CD28 co-stimulation via tumour-specific chimaeric receptors induces an incomplete activation response in Epstein-Barr virus-specific effector memory T cells

Background: Patients with multiple sclerosis (MS) have a deficiency of circulating CD8+ T cells, which might impair control of Epstein–Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells. Objective: Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course. Methods: We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MS patients and 112 healthy subjects. Results: MS patients had a decreased frequency of EM (CD45RA–CD62L–) and EMRA (CD45RA+CD62L–) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal. Conclusion: Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.

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Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer

Nature Communications ◽

10.1038/s41467-021-23356-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jieti Wang ◽

Ruochen Li ◽

Yifan Cao ◽

Yun Gu ◽

Hanji Fang ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

T Cells ◽

Epstein Barr Virus ◽

Effector Memory ◽

Feature Identification ◽

Barr Virus ◽

T Cell Infiltration ◽

Epstein Barr ◽

Gastric Cancer Patients

AbstractStudies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.

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IL-15 Enhances in-vitro Expansion And Functional Activity Of Antigen-Specific Effector Memory T Cells (TEM) While Co-Expression Of IL-15 And IL-15 Rα On Antigen Presenting Cells Also Promotes Enrichment And Preferential Expansion Of Central Memory T-Cells (TCM)

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2009.12.025 ◽

2010 ◽

Vol 16 (2) ◽

pp. S159 ◽

Cited By ~ 1

Author(s):

A.N. Hasan ◽

A. Selvakumar ◽

X.-R. Liu ◽

M.W. Sadelain ◽

I. Riviere ◽

...

Keyword(s):

T Cells ◽

Functional Activity ◽

Memory T Cells ◽

Effector Memory ◽

Central Memory T Cells ◽

Effector Memory T Cells ◽

Specific Effector ◽

In Vitro Expansion ◽

Antigen Presenting

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Unidirectional development of CD8+ central memory T cells into protectiveListeria-specific effector memory T cells

European Journal of Immunology ◽

10.1002/eji.200635874 ◽

2006 ◽

Vol 36 (6) ◽

pp. 1453-1464 ◽

Cited By ~ 61

Author(s):

Katharina M. Huster ◽

Martina Koffler ◽

Christian Stemberger ◽

Matthias Schiemann ◽

Hermann Wagner ◽

...

Keyword(s):

T Cells ◽

Memory T Cells ◽

Central Memory ◽

Effector Memory ◽

Central Memory T Cells ◽

Effector Memory T Cells ◽

Specific Effector

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Fas Down-Modulation in Epstein Barr Virus (EBV)-Specific Cytotoxic T-Lymphocytes (CTLs) Reduces Their Sensitivity to Fas/Fasl-Induced Apoptosis.

Blood ◽

10.1182/blood.v104.11.2647.2647 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2647-2647

Author(s):

Gianpietro Dotti ◽

Barbara Savoldo ◽

Martin Pule ◽

Karin C. Straathof ◽

Ettore Biagi ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Tumor Antigen ◽

Epstein Barr Virus ◽

Genetically Modified ◽

Effector Memory ◽

Antigen Specificity ◽

Barr Virus ◽

Specific Ctls ◽

Epstein Barr

Abstract Adoptive immunotherapy with Epstein Barr Virus (EBV)-specific CTL has been successfully used to treat patients with EBV related malignancies including Post Transplant Lymphoproliferative disorder, Hodgkin’s lymphoma and Nasopharyngeal carcinoma. However, these and other potentially immunogenic tumors have evolved evasion strategies that subvert the effectiveness of the immune response. One such strategy involves expression of FasL, which likely impedes the host immune response by accelerating the apoptotic death of Fas-expressing tumor infiltrating T-cells. EBV-specific CTLs, like most effector memory T cells express high levels of Fas and are highly sensitive to cross-linking of the ligand. We therefore determined whether EBV-specific CTLs could be genetically modified to resist FasL-mediated immune evasion. We used retroviral siRNA (pSUPER.retro) directed against the Fas gene product to knockdown receptor expression in tumor-antigen specific CTLs. Transduction of CTLs with siRNA targeting Fas mRNA significantly knocked down Fas expression compared to control cells (Fas MFI 107 ± 47 vs. 402 ± 47, p<0.001). This effect was paralleled by a significant reduction of apoptosis induced by the Fas agonistic antibody (clone CH-11) in modified CTLs compared to control cells (23% ± 3% vs. 44% ± 7% p=0.006). Fas down-modulation was stable over time in CTLs modified, and addition of CH-11 antibody to the culture selected a uniformly Faslow CTL population (Fas MFI 79 ± 29) that was entirely resistant to FasL mediated lysis. However, germ line deletions as well as function-impairing mutations of Fas and FasL can induce T-lymphoproliferation and autoimmune diseases. We therefore compared the growth characteristics and the antigen specificity of unmodified and Fas knockdown CTLs. Survival and proliferation of genetically modified CTLs remain completely dependent on antigen specific stimulation and the presence of other physiological growth signals. Moreover, as assessed by the analysis of the Vb TcR repertoire, IFN-g-release (Elispot) and tetramer staining the modified CTLs remained polyclonal and conserved their antigen specificity. These data suggest that responsiveness to this single death signal may be removed from an effector-memory population of CTLs without adversely affecting their safety. Tumor-antigen-specific CTLs with lower expression of Fas receptor should have a selective functional and survival advantage over unmodified CTLs in the presence of tumors expressing FasL, and may be of value for adoptive cellular therapy of such malignancies.

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Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19

Science Immunology ◽

10.1126/sciimmunol.aaw2707 ◽

2019 ◽

Vol 4 (40) ◽

pp. eaaw2707 ◽

Cited By ~ 19

Author(s):

Masahiko Akamatsu ◽

Norihisa Mikami ◽

Naganari Ohkura ◽

Ryoji Kawakami ◽

Yohko Kitagawa ◽

...

Keyword(s):

T Cells ◽

Autoimmune Disease ◽

Cell Function ◽

Memory T Cells ◽

Contact Hypersensitivity ◽

Effector Memory ◽

Skin Contact ◽

Effector Memory T Cells ◽

Specific Effector

A promising way to restrain hazardous immune responses, such as autoimmune disease and allergy, is to convert disease-mediating T cells into immunosuppressive regulatory T (Treg) cells. Here, we show that chemical inhibition of the cyclin-dependent kinase 8 (CDK8) and CDK19, or knockdown/knockout of the CDK8 or CDK19 gene, is able to induce Foxp3, a key transcription factor controlling Treg cell function, in antigen-stimulated effector/memory as well as naïve CD4+ and CD8+ T cells. The induction was associated with STAT5 activation, independent of TGF-β action, and not affected by inflammatory cytokines. Furthermore, in vivo administration of a newly developed CDK8/19 inhibitor along with antigen immunization generated functionally stable antigen-specific Foxp3+ Treg cells, which effectively suppressed skin contact hypersensitivity and autoimmune disease in animal models. The results indicate that CDK8/19 is physiologically repressing Foxp3 expression in activated conventional T cells and that its pharmacological inhibition enables conversion of antigen-specific effector/memory T cells into Foxp3+ Treg cells for the treatment of various immunological diseases.

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Distinct memory CD4+ T-cell subsets mediate immune recognition of Epstein Barr virus nuclear antigen 1 in healthy virus carriers

Blood ◽

10.1182/blood-2006-05-023663 ◽

2006 ◽

Vol 109 (3) ◽

pp. 1138-1146 ◽

Cited By ~ 43

Author(s):

Kevin N. Heller ◽

Jenica Upshaw ◽

Beza Seyoum ◽

Henry Zebroski ◽

Christian Münz

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Epstein Barr Virus ◽

T Cell Subsets ◽

Nuclear Antigen ◽

Effector Memory ◽

Immune Recognition ◽

T Helper 1 ◽

Barr Virus ◽

Epstein Barr

AbstractCD4+ T cells, specific for transforming latent infection with the Epstein Barr virus (EBV), consistently recognize the nuclear antigen 1 of EBV (EBNA1). EBNA1-specific effector CD4+ T cells are primarily T-helper 1 (TH1) polarized. Here we show that most healthy EBV carriers have such IFN-secreting EBNA1-specific CD4+ T cells at a frequency of 0.03% of circulating CD4+ T cells. In addition, healthy carriers have a large pool of CD4+ T cells that proliferated in response to EBNA1 and consisted of distinct memory-cell subsets. Despite continuous antigen presence due to persistent EBV infection, half of the proliferating EBNA1-specific CD4+ T cells belonged to the central-memory compartment (TCM). The remaining EBNA1-specific CD4+ T cells displayed an effector-memory phenotype (TEM), of which a minority rapidly secreted IFN upon stimulation with EBNA1. Based on chemokine receptor analysis, all EBNA1-specific TCM CD4+ T cells were TH1 committed. Our results suggest that protective immune control of chronic infections, like EBV, includes a substantial reservoir of TCM CD4+ TH1 precursors, which continuously fuels TH1-polarized effector cells.

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Progressive Telomere Shortening of Epstein‐Barr Virus–Specific Memory T Cells during HIV Infection: Contributor to Exhaustion?

The Journal of Infectious Diseases ◽

10.1086/592170 ◽

2008 ◽

Vol 198 (9) ◽

pp. 1353-1357 ◽

Cited By ~ 23

Author(s):

Debbie van Baarle ◽

Nening M. Nanlohy ◽

Sigrid Otto ◽

Fiona J. Plunkett ◽

Jean M. Fletcher ◽

...

Keyword(s):

T Cells ◽

Hiv Infection ◽

Epstein Barr Virus ◽

Memory T Cells ◽

Telomere Shortening ◽

Barr Virus ◽

Specific Memory ◽

Epstein Barr

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Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus

Journal of Experimental Medicine ◽

10.1084/jem.20112391 ◽

2012 ◽

Vol 209 (5) ◽

pp. 913-924 ◽

Cited By ~ 41

Author(s):

Umaimainthan Palendira ◽

Carol Low ◽

Andrew I. Bell ◽

Cindy S. Ma ◽

Rachel J.M. Abbott ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Epstein Barr Virus ◽

Selective Pressure ◽

Lymphoproliferative Disease ◽

Effector Memory ◽

Barr Virus ◽

Ebv Infection ◽

Somatic Reversion ◽

Epstein Barr

Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8+ T cell subset, displayed a CD45RA−CCR7− effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8+ SAP+ T cells, but not SAP− cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection.

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