Anti-CD8 Antibodies Can Trigger CD8+ T Cell Effector Function in the Absence of TCR Engagement and Improve Peptide–MHCI Tetramer Staining

Clement, Mathew; Ladell, Kristin; Makinde, Julia; Miles, John J.; Edwards, Emily S.J.; Dolton, Garry; Williams, Tamsin; Schauenburg, Andrea J. A.; Cole, David K.; Lauder, Sarah N.; Gallimore, Awen; Godkin, Andrew; Burrows, Scott R.; Price, David A.; Sewell, Andrew K.; Wooldridge, Linda

doi:10.4049/jimmunol.1003941

Cited by 35 publications

(48 citation statements)

References 59 publications

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“…Ten human CD8 + T‐cell clones spanning eight different specificities were used in this study (Table 1). The index peptides for the following CD8 + T‐cell clones are derived from viral proteins: E7NLV, SB16, SB12, ALF3, 41 SB14, 42 SB27, 43 003 44 and 868 44 . The index peptides for the remaining two CD8 + T‐cell clones, ILA1 45 and MEL5, 46 are derived from human self proteins.…”

Section: Methodsmentioning

confidence: 99%

Identification of human viral protein‐derived ligands recognized by individual MHCI‐restricted T‐cell receptors

et al. 2016

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Evidence indicates that autoimmunity can be triggered by virus-specific CD8+ T cells that crossreact with self-derived peptide epitopes presented on the cell surface by major histocompatibility complex class I (MHCI) molecules. Identification of the associated viral pathogens is challenging because individual T-cell receptors can potentially recognize up to a million different peptides. Here, we generate peptide length-matched combinatorial peptide library (CPL) scan data for a panel of virus-specific CD8+ T-cell clones spanning different restriction elements and a range of epitope lengths. CPL scan data drove a protein database search limited to viruses that infect humans. Peptide sequences were ranked in order of likelihood of recognition. For all anti-viral CD8+ T-cell clones examined in this study, the index peptide was either the top-ranked sequence or ranked as one of the most likely sequences to be recognized. Thus, we demonstrate that anti-viral CD8+ T-cell clones are highly focused on their index peptide sequence and that ‘CPL-driven database searching' can be used to identify the inciting virus-derived epitope for a given CD8+ T-cell clone. Moreover, to augment access to CPL-driven database searching, we have created a publicly accessible webtool. Application of these methodologies in the clinical setting may clarify the role of viral pathogens in the etiology of autoimmune diseases.

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Section: Methodsmentioning

confidence: 99%

Identification of human viral protein‐derived ligands recognized by individual MHCI‐restricted T‐cell receptors

et al. 2016

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“…49 Also OKT8-induced effector functions occur in absence of cytokine release. 30 Taken together, it is probable that at least 2 mechanisms contribute to the enhanced tumor cell killing induced by CD8-LV: (1) activation of effector functions by binding of the displayed OKT8-derived scFv molecules to CD8 on the surface of CD8 ϩ T cells via multiple contacts; and (2) up-regulation of CD8 surface expression in a small subpopulation of TCR ϩ cells. Accordingly, CD8-LV-transduced T cells would better stabilize the TCR/p-MHC complex and reduce the TCR-dependent activation threshold, leading to a stronger T-cell activation, more GrB and perforin production, and more efficient tumor cell lysis compared with T cells transduced by the conventional lentiviral vector.…”

Section: Discussionmentioning

confidence: 99%

“…30 Although a monovalent Fab fragment of OKT8 failed to activate CD8 ϩ T cells, the corresponding bivalent F(abЈ) 2 fragment retained some ability to enhance pMHCI tetramer staining. 30 This suggests that for activation the Fc part of the antibody itself is not essential, whereas multiple CD8 contacts are indeed important. Lentiviral vectors produced in packaging cells can contain approximately 100 envelope proteins per particle.…”

Section: Discussionmentioning

confidence: 99%

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T-cell receptor gene transfer exclusively to human CD8+ cells enhances tumor cell killing

Zhou

Schneider

Edes

et al. 2012

Blood

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Transfer of tumor-specific T-cell receptor (TCR) genes into patient T cells is a promising strategy in cancer immunotherapy. We describe here a novel vector (CD8-LV) derived from lentivirus, which delivers genes exclusively and specifically to CD8 ؉ cells. CD8-LV mediated stable in vitro and in vivo reporter gene transfer as well as efficient transfer of genes encoding TCRs recognizing the melanoma antigen tyrosinase. Strikingly, T cells genetically modified with CD8-LV killed melanoma cells reproducibly more efficiently than CD8 ؉ cells transduced with a conventional lentiviral vector. Neither TCR expression levels, nor the rate of activation-induced death of transduced cells differed between both vector types. Instead, CD8-LV transduced cells showed increased granzyme B and perforin levels as well as an up-regulation of CD8 surface expression in a small subpopulation of cells. Thus, a possible mechanism for CD8-LV enhanced tumor cell killing may be based on activation of the effector functions of CD8 ؉ T cells by the vector particle displaying OKT8-derived CD8-scFv and an increase of the surface density of CD8, which functions as coreceptor for tumor-cell recognition. CD8-LV represents a powerful novel vector for TCR gene therapy and other applications in immunotherapy and IntroductionIn the human body, a vast diversity of immune cells constantly patrols the blood stream and tissues to protect from invaders. Each type of these immune cells fulfills different functions. Genetic modification of these cells is a key technology to elucidate their physiologic functions and to develop novel therapeutic strategies. Among the different types of gene vector systems available, ␥-retroviral and lentiviral vectors (LVs) have become state-of-theart technology for lymphocyte gene transfer. [1][2][3] Failure to distinguish between subtypes of cells and thereby transferring genes to both target and nontarget cells is a limitation of vector systems currently in use. Selective and specific delivery of transgenes into particular types of lymphocytes is highly desirable for immunotherapy and gene therapy. Although few attempts have been undertaken to retarget LVs to CD3 ϩ T cells, 4 the transduction of subpopulations or even the transfer of therapeutic genes by such targeting vectors has not been described. In addition, no targeting vector specific for CD8 ϩ T cells has been described. CD8 ϩ T cells are among the most important immune cell types and also a primary target for immunotherapy because of their capacity to directly engage and kill pathogen infected cells or tumor cells. 5 Adoptive transfer of tumor-specific T cells is a promising strategy of directed tumor cell killing, which is currently under investigation in clinical trials worldwide. 6-9 Tumor specificity is provided by an antigen receptor, which can be natural (T-cell receptor; TCR) or engineered (chimeric antigen receptor, CAR). Whereas TCR gene-modified T cells recognize peptide-major histocompatibility complex (pMHC), CAR recognize antigen in an MHC-independen...

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“…1). Moreover, the unique property of OKT8 of inducing effector functions of CD8 + cells 10 suggests that the multiple OKT8-derived scFv/CD8 contacts formed during the entry of CD8-LV particles into CD8 + effector cells likewise trigger the activation of effector functions and enhance the killing activity of CD8-LV-transduced cells (Fig. 1).…”

mentioning

confidence: 99%

Cell type specific gene delivery by lentiviral vectors

Zhou

Buchholz²

2013

OncoImmunology

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Anti-CD8 Antibodies Can Trigger CD8+ T Cell Effector Function in the Absence of TCR Engagement and Improve Peptide–MHCI Tetramer Staining

Cited by 35 publications

References 59 publications

Identification of human viral protein‐derived ligands recognized by individual MHCI‐restricted T‐cell receptors

Identification of human viral protein‐derived ligands recognized by individual MHCI‐restricted T‐cell receptors

T-cell receptor gene transfer exclusively to human CD8+ cells enhances tumor cell killing

Cell type specific gene delivery by lentiviral vectors

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