CD8+ T-cell selection, function, and death in the primary immune response in vivo

Callan, Margaret; Fazou, Chrysoula; Yang, Hongbing; Rostron, Tim; Poon, Kathryn; Hatton, Chris; McMichael, Andrew J.

doi:10.1172/jci10590

Cited by 139 publications

(128 citation statements)

References 44 publications

(51 reference statements)

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“…After acute EBV infection, a large CD8 + T cell response is elicited which contracts subsequently into a smaller memory pool 57, 58, 59. Interestingly, it is known that at least one HLA‐A*02‐restricted lytic epitope reactivity present in the acute phase consistently disappears once infection resolves 57.…”

Section: Discussionmentioning

confidence: 99%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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SummaryIn 40% of cases of classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV) latency‐II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV+cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA‐A*02 is protective in EBV+cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA‐A*02– versus HLA‐A*02+ EBV+cHL patients, suggesting that LMP2A‐specific CD8+ T cell anti‐tumoral immunity may be relatively ineffective in HLA‐A*02– EBV+cHL. To ascertain the impact of HLA class I on EBV latency antigen‐specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV+cHL, the magnitude of ex‐vivo LMP1/2A‐specific CD8+ T cell responses was elevated in HLA‐A*02+ patients. Furthermore, in a controlled in‐vitro assay, LMP2A‐specific CD8+ T cells from healthy HLA‐A*02 heterozygotes expanded to a greater extent with HLA‐A*02‐restricted compared to non‐HLA‐A*02‐restricted cell lines. In an extensive analysis of HLA class I‐restricted immunity, immunodominant EBNA3A/3B/3C‐specific CD8+ T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A‐specific responses were confined largely to HLA‐A*02. Our results demonstrate that HLA‐A*02 mediates a modest, but none the less stronger, EBV‐specific CD8+ T cell response than non‐HLA‐A*02 alleles, an effect confined to EBV latency‐II antigens. Thus, the protective effect of HLA‐A*02 against EBV+cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency‐II antigen‐specific CD8+ T cell hierarchies.

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Section: Discussionmentioning

confidence: 99%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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“…Serum IFN-γ concentration was also observed to have increased simultaneously. Administration of activated CD4 + cells and CD8 + cells would promote the secretion of IL-2 and IFN-γ, thus inducing proliferation and activation of T and NK cells, and further accelerating IFN-γ production [6,7]. Serum IFN-γ concentration was increased first, and then, the cytotoxic ability of the PBMCs might be have been enhanced, since IFN-γ promoted the activation of NK cells [35].…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Analysis and Effects of Sequential Administration of Activated Canine Lymphocytes on Healthy Beagles

et al. 2008

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ABSTRACT. We attempted to accumulate the basic data for evaluation of activated lymphocyte therapy for small animal medicine. The peripheral blood mononuclear cells (PBMCs) collected from healthy dogs were activated using anti-CD3 antibody and human recombinant (hr) interleukin (IL)-2 and reactivated using hr interferon (IFN)-α and hr IL-2. The property of obtained cells was compared with PBMCs. The number of cells was shown to have increased approximately > 50 -fold by cultivation. The proportion of CD8 + cells was significantly increased, the cytotoxicity of the cultured cells was revealed to have been reinforced. Additionally, CD56 mRNA levels tended to have increased. The cells obtained by this method were confirmed to be activated lymphocytes. Furthermore, we investigated the effects of sequential administration of the obtained cells to healthy dogs. By sequential administration of the activated lymphocytes, the cell proliferative activity, proportion of CD4 + cells and CD8 + cells, and serum IFN-γ concentration were shown to have increased, and no severe adverse effects were observed. Consequently, activated lymphocytes could be induced using anti-CD3 antibody and IL-2 in healthy dogs, and sequential administration of activated lymphocytes reinforced the recipient's immunity.

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“…In humans, an in vivo study analyzing the primary antiviral response in Epstein-Barr virus (EBV)-infected patients showed that the deletion of activated antiviral CD8 ϩ T cells takes place through cytokine deprivation. 10 Using Bim knockout mice, it has been shown that deletion of CD8 ϩ T-cell responses is mainly dependent on cytokine deprivation after antigen clearance and that this process is strictly dependent on Bim expression. 11,12 Using CD8 ϩ human T-cell blasts we have confirmed that apoptosis by cytokine deprivation predominates over death receptor ligation and that the maintenance of high Bim levels is necessary for apoptosis to occur.…”

Section: Introductionmentioning

confidence: 99%

The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling

Bosque

Aguilo

Álava

et al. 2006

Blood

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The BH3-only protein Bim is required for maintaining the homeostasis of the immune system, since Bim regulates the down-modulation of T-cell responses, mainly through cytokine deprivation. Using T-cell blasts from healthy donors and also from patients with autoimmune lymphoproliferative syndromes (ALPSs) due to homozygous loss-of-function mutation of FasL (ALPS-Ic) or heterozygous mutation in the Fas/CD95 death domain (ALPSIa), it is shown that the induction of Bim expression during the process of human T-cell blast generation is strictly dependent on FasL/Fas-mediated signaling IntroductionThe regulated termination of T-cell immune responses is one of the mechanisms responsible for peripheral tolerance. Cytokine deprivation as a consequence of antigen exhaustion 1,2 and activationinduced cell death (AICD) 3 are 2 major mechanisms implicated in this regulation. This last mechanism was reported to be dependent on the Fas/Fas ligand (FasL) system 4-6 and also on APO2 ligand/ TNF-related apoptosis-inducing ligand (APO2L/TRAIL) and its receptors DR4 and DR5. 7,8 It is generally accepted that CD4 ϩ T cells are deleted mainly through the Fas/FasL system, 9 whereas CD8 ϩ T-cell deletion seems to be more dependent on cytokine deprivation. In humans, an in vivo study analyzing the primary antiviral response in Epstein-Barr virus (EBV)-infected patients showed that the deletion of activated antiviral CD8 ϩ T cells takes place through cytokine deprivation. 10 Using Bim knockout mice, it has been shown that deletion of CD8 ϩ T-cell responses is mainly dependent on cytokine deprivation after antigen clearance and that this process is strictly dependent on Bim expression. 11,12 Using CD8 ϩ human T-cell blasts we have confirmed that apoptosis by cytokine deprivation predominates over death receptor ligation and that the maintenance of high Bim levels is necessary for apoptosis to occur. 13 Defects of the Fas pathway were identified in human patients and the disease was named autoimmune lymphoproliferative syndrome (ALPS). 14,15 ALPS associates lymphoproliferative manifestations, such as lymphadenopathies and hepatosplenomegaly, with a specific immunologic disorder consisting of hypergammaglobulinemia G sometimes associated with hyper IgA and the presence of an expanded population of TcR ϩ CD4 Ϫ CD8 Ϫ double-negative (DN) T lymphocytes. Autoimmune manifestations are observed in most cases. ALPS (Online Mendelian Inheritance in Man [OMIM] 601859) is classified according to the underlying genetic defect: homozygous Fas mutation in type 0; heterozygous Fas mutation in type Ia; and, more rarely, heterozygous FasL mutation in type Ib; caspase 10 mutation in type IIa or caspase 8 mutation in type IIb; or unknown mutations in type III. 16 We previously characterized 3 different ALPS patients: (1) one with a new homozygous mutation in the FasL gene (patient 1), which resulted in loss of function, and that could be considered as the first reported case of ALPS-Ic 17 ; (2) a child and his father (patients 2 and 3) with a new heterozygou...

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CD8+ T-cell selection, function, and death in the primary immune response in vivo

Cited by 139 publications

References 44 publications

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Phenotypic Analysis and Effects of Sequential Administration of Activated Canine Lymphocytes on Healthy Beagles

The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling

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