Programmed death 1 is highly expressed on CD8+CD57+T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus

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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Deficiency of CD8 effector memory T cells impairs response to Epstein-Barr virus in multiple sclerosis

Frontiers in Immunology ◽

10.3389/conf.fimmu.2013.02.00178 ◽

2013 ◽

Vol 4 ◽

Author(s):

Pender Michael ◽

Csurhes Peter ◽

Pfluger Casey ◽

Burrows Scott

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Epstein Barr Virus ◽

Memory T Cells ◽

Effector Memory ◽

Barr Virus ◽

Effector Memory T Cells ◽

Epstein Barr

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Upregulation of Interleukin 7 Receptor Alpha and Programmed Death 1 Marks an Epitope-Specific CD8+ T-Cell Response That Disappears following Primary Epstein-Barr Virus Infection

Journal of Virology ◽

10.1128/jvi.00141-09 ◽

2009 ◽

Vol 83 (18) ◽

pp. 9068-9078 ◽

Cited By ~ 13

Author(s):

Delphine Sauce ◽

Martin Larsen ◽

Rachel J. M. Abbott ◽

Andrew D. Hislop ◽

Alison M. Leese ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

Epstein Barr Virus ◽

T Cell Response ◽

Receptor Alpha ◽

Barr Virus ◽

Interleukin 7 ◽

Programmed Death ◽

Programmed Death 1 ◽

Epstein Barr

ABSTRACT In immunocompetent individuals, the stability of the herpesvirus-host balance limits opportunities to study the disappearance of a virus-specific CD8+ T-cell response. However, we noticed that in HLA-A*0201-positive infectious mononucleosis (IM) patients undergoing primary Epstein-Barr virus (EBV) infection, the initial CD8 response targets three EBV lytic antigen-derived epitopes, YVLDHLIVV (YVL), GLCTLVAML (GLC), and TLDYKPLSV (TLD), but only the YVL and GLC reactivities persist long-term; the TLD response disappears within 10 to 27 months. While present, TLD-specific cells remained largely indistinguishable from YVL and GLC reactivities in many phenotypic and functional respects but showed unique temporal changes in two markers of T-cell fate, interleukin 7 receptor alpha (IL-7Rα; CD127) and programmed death 1 (PD-1). Thus, following the antigen-driven downregulation of IL-7Rα seen on all populations in acute IM, in every case, the TLD-specific population recovered expression unusually quickly post-IM. As well, in four of six patients studied, TLD-specific cells showed very strong PD-1 upregulation in the last blood sample obtained before the cells’ disappearance. Our data suggest that the disappearance of this individual epitope reactivity from an otherwise stable EBV-specific response (i) reflects a selective loss of cognate antigen restimulation (rather than of IL-7-dependent signals) and (ii) is immediately preceded, and perhaps mediated, by PD-1 upregulation to unprecedented levels.

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Cerebrospinal fluid T cells from multiple sclerosis patients recognize autologous Epstein-Barr virus–transformed B cells

Journal of NeuroVirology ◽

10.1080/13550280490261671 ◽

2004 ◽

Vol 10 (1) ◽

pp. 52-56 ◽

Cited By ~ 28

Author(s):

Trygve Holmøy ◽

Frode Vartdal

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cerebrospinal Fluid ◽

B Cells ◽

Epstein Barr Virus ◽

Barr Virus ◽

Epstein Barr ◽

Multiple Sclerosis Patients

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Epstein–Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514521888 ◽

2014 ◽

Vol 20 (11) ◽

pp. 1541-1544 ◽

Cited By ~ 36

Author(s):

Michael P Pender ◽

Peter A Csurhes ◽

Corey Smith ◽

Leone Beagley ◽

Kaye D Hooper ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Adoptive Immunotherapy ◽

Epstein Barr Virus ◽

Progressive Multiple Sclerosis ◽

Resonance Imaging ◽

Barr Virus ◽

The Central Nervous System ◽

Epstein Barr

Defective control of Epstein–Barr virus (EBV) infection by cytotoxic CD8+ T cells might predispose to multiple sclerosis (MS) by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins. This adoptive immunotherapy had no adverse effects and the patient showed clinical improvement with reduced disease activity on magnetic resonance imaging and decreased intrathecal immunoglobulin production. This is the first report of the use of EBV-specific adoptive immunotherapy to treat MS or any other autoimmune disease.

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Multiple Sclerosis: Are Protective Immune Mechanisms Compromised by a Complex Infectious Background?

Autoimmune Diseases ◽

10.4061/2011/708750 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Bernd Krone ◽

John M. Grange

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Immune System ◽

Epstein Barr Virus ◽

Immune Dysregulation ◽

Gene Products ◽

Diverse Range ◽

Barr Virus ◽

Epstein Barr ◽

Self Antigen

The immunological background of multiple sclerosis (MS) manifests as an altered reactivity against a diverse range of infections, particularly with the Epstein-Barr virus. Although this could be only an epiphenomenon of a more generalised dysfunction of the immune system in MS, it is also possible that a complex infectious background forms the basis of a specific immune dysregulation finally causing the disease. It is thus suggested that the complex infectious background bears the key for an understanding of the immune pathogenesis of the disease. It appears probable that improved standards of hygiene cause regulatory defects in the immune system, allowing the abnormal expression of human endogenous retroviral (HERV) genes. On the basis of epidemiological observations we describe how a failure of expansion or an eclipse of a subfraction of self-antigen-specific CD8+T cells mediating immune repair, and a deleterious mode of action of HERV gene products, could underlie the pathogenesis of MS.

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Successful Outcome of Programmed Death 1 Blockade Plus GemOx for Epstein-Barr Virus-Associated Primary Nodal T/NK Cell Lymphoma: A Case Report

Frontiers in Oncology ◽

10.3389/fonc.2021.706865 ◽

2021 ◽

Vol 11 ◽

Author(s):

Liang Xia ◽

Han-Shuo Zhang ◽

Jing Bao ◽

Yu-Chen Zhao ◽

Hai-Long Xia

Keyword(s):

Epstein Barr Virus ◽

Nk Cell ◽

Cell Lymphoma ◽

Successful Outcome ◽

Salvage Regimen ◽

Therapy Regimen ◽

Barr Virus ◽

Programmed Death ◽

Programmed Death 1 ◽

Epstein Barr

Epstein-Barr virus (EBV)-associated lymph nodal T/NK cell lymphoma (nodal TNKL) is a rare and aggressive malignancy with an extremely poor prognosis. Although treatments of extranodal NK/T cell lymphoma are frequently reported, the characteristics and pathogenesis of EBV-associated nodal TNKL are different. However, there is no known effective therapy regimen at present. Here, we reported the clinical efficacy and feasibility of the programmed death 1 (PD-1) blockade therapy regimen in an elderly female patient with EBV-associated nodal TNKL. The patient failed to respond to cyclophosphamide, doxorubicin, vindesine, and prednisone regimen but achieved complete response after three cycles of anti-PD-1 antibody (tislelizumab) combined with gemcitabine and oxaliplatin (GemOx) regimen. The finding indicated that tislelizumab combined with the GemOx regimen may be a potent salvage regimen for EBV-associated nodal TNKL.

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Clinicopathological features of program death ligand-1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4040 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4040-4040 ◽

Cited By ~ 1

Author(s):

Akihito Kawazoe ◽

Kohei Shitara ◽

Yasutoshi Kuboki ◽

Hideaki Bando ◽

Takashi Kojima ◽

...

Keyword(s):

Gastric Cancer ◽

Mismatch Repair ◽

Epstein Barr Virus ◽

Metastatic Gastric Cancer ◽

Cancer Genome ◽

Clinicopathological Features ◽

Barr Virus ◽

Programmed Death ◽

Programmed Death 1 ◽

Epstein Barr

4040 Background: Recently, anti-programmed death 1 (PD-1) or its ligand (PD-L1) antibodies have shown promising activities in metastatic gastric cancer (MGC). However, little is known about detailed clinicopathological features of PD-L1 expression in patients (pts) with MGC. Methods: Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression on tumor cell (TC) or inflammatory cell (IC) and mismatch repair (MMR) were analyzed by immunohistochemistry (IHC). Epstein–Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) such as HER2, EGFR and MET and cancer genome alterations were also evaluated by IHC or next generation sequencing. Results: A total of 237 pts were enrolled from September 2015 to December 2016. Samples of 199 (84.0%) pts were obtained from biopsy. PD-L1 expression on TC and IC was positive in 27 (11.4%) and 167 pts (70.5%), respectively. One hundred and seventy-one pts (72.2%) had positive PD-L1 expression on either TC or IC. MMR deficient (D-MMR) and EBV was detected in 14 (6.9%, n = 203) and 14 pts (5.9%, n = 237), respectively. PD-L1 expression on TC was more frequently observed in pts with D-MMR (P < 0.001) and KRAS mutation (P < 0.001), while that on IC was more frequently observed in pts with EBV+ (P = 0.045), lymph node metastasis (P = 0.001), and lung metastasis (P = 0.045). In contrast, pts with peritoneal metastasis were associated with less frequent PD-L1 expression in IC (P = 0.003). A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. D-MMR was significantly associated with intestinal type (P = 0.026) and absence of liver metastasis (P = 0.022). PD-L1 expression on either TC or IC was not prognostic factor (hazard ratio; 0.92, P = 0.741). Seven pts with D-MMR and seven pts with EBV+ MGC were enrolled in clinical trials of anti-PD-1/PD-L1 antibodies. Conclusions: PD-L1 expression in MGC was associated with some clinicopathological features. Impact of these characteristics on efficacy of anti-PD-1/PD-L1 antibody warrants further evaluation.

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