-I and by controlling levels of IRF7, a transcription factor essential for IFN-I production. Infection of IRF9- or IFNAR-deficient mice led to a loss of early restriction of viral replication and impaired antiviral responses in dendritic cells, resulting in CD8+ T cell exhaustion and chronic infection. Differences in the antiviral activities of IRF9- and IFNAR-deficient mice and dendritic cells provided further evidence of IRF9-independent IFN-I signaling. Thus, our findings illustrate a CD8+ T cell-extrinsic function for IRF9, as a signaling factor downstream of IFNAR, in preventing overwhelming antigen exposure resulting in CD8+ T cell exhaustion and, ultimately, chronic infection. IMPORTANCE During early viral infection, overwhelming antigen exposure can cause functional exhaustion of CD8+ T cells and lead to chronic infection. Here we show that the transcription factor interferon regulatory factor 9 (IRF9) plays a decisive role in preventing CD8+ T cell exhaustion. Using acute infection of mice with LCMV strain Armstrong, we found that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and Irf7, encoding a transcription factor crucial for type I interferon (IFN-I) production, as well as by controlling the levels of IFN-I. Infection of IRF9-deficient mice led to a chronic infection that was accompanied by CD8+ T cell exhaustion due to defects extrinsic to T cells. Our findings illustrate an essential role for IRF9, as a mediator downstream of IFNAR, in preventing overwhelming antigen exposure causing CD8+ T cell exhaustion and leading to chronic viral infection.

scholarly journals PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains ofToxoplasma gondii

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Samantha D. Splitt ◽  
Scott P. Souza ◽  
Kristen M. Valentine ◽  
Brayan E. Castellanos ◽  
Andrew B. Curd ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Secondary Infection ◽  
Parasite Burden ◽  
Checkpoint Blockade ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Virulent Strains

ABSTRACTT cell exhaustion is a state of hyporesponsiveness that develops during many chronic infections and cancer. Neutralization of inhibitory receptors, or “checkpoint blockade,” can reverse T cell exhaustion and lead to beneficial prognoses in experimental and clinical settings. Whether checkpoint blockade can resolve lethal acute infections is less understood but may be beneficial in vaccination protocols that fail to elicit sterilizing immunity. Since a fully protective vaccine for any human parasite has yet to be developed, we explored the efficacy of checkpoint inhibitors in a mouse model ofToxoplasma gondiireinfection. Mice chronically infected with an avirulent type III strain survive reinfection with the type I RH strain but not the MAS, GUY-DOS, and GT1 parasite strains. We report here that mouse susceptibility to secondary infection correlates with the initial parasite burden and that protection against the RH strain is dependent on CD8 but not CD4 T cells in this model. When given a lethal secondary infection, CD8 and CD4 T cells upregulate several coinhibitory receptors, including PD-1, TIM-3, 4-1bb, and CTLA-4. Moreover, the gamma interferon (IFN-γ) response of CD8 but not CD4 T cells is significantly reduced during secondary infection with virulent strains, suggesting that checkpoint blockade may reduce disease severity. However, single and combination therapies targeting TIM-3, CTLA-4, and/or PD-L1 failed to reverse susceptibility to secondary infection. These results suggest that additional host responses, which are refractory to checkpoint blockade, are likely required for immunity to this pathogen.

scholarly journals Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

2016 ◽  
Vol 213 (9) ◽  
pp. 1799-1818 ◽  
Author(s):  
SuJin Hwang ◽  
Dustin A. Cobb ◽  
Rajarshi Bhadra ◽  
Ben Youngblood ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches.

scholarly journals Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells

2015 ◽  
Vol 212 (7) ◽  
pp. 1125-1137 ◽  
Author(s):  
Pamela M. Odorizzi ◽  
Kristen E. Pauken ◽  
Michael A. Paley ◽  
Arlene Sharpe ◽  
E. John Wherry
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
T Cell Survival

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.

scholarly journals Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2274
Author(s):  
Didem Saka ◽  
Muazzez Gökalp ◽  
Betül Piyade ◽  
Nedim Can Cevik ◽  
Elif Arik Sever ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Single Agent ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Cell Exhaustion

T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

scholarly journals Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)

2020 ◽  
Author(s):  
Bo Diao ◽  
Chenhui Wang ◽  
Yingjun Tan ◽  
Xiewan Chen ◽  
Ying Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
T Cell Subsets ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Counts ◽  
Tnf Α ◽  
Functional Exhaustion ◽  
Routine Physical Examination

SummaryBACKGROUNDThe outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health, which has been declared a public health emergency of international concern (PHEIC) by the WHO. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear.METHODSWe retrospectively reviewed the counts of total T cells, CD4+, CD8+ T cell subsets, and serum cytokine concentration from inpatient data of 522 patients with laboratory-confirmed COVID-19, admitted into two hospitals in Wuhan from December 2019 to January 2020, and 40 healthy controls, who came to the hospitals for routine physical examination. In addition, the expression of T cell exhaustion markers PD-1 and Tim-3 were measured by flow cytometry in the peripheral blood of 14 COVID-19 cases.RESULTSThe number of total T cells, CD4+ and CD8+ T cells were dramatically reduced in COVID-19 patients, especially among elderly patients (⩾60 years of age) and in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8+T cells or CD4+T cells lower than 800/μL, 300/μL, or 400/μL, respectively, are negatively correlated with patient survival. Statistical analysis demonstrated that T cell numbers are negatively correlated to serum IL-6, IL-10 and TNF-α concentration, with patients in decline period showing reduced IL-6, IL-10 and TNF-α concentrations and restored T cell counts. Finally, T cells from COVID-19 patients have significantly higher levels of the exhausted marker PD-1 as compared to health controls. Moreover, increasing PD-1 and Tim-3 expression on T cells could be seen as patients progressed from prodromal to overtly symptomatic stages, further indicative of T cell exhaustion.CONCLUSIONST cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients, with total T cells, CD8+T cells CD4+T cells counts lower than 800/μL, 300/μL, and 400/μL, respectively, may still require aggressive intervention even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.

Sign in / Sign up

Export Citation Format

Share Document