scholarly journals Stand by me(mory): Chronic infection diminishes memory pool via IL-6/STAT1

2019 ◽  
Vol 216 (3) ◽  
pp. 474-475
Author(s):  
Philipp A. Lang ◽  
Karl S. Lang
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Viral Infections ◽  
Memory T Cells ◽  
Chronic Viral Infection ◽  
Virus Infections ◽  
Chronic Viral Infections ◽  
Immune Mediated ◽  
Memory Pool ◽  
And Function

Despite great efforts to eradicate chronic viral infections, they still remain a global health problem. In this issue, Barnstorf et al. (2019. J. Exp. Med. https://doi.org/10.1084/jem.20181589) show that virus-unspecific bystander memory T cells are highly affected during chronic viral infection via IL-6/STAT1. Bystander memory T cells are strongly decimated in numbers and change in phenotype and function during chronic viral infection. These data provide new explanations for immune-mediated problems during chronic virus infections.

scholarly journals A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Torben Knuschke ◽  
Sebastian Kollenda ◽  
Christina Wenzek ◽  
Gennadiy Zelinskyy ◽  
Philine Steinbach ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
Viral Infection ◽  
Viral Infections ◽  
T Cell Immunity ◽  
Chronic Viral Infection ◽  
Therapeutic Vaccination ◽  
Chronic Viral Infections ◽  
Cell Immunity

ABSTRACT PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8+ T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8+ T cell responses and improved viral clearance. We characterized the CD8+ T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8+ T cells were reactivated at the same time. While CD8+ T cells with high PD-1 (PD-1hi) expression turned into a large population of granzyme B-expressing CD8+ T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8+ T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8+ T cell immunity. A better understanding of CD8+ T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer. IMPORTANCE Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8+ T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.

scholarly journals Control of T Cell Responses, Tolerance and Autoimmunity by Regulatory T Cells: Current Concepts

2003 ◽  
Vol 46 (4) ◽  
pp. 131-137 ◽  
Author(s):  
Pavel Chrobák
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cell Responses ◽  
Chronic Viral Infections ◽  
And Function ◽  
Special Circumstances ◽  
Immunosuppressive Cytokines

Regulatory T cells have emerged as an important mechanism of regulating tolerance and T cell responses. CD4+ regulatory T cells can be divided into two main groups, natural regulatory T cells, which express high levels of CD25 on their cell surface and phenotypically diverse adaptive (antigen induced) regulatory T cells. Natural regulatory T cells are made in the thymus, and require strong costimulatory signals for induction and maintenance, express a transcription factor called Foxp3, and function by a largely unknown mechanism. Adaptive (antigen induced) regulatory T cells are made by sub-optimal antigenic signals in the periphery, in the presence of immunosuppressive cytokines, often in special circumstances, such as chronic viral infections or after mucosal administration of antigen, and rely on cytokines such as IL-10 and TGF-β for suppression. Regulatory T cells offer a great potential for the treatment of autoimmune diseases and during transplantation.

Characterizing Immunophenotypic and Functional Pseudo-Exhaustion in T Cells From CLL Patients: The Impact of Lenalidomide

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 564-564
Author(s):  
John C. Riches ◽  
Jeff K. Davies ◽  
Fabienne McClanahan ◽  
Rewas Fatah ◽  
Sameena Iqbal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Lymphocyte Activation ◽  
Interferon Γ ◽  
Chronic Viral Infections ◽  
And Function ◽  
The Impact ◽  
Functional Defects

Abstract Abstract 564 The ability to evade immune destruction is increasingly being recognised as a crucial feature of cancer cells. Chronic lymphocytic leukemia (CLL) is associated with profound defects in T-cell function, resulting in failure of anti-tumor immunity and increased susceptibility to infections. T cells from CLL patients exhibit functional defects and alterations in gene expression, that show similarities to exhausted T cells in chronic viral infections. However, it is unclear whether CLL T cells are truly exhausted, or whether these defects are restricted to expanded populations of CMV specific T cells. We investigated the phenotype and function of CD8+ T cells from CLL patients and controls matched for age and CMV-serostatus. We demonstrate an increased proportion of CCR7- effector T cells in both CLL patients and CMV-seropositive individuals (p<0.05). CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD160 and CD244 irrespective of CMV-serostatus (p<0.01), whereas increased PD1 expression on CD8+ T cells was limited to CMV-seronegative patients (p=0.002). CLL CD8+ T cells also showed functional defects in proliferation and cytotoxicity irrespective of CMV-serostatus, with the cytolytic defect caused by a combination of impaired granzyme B packaging into secretory vesicles and non-polarized degranulation. In contrast to virally-induced exhaustion, CLL T cells showed increased production of interferon-γ with increased T-BET expression (p<0.01), normal IL-2 production, and no downregulation of IL-7R. Therefore, while CLL CD8+ T cells exhibit some features of T-cell exhaustion, they show important differences (Table 1). These findings also exclude CMV as the sole cause of T cell defects in CLL. Lenalidomide has recently been demonstrated to have significant clinical activity in CLL. Its mechanism of action in this disease is not well understood, but it thought to act primarily by a combination of CLL cell and immune cell activation. We therefore examined the ability of lenalidomide to repair the observed T cell defects by investigating the impact of this agent on the gene expression profiles and function of CLL T cells. Treatment of CLL CD8+ T cells with lenalidomide increased the expression of 137 genes, while 34 genes were downregulated. The most prominent changes in expression were of genes involved in cytoskeletal signaling including WASF1 (Wiskott-Aldrich syndrome protein, family member 1), and TPM2 (tropomyosin 2). There was also upregulation of genes involved in lymphocyte activation, including TNFSF4 (Tumor necrosis factor ligand superfamily, member 4: OX40L), LAG3 (Lymphocyte-activation gene 3), and TNF, and genes involved in cell proliferation such as IKZF1 (Ikaros) and GRN (Granulin). Although lenalidomide treatment or anti-CD3 stimulation alone had no impact on T-bet expression, co-treatment with both anti-CD3 stimulation and lenalidomide resulted in significantly enhanced T-bet expression and increased production of interferon-γ. In contrast, lenalidomide treatment alone was able to improve T cell cytotoxic function, associated with repair of trafficking of granzyme B into the immunological synapse. In conclusion, T cells from CLL patients exhibit features of T-cell pseudo-exhaustion that are present irrespective of CMV serostatus. Treatment of CLL T cells with lenalidomide results in upregulation of genes involved in proliferation, activation, and cytoskeletal pathways, resulting in repair of the functional T cell defects. Table 1. Comparison of the phenotypic and functional defects of T cells from CLL patients with T-cell “exhaustion” in chronic viral infections Exhausted T cells in chronic viral infections T cells from CLL patients Increased expression of inhibitory receptors Yes Yes Abnormal transcription factor profile Yes Yes Reduced proliferative potential Yes Yes Decreased expression of IL-7R (CD127) Yes No Decreased cytokine production ↓IL-2, ↓IFN-γ Yes No Impaired cytotoxicity Yes Yes Disclosures: Riches: Celgene: Research Funding. Gribben:Celgene: Honoraria; Roche: Honoraria; Pharmacyclics: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

scholarly journals A Role for Perforin in Downregulating T-Cell Responses during Chronic Viral Infection

1999 ◽  
Vol 73 (3) ◽  
pp. 2527-2536 ◽  
Author(s):  
Mehrdad Matloubian ◽  
M. Suresh ◽  
Alison Glass ◽  
Marisa Galvan ◽  
Kit Chow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Chronic Viral Infection ◽  
Persistently Infected ◽  
Cell Responses ◽  
Immune Mediated ◽  
Lcmv Infection

ABSTRACT Cytotoxic T cells secrete perforin to kill virus-infected cells. In this study we show that perforin also plays a role in immune regulation. Perforin-deficient (perf −/−) mice chronically infected with lymphocytic choriomeningitis virus (LCMV) contained greater numbers of antiviral T cells compared to persistently infected +/+ mice. The enhanced expansion was seen in both CD4 and CD8 T cells, but the most striking difference was in the numbers of LCMV-specific CD8 T cells present in infected perf −/− mice. Persistent LCMV infection of +/+ mice results in both deletion and anergy of antigen-specific CD8 T cells, and our results show that this peripheral “exhaustion” of activated CD8 T cells occurred less efficiently in perf −/− mice. This excessive accumulation of activated CD8 T cells resulted in immune-mediated damage in persistently infected perf −/− mice; ∼50% of these mice died within 2 to 4 weeks, and mortality was fully reversed by in vivo depletion of CD8 T cells. This finding highlights an interesting dichotomy between the role of perforin in viral clearance and immunopathology; perforin-deficient CD8 T cells were unable to clear the LCMV infection but were capable of causing immune-mediated damage. Finally, this study shows that perforin also plays a role in regulating T-cell-mediated autoimmunity. Mice that were deficient in both perforin and Fas exhibited a striking acceleration of the spontaneous lymphoproliferative disease seen in Fas-deficient (lpr) mice. Taken together, these results show that the perforin-mediated pathway is involved in downregulating T-cell responses during chronic viral infection and autoimmunity and that perforin and Fas act independently as negative regulators of activated T cells.

Real-world outcomes of treatment with immune checkpoint inhibitors in unique patient cohorts: Elderly, non-caucasian race, poor performance status, obese, chronic viral infections, and autoimmune diseases.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2641-2641
Author(s):  
Neil J. Shah ◽  
Shuo Wang ◽  
Aquino Williams ◽  
Melinda Weber ◽  
Brittany Sinclaire ◽  
...  
Keyword(s):  
Viral Infection ◽  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Viral Infections ◽  
Checkpoint Inhibitors ◽  
Chronic Viral Infection ◽  
Poor Performance Status ◽  
Chronic Viral Infections ◽  
Ecog Ps

2641 Background: Immune Checkpoint Inhibitors (ICI) have revolutionized current cancer treatment. Nevertheless, outcomes data across various patient cohorts are lacking. To address this knowledge gap, we conducted a comprehensive analysis of real-world data (RWD) that included patient cohorts traditionally underrepresented in clinical trials. Methods: We identified patients (pts) treated with ICI (anti-CTLA-4, anti-PD(L)1 or their combination at 6 US academic and community hospitals from 1/2011 – 4/2018. Clinical data obtained from EHR and CTCAE V4.03 was used to define immune-related adverse events (irAEs). Results: A total of 1332 pts treated with 1443 unique ICI treatments were included in the cohort. The median age was 66 (21-87), Male 58% (827), Caucasian 70% (1004), African American (AA) 16% (232), other race 14% (207), ECOG PS 0,1 79% (1130), chronic viral infection 5% [hepatitis B (24), hepatitis C (32) and HIV (17)], with BMI > 30 22% (287) and autoimmune disease (AID) 15% (215). Lung cancer (NSCLC) 34% (423), and melanoma 27% (389) were top 2 tumor types and nivolumab 38% (544), pembrolizumab 23% (332), and ipilimumab plus nivolumab 12% (180) were the most common ICI treatments. Overall survival (OS) was worse for patients with ECOG ≥2 (0.34 - 0.63) vs. ECOG 0,1 (1.27 - 1.73, P <0.001), and better with AID (1.21 - 2.63) vs. no AID ( 0.90 - 1.24, P=0.01) and Caucasian (1.02 - 1.45) vs AA (0.72 - 1.30, P=0.02). No difference in OS was noted for sex, other races, h/o chronic viral infection or obesity. We performed an analysis of OS and irAEs restricted to NSCLC patients (n=423); (N=447 unique ICI treatments); age >75 27% (120), AA 28% (124), Female 50% (224), ECOG PS ≥2 23% (104), BMI >30 15% (62), chronic viral infections 10% (44), and AID 14% (62). The ICI therapies were nivolumab 55% (245), pembrolizumab 23% (102), and atezolizumab 6% (27) and 16% (others). Data is contained in the table. Conclusions: Overall, in our RWD, OS appeared to be similar across above cohorts except poor OS for pts with ECOG ≥2. irAEs also appeared to be similar across cohorts except less with ECOG ≥2. In NSCLC cohort, we noted similar findings except less irAEs in Male cohort. Prospective studies are needed to confirm the above findings.[Table: see text]

scholarly journals Chronic virus infection compromises memory bystander T cell function in an IL-6/STAT1-dependent manner

2019 ◽  
Vol 216 (3) ◽  
pp. 571-586 ◽  
Author(s):  
Isabel Barnstorf ◽  
Mariana Borsa ◽  
Nicolas Baumann ◽  
Katharina Pallmer ◽  
Alexander Yermanos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Dependent Manner ◽  
Chronic Viral Infections ◽  
And Function ◽  
The Impact ◽  
Lcmv Infection

Chronic viral infections are widespread among humans, with ∼8–12 chronic viral infections per individual, and there is epidemiological proof that these impair heterologous immunity. We studied the impact of chronic LCMV infection on the phenotype and function of memory bystander CD8+ T cells. Active chronic LCMV infection had a profound effect on total numbers, phenotype, and function of memory bystander T cells in mice. The phenotypic changes included up-regulation of markers commonly associated with effector and exhausted cells and were induced by IL-6 in a STAT1-dependent manner in the context of chronic virus infection. Furthermore, bystander CD8 T cell functions were reduced with respect to their ability to produce inflammatory cytokines and to undergo secondary expansion upon cognate antigen challenge with major cell-extrinsic contributions responsible for the diminished memory potential of bystander CD8+ T cells. These findings open new perspectives for immunity and vaccination during chronic viral infections.

Detection of virus-specific T cells and CD8+ T-cell epitopes by acquisition of peptide–HLA-GFP complexes: analysis of T-cell phenotype and function in chronic viral infections

10.1038/nm845 ◽  
2003 ◽  
Vol 9 (4) ◽  
pp. 469-475 ◽  
Author(s):  
Utano Tomaru ◽  
Yoshihisa Yamano ◽  
Masahiro Nagai ◽  
Dragan Maric ◽  
Previn T.P. Kaumaya ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Cd8 T Cell ◽  
Cell Phenotype ◽  
T Cell Epitopes ◽  
Chronic Viral Infections ◽  
And Function

scholarly journals PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Roberto Tinoco ◽  
Emily N. Neubert ◽  
Christopher J. Stairiker ◽  
Monique L. Henriquez ◽  
Linda M. Bradley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Memory T Cells ◽  
Effector T Cells ◽  
T Cell Differentiation ◽  
Virus Infections ◽  
Effector T Cell ◽  
Memory T Cell ◽  
Cell Responses

Effective T cell differentiation during acute virus infections leads to the generation of effector T cells that mediate viral clearance, as well as memory T cells that confer protection against subsequent reinfection. While inhibitory immune checkpoints have been shown to promote T cell dysfunction during chronic virus infections and in tumors, their roles in fine tuning the differentiation and responses of effector and memory T cells are only just beginning to be appreciated. We previously identified PSGL-1 as a fundamental regulator of T cell exhaustion that sustains expression of several inhibitory receptors, including PD-1. We now show that PSGL-1 can restrict the magnitude of effector T cell responses and memory T cell development to acute LCMV virus infection by limiting survival, sustaining PD-1 expression, and reducing effector responses. After infection, PSGL-1-deficient effector T cells accumulated to a greater extent than wild type T cells, and preferentially generated memory precursor cells that displayed enhanced accumulation and functional capacity in response to TCR stimulation as persisting memory cells. Although, PSGL-1-deficient memory cells did not exhibit inherent greater sensitivity to cell death, they failed to respond to a homologous virus challenge after adoptive transfer into naïve hosts indicating an impaired capacity to generate memory effector T cell responses in the context of viral infection. These studies underscore the function of PSGL-1 as a key negative regulator of effector and memory T cell differentiation and suggest that PSGL-1 may limit excessive stimulation of memory T cells during acute viral infection.

scholarly journals Therapeutic Memory T Cells Require Costimulation for Effective Clearance of a Persistent Viral Infection

2009 ◽  
Vol 83 (17) ◽  
pp. 8905-8915 ◽  
Author(s):  
Lucile Garidou ◽  
Sara Heydari ◽  
Phi Truong ◽  
David G. Brooks ◽  
Dorian B. McGavern
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Persistent Infection ◽  
Cell Function ◽  
Viral Infections ◽  
Memory T Cells ◽  
Health Concern ◽  
Persistent Viral Infection

ABSTRACT Persistent viral infections are a major health concern worldwide. During persistent infection, overwhelming viral replication and the rapid loss of antiviral T-cell function can prevent immune-mediated clearance of the infection, and therapies to reanimate the immune response and purge persistent viruses have been largely unsuccessful. Adoptive immunotherapy using memory T cells is a highly successful therapeutic approach to eradicate a persistent viral infection. Understanding precisely how therapeutically administered memory T cells achieve clearance should improve our ability to terminate states of viral persistence in humans. Mice persistently infected from birth with lymphocytic choriomeningitis virus are tolerant to the pathogen at the T-cell level and thus provide an excellent model to evaluate immunotherapeutic regimens. Previously, we demonstrated that adoptively transferred memory T cells require recipient dendritic cells to effectively purge an established persistent viral infection. However, the mechanisms that reactivate and sustain memory T-cell responses during clearance of such an infection remain unclear. Here we establish that therapeutic memory T cells require CD80 and CD86 costimulatory signals to efficiently clear an established persistent viral infection in vivo. Early blockade of costimulatory pathways with CTLA-4-Fc decreased the secondary expansion of virus-specific CD8+ and CD4+ memory T cells as well as their ability to produce antiviral cytokines and purge the persistent infection. Late costimulation blockade also reduced virus-specific T-cell numbers, illustrating that sustained interactions with costimulatory molecules is required for efficient T-cell expansion. These findings indicate that antiviral memory T cells require costimulation to efficiently clear a persistent viral infection and that costimulatory pathways can be targeted to modulate the magnitude of an adoptive immunotherapeutic regimen.

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