scholarly journals The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Caterina Veroni ◽  
Francesca Aloisi
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Barr Virus ◽  
Epstein Barr

The cause and the pathogenic mechanisms leading to multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), are still under scrutiny. During the last decade, awareness has increased that multiple genetic and environmental factors act in concert to modulate MS risk. Likewise, the landscape of cells of the adaptive immune system that are believed to play a role in MS immunopathogenesis has expanded by including not only CD4 T helper cells but also cytotoxic CD8 T cells and B cells. Once the key cellular players are identified, the main challenge is to define precisely how they act and interact to induce neuroinflammation and the neurodegenerative cascade in MS. CD8 T cells have been implicated in MS pathogenesis since the 80’s when it was shown that CD8 T cells predominate in MS brain lesions. Interest in the role of CD8 T cells in MS was revived in 2000 and the years thereafter by studies showing that CNS-recruited CD8 T cells are clonally expanded and have a memory effector phenotype indicating in situ antigen-driven reactivation. The association of certain MHC class I alleles with MS genetic risk implicates CD8 T cells in disease pathogenesis. Moreover, experimental studies have highlighted the detrimental effects of CD8 T cell activation on neural cells. While the antigens responsible for T cell recruitment and activation in the CNS remain elusive, the high efficacy of B-cell depleting drugs in MS and a growing number of studies implicate B cells and Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus that is strongly associated with MS, in the activation of pathogenic T cells. This article reviews the results of human studies that have contributed to elucidate the role of CD8 T cells in MS immunopathogenesis, and discusses them in light of current understanding of autoreactivity, B-cell and EBV involvement in MS, and mechanism of action of different MS treatments. Based on the available evidences, an immunopathological model of MS is proposed that entails a persistent EBV infection of CNS-infiltrating B cells as the target of a dysregulated cytotoxic CD8 T cell response causing CNS tissue damage.

scholarly journals Combined immunodeficiency and Epstein-Barr virus–induced B cell malignancy in humans with inherited CD70 deficiency

2016 ◽  
Vol 214 (1) ◽  
pp. 91-106 ◽  
Author(s):  
Hassan Abolhassani ◽  
Emily S.J. Edwards ◽  
Aydan Ikinciogullari ◽  
Huie Jing ◽  
Stephan Borte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Combined Immunodeficiency ◽  
Memory Cd8 T Cells ◽  
Barr Virus ◽  
Epstein Barr

In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)–related diseases. Three patients presented with EBV-associated Hodgkin’s lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+ T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro–generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70–CD27 interactions therefore play a nonredundant role in T and B cell–mediated immunity, especially for protection against EBV and humoral immunity.

scholarly journals Preferential Localization of the Epstein-Barr Virus (EBV) Oncoprotein LMP-1 to Nuclei in Human T Cells: Implications for Its Role in the Development of EBV Genome-Positive T-Cell Lymphomas

2002 ◽  
Vol 76 (8) ◽  
pp. 4080-4086 ◽  
Author(s):  
Jingwu Xu ◽  
Ali Ahmad ◽  
José Menezes
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Phenotypic Changes ◽  
Barr Virus ◽  
T Cell Lymphomas ◽  
Cell Clones ◽  
Epstein Barr

ABSTRACT The Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP-1) is thought to play a role in the EBV-induced B-cell transformation and immortalization. EBV has also been implicated in certain human T-cell lymphomas; however, the phenotypic effects of the expression of this oncoprotein in T cells are not known. To learn whether LMP-1 also induces phenotypic changes in T cells, we stably expressed it in human cell lines of T and B lineages and 25 LMP-1-expressing T-cell clones and 7 B-cell clones were examined. Our results show for the first time that, in sharp contrast to B cells, LMP-1 preferentially localizes to nuclei in T cells and does not induce the phenotypic changes in these cells that it induces in B cells, does not associate with TRAF proteins, and does not arrest the cell cycle in the G2/M phase. A computer-assisted analysis revealed that LMP-1 lacks the canonical nuclear localization signal. Our results suggest that this oncoprotein may not play the same role in the lymphomagenesis of T cells as it does in B cells.

scholarly journals CD8 T Cell Recognition of Endogenously Expressed Epstein-Barr Virus Nuclear Antigen 1

2004 ◽  
Vol 199 (10) ◽  
pp. 1409-1420 ◽  
Author(s):  
Steven P. Lee ◽  
Jill M. Brooks ◽  
Hatim Al-Jarrah ◽  
Wendy A. Thomas ◽  
Tracey A. Haigh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Class I ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

The Epstein-Barr virus (EBV) nuclear antigen (EBNA)1 contains a glycine-alanine repeat (GAr) domain that appears to protect the antigen from proteasomal breakdown and, as measured in cytotoxicity assays, from major histocompatibility complex (MHC) class I–restricted presentation to CD8+ T cells. This led to the concept of EBNA1 as an immunologically silent protein that although unique in being expressed in all EBV malignancies, could not be exploited as a CD8 target. Here, using CD8+ T cell clones to native EBNA1 epitopes upstream and downstream of the GAr domain and assaying recognition by interferon γ release, we show that the EBNA1 naturally expressed in EBV-transformed lymphoblastoid cell lines (LCLs) is in fact presented to CD8+ T cells via a proteasome/peptide transporter–dependent pathway. Furthermore, LCL recognition by such CD8+ T cells, although slightly lower than seen with paired lines expressing a GAr-deleted EBNA1 protein, leads to strong and specific inhibition of LCL outgrowth in vitro. Endogenously expressed EBNA1 is therefore accessible to the MHC class I pathway despite GAr-mediated stabilization of the mature protein. We infer that EBNA1-specific CD8+ T cells do play a role in control of EBV infection in vivo and might be exploitable in the control of EBV+ malignancies.

scholarly journals CD4+ T-Cell Effectors Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation

2001 ◽  
Vol 75 (8) ◽  
pp. 3740-3752 ◽  
Author(s):  
Sarah Nikiforow ◽  
Kim Bottomly ◽  
George Miller
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT In immunodeficient hosts, Epstein-Barr virus (EBV) often induces extensive B-cell lymphoproliferative disease and lymphoma. Without effective in vitro immune surveillance, B cells infected by the virus readily form immortalized cell lines. In the regression assay, memory T cells inhibit the formation of foci of EBV-transformed B cells that follows recent in vitro infection by EBV. No one has yet addressed which T cell regulates the early proliferative phase of B cells newly infected by EBV. Using new quantitative methods, we analyzed T-cell surveillance of EBV-mediated B-cell proliferation. We found that CD4+ T cells play a significant role in limiting proliferation of newly infected, activated CD23+ B cells. In the absence of T cells, EBV-infected CD23+ B cells divided rapidly during the first 3 weeks after infection. Removal of CD4+ but not CD8+ T cells also abrogated immune control. Purified CD4+ T cells eliminated outgrowth when added to EBV-infected B cells. Thus, unlike the killing of EBV-infected lymphoblastoid cell lines, in which CD8+ cytolytic T cells play an essential role, prevention of early-phase EBV-induced B-cell proliferation requires CD4+ effector T cells.

scholarly journals Functional Analysis of the CD4+ T-Cell Response to Epstein-Barr Virus: T-Cell-Mediated Activation of Resting B Cells and Induction of Viral BZLF1 Expression

2000 ◽  
Vol 74 (14) ◽  
pp. 6675-6679 ◽  
Author(s):  
Zheng Fu ◽  
Martin J. Cannon
Keyword(s):  
Functional Analysis ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disorders ◽  
T Cell Response ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT In contrast to the major role played by Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T-cell responses in immunosurveillance, recent studies have offered the apparently paradoxical suggestion that development of EBV-driven human B-cell lymphoproliferative disorders and tumors in SCID/hu mice is dependent on the presence of T cells, in particular CD4+ T cells. This study presents a functional analysis of the CD4+T-cell response to EBV and shows that while CD4+ T cells may be cytotoxic, they also express Th2 cytokines and CD40 ligand (gp39) and possess B-cell helper function. We show that EBV-specific CD4+ T cells can provide non-HLA-restricted help for activation of resting B cells via a gp39-CD40-dependent pathway and are able to induce expression of BZLF1, a viral lytic cycle transactivator in latently infected resting B cells, ultimately resulting in rapid outgrowth of transformed B-cell colonies. These results support the proposal that CD4+ T cells may play a key role in reactivation of latent EBV infection and may thus contribute to the pathogenesis of EBV-driven lymphoproliferative disorders.

scholarly journals Functional Diversity of the CD8+ T-Cell Response to Epstein-Barr Virus (EBV): Implications for the Pathogenesis of EBV-Associated Lymphoproliferative Disorders

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3875-3883 ◽  
Author(s):  
Rachel A. Nazaruk ◽  
Rosemary Rochford ◽  
Monte V. Hobbs ◽  
Martin J. Cannon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Lymphoproliferative Disorders ◽  
Barr Virus ◽  
Specific Cytotoxicity ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T cells are thought to be critical for the control of EBV, which persists in healthy individuals as a latent infection of B cells. However, recent observations have indicated that CD8+ T-cell responses are not uniformly cytotoxic and that CD8+ T cells may be subdivided into type 1 and type 2 subsets that parallel the classically described Th1 and Th2 subsets of CD4+ T cells. Using two-color flow cytometric analysis of intracellular cytokine expression at the single-cell level, we have identified two distinct but overlapping subsets of EBV-specific CD8+ T cells, the first of which expressed high levels of interferon γ (IFNγ), but little or no interleukin-4 (IL-4), whereas the second subset was IFNγ+/IL-4+ double-positive. A significant proportion of EBV-specific CD8+ T cells also expressed IL-13. Subsequent analysis of a panel of 27 EBV-specific CD8+ T-cell clones showed inverse relationships between EBV-specific cytotoxicity and secretion of IL-4, IL-10, and IFNγ, respectively. IL-10 was not secreted by the 11 most strongly cytotoxic clones, suggesting that IL-10 secretion may provide a functional definition of an EBV-specific type 2 CD8+ T-cell subset with reduced EBV-specific cytotoxicity. Finally, we have demonstrated that EBV-specific CD8+ T cells that express type 2 cytokines possess the ability to activate resting B cells. EBV-specific CD8+ T cells thus have the potential to reactivate latent EBV infection in vivo and may contribute to the development of EBV-associated lymphoproliferative disorders and lymphoma.

scholarly journals Signaling by the Epstein–Barr virus LMP1 protein induces potent cytotoxic CD4+ and CD8+ T cell responses

2018 ◽  
Vol 115 (4) ◽  
pp. E686-E695 ◽  
Author(s):  
Il-Kyu Choi ◽  
Zhe Wang ◽  
Qiang Ke ◽  
Min Hong ◽  
Yu Qian ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Epstein Barr Virus ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 Cells ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr

The B-lymphotropic Epstein–Barr virus (EBV), pandemic in humans, is rapidly controlled on initial infection by T cell surveillance; thereafter, the virus establishes a lifelong latent infection in the host. If surveillance fails, fatal lymphoproliferation and lymphomagenesis ensue. The initial T cell response consists of predominantly CD8+ cytotoxic T cells and a smaller expansion of CD4+ cells. A major approach to treating EBV-associated lymphomas is adoptive transfer of autologous or allogeneic T cells that are stimulated/expanded on EBV-transformed B cells. Strikingly, the clinical response correlates with the frequency of CD4 cells in the infused T cells. Although in vitro studies suggested that EBV-specific CD4 cells develop cytotoxicity, they have not been comprehensively characterized and the molecular mechanism underlying their formation remains unknown. Our recent work, using a transgenic approach in mice, has revealed a central role for the EBV signaling molecule LMP1 in immune surveillance and transformation of EBV-infected B cells. The mouse model offers a unique tool for uncovering basic features of EBV immunity. Here, we show that LMP1 expression in B cells induces potent cytotoxic CD4 and CD8 T cell responses, by enhancing antigen presentation and costimulation by CD70, OX40 ligand, and 4-1BB ligand. Our data further suggest that cytotoxic CD4 cells hold superior therapeutic value for LMP1 (EBV)-driven lymphomas. These findings provide insights into EBV immunity, demonstrating that LMP1 signaling alone is sufficient to induce a prominent cytotoxic CD4 response, and suggest strategies for immunotherapy in EBV-related and other cancers.

scholarly journals Functional Diversity of the CD8+ T-Cell Response to Epstein-Barr Virus (EBV): Implications for the Pathogenesis of EBV-Associated Lymphoproliferative Disorders

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3875-3883 ◽  
Author(s):  
Rachel A. Nazaruk ◽  
Rosemary Rochford ◽  
Monte V. Hobbs ◽  
Martin J. Cannon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Lymphoproliferative Disorders ◽  
Barr Virus ◽  
Specific Cytotoxicity ◽  
Epstein Barr

Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T cells are thought to be critical for the control of EBV, which persists in healthy individuals as a latent infection of B cells. However, recent observations have indicated that CD8+ T-cell responses are not uniformly cytotoxic and that CD8+ T cells may be subdivided into type 1 and type 2 subsets that parallel the classically described Th1 and Th2 subsets of CD4+ T cells. Using two-color flow cytometric analysis of intracellular cytokine expression at the single-cell level, we have identified two distinct but overlapping subsets of EBV-specific CD8+ T cells, the first of which expressed high levels of interferon γ (IFNγ), but little or no interleukin-4 (IL-4), whereas the second subset was IFNγ+/IL-4+ double-positive. A significant proportion of EBV-specific CD8+ T cells also expressed IL-13. Subsequent analysis of a panel of 27 EBV-specific CD8+ T-cell clones showed inverse relationships between EBV-specific cytotoxicity and secretion of IL-4, IL-10, and IFNγ, respectively. IL-10 was not secreted by the 11 most strongly cytotoxic clones, suggesting that IL-10 secretion may provide a functional definition of an EBV-specific type 2 CD8+ T-cell subset with reduced EBV-specific cytotoxicity. Finally, we have demonstrated that EBV-specific CD8+ T cells that express type 2 cytokines possess the ability to activate resting B cells. EBV-specific CD8+ T cells thus have the potential to reactivate latent EBV infection in vivo and may contribute to the development of EBV-associated lymphoproliferative disorders and lymphoma.

Dendritic Cells Expand Epstein Barr Virus Specific CD8+ T Cell Responses More Efficiently Than EBV Transformed B Cells

2005 ◽  
Vol 66 (9) ◽  
pp. 938-949 ◽  
Author(s):  
Marion Subklewe ◽  
Kathrin Sebelin ◽  
Andrea Block ◽  
Antje Meier ◽  
Anna Roukens ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Epstein Barr Virus ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr

scholarly journals Survival and Clonal Expansion of Mutating “Forbidden” (Immunoglobulin Receptor–Deficient) Epstein-Barr Virus–Infected B Cells in Angioimmunoblastic T Cell Lymphoma

2001 ◽  
Vol 194 (7) ◽  
pp. 927-940 ◽  
Author(s):  
Andreas Bräuninger ◽  
Tilmann Spieker ◽  
Klaus Willenbrock ◽  
Philippe Gaulard ◽  
Hans-Heinrich Wacker ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Clonal Expansion ◽  
Barr Virus ◽  
Cell Clones ◽  
Epstein Barr

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV+ cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV+ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV− B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of “forbidden” (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.

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