Artificial antigen-presenting constructs efficiently stimulate minor histocompatibility antigen–specific cytotoxic T lymphocytes

Oosten, L.; Blokland, E.; Halteren, Astrid G. S. van; Curtsinger, Julie; Mescher, Matthew F.; Falkenburg, J.H. Frederik; Mutis, Tuna; Goulmy, Els

doi:10.1182/blood-2003-07-2461

Cited by 37 publications

(22 citation statements)

References 23 publications

(18 reference statements)

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“…HLA-A*0201 tetramers were generated with each of these peptides using UV peptide exchange technology (45). In addition, these peptide-MHC class I complexes were attached to latex beads to generate artificial Ag-presenting beads as described previously (46).…”

Section: Peptides and Peptide-mhc Class I Tetramersmentioning

confidence: 99%

Allogeneic HLA-A*02–Restricted WT1-Specific T Cells from Mismatched Donors Are Highly Reactive but Show Off-Target Promiscuity

Falkenburg

Melenhorst

Meent

et al. 2011

The Journal of Immunology

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T cells recognizing tumor-associated Ags such as Wilms tumor protein (WT1) are thought to exert potent antitumor reactivity. However, no consistent high-avidity T cell responses have been demonstrated in vaccination studies with WT1 as target in cancer immunotherapy. The aim of this study was to investigate the possible role of negative thymic selection on the avidity and specificity of T cells directed against self-antigens. T cell clones directed against the HLA-A*0201–binding WT1126–134 peptide were generated from both HLA-A*02–positive (self-HLA–restricted) and HLA-A*02–negative [nonself (allogeneic) HLA [allo-HLA]-restricted] individuals by direct ex vivo isolation using tetramers or after in vitro priming and selection. The functional avidity and specificity of these T cell clones was analyzed in-depth. Self-HLA–restricted WT1-specific clones only recognized WT1126–134 with low avidities. In contrast, allo-HLA–restricted WT1 clones exhibited profound functional reactivity against a multitude of HLA-A*02–positive targets, even in the absence of exogenously loaded WT1 peptide, indicative of Ag-binding promiscuity. To characterize this potential promiscuity, reactivity of the T cell clones against 400 randomly selected HLA-A*0201–binding peptides was investigated. The self-HLA–restricted WT1-specific T cell clones only recognized the WT1 peptide. In contrast, the allo-HLA–restricted WT1-reactive clones recognized besides WT1 various other HLA-A*0201–binding peptides. In conclusion, allogeneic HLA-A*02–restricted WT1-specific T cells isolated from mismatched donors may be more tumor-reactive than their autologous counterparts but can show specific off-target promiscuity of potential clinical importance. As a result of this, administration of WT1-specific T cells generated from HLA-mismatched donors should be performed with appropriate precautions against potential off-target effects.

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Section: Peptides and Peptide-mhc Class I Tetramersmentioning

confidence: 99%

Allogeneic HLA-A*02–Restricted WT1-Specific T Cells from Mismatched Donors Are Highly Reactive but Show Off-Target Promiscuity

Falkenburg

Melenhorst

Meent

et al. 2011

The Journal of Immunology

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“…The biotinylated recombinant HLA class I/peptide complexes were generated as described previously (33), using the peptides listed in Table II. The aAPCs were only used for functional assays if ligand densities were within the range previously established to be optimal for T cell stimulation, as established by FACS analysis (32).…”

Section: Preparation Of Aapcsmentioning

confidence: 99%

“…The aAPCs coated with HLA class I/peptide complexes, CD80 and CD54 were prepared as described previously (32). In brief, polystyrene sulfate latex beads (Interfacial Dynamics) were incubated sequentially with streptavidin (10 g/10 7 beads) (Molecular Probes), recombinant human CD54/Fc-chimera (0.5 g/10 7 beads) and CD80/Fc-chimera (0.25 g/10 7 beads) (both from R&D Systems), 1% human albumin (Sanquin), and biotinylated HLA class I/peptide complexes (0.5 g/10 7 beads).…”

Section: Preparation Of Aapcsmentioning

confidence: 99%

Investigation of Peptide Involvement in T Cell Allorecognition Using Recombinant HLA Class I Multimers

Whitelegg

Oosten²,

Jordan³

et al. 2005

The Journal of Immunology

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Alloreactive T cells are involved in injurious graft rejection and graft-vs-host disease. However, they can also evoke beneficial responses to tumor Ags restricted by foreign MHC molecules. Manipulation of these alloreactivities requires information on the basis of T cell allorecognition. The vigorous T cell response to foreign MHC molecules may arise from peptide-independent recognition of polymorphic residues of foreign MHC molecules or peptide-specific recognition of novel peptides presented by foreign MHC molecules. We investigated CD8+ T cell allorecognition using recombinant HLA class I/peptide complexes. Peptide-specific allorecognition was examined using tetramers of HLA-A*0201 representing five peptides derived from ubiquitously expressed self-proteins that are known to bind endogenously to HLA-A*0201. Distinct subsets of CD8+ T cells specific for each HLA-A*0201/peptide combination were detected within four in vitro-stimulated T cell populations specific for foreign HLA-A*0201. Peptide-independent allorecognition was investigated using artificial Ag-presenting constructs (aAPCs) coated with CD54, CD80, and functional densities of a single HLA-A*0201/peptide combination for four different peptides. None of the four T cell populations specific for foreign HLA-A*0201 were stimulated by the aAPCs, whereas they did produce IFN-γ upon stimulation with cells naturally expressing HLA-A*0201. Thus, aAPCs did not stimulate putative peptide-independent allorestricted T cells. The results show that these alloreactive populations comprise subsets of T cells, each specific for a self-peptide presented by foreign class I molecules, with no evidence of peptide-independent components.

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“…Mouse fibroblasts yielded on average 30 × 10 6 specific CTLs, however much higher T-cell doses may be required in the clinic (18)(19)(20). The bead-based systems also have some drawbacks, including high cost of the beads, the labor-intensive process of removing the beads from the culture before infusion, and the inability of these beads to expand CD8 + T cells (21)(22)(23)(24). The artificial liposomes and exsomes show some potential for T-cell expansion, but the high cost, long-time procedure and biosafety should be considered for clinical therapy (25,26).…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of a Cell Based Artificial Antigen-Presenting Cell for Expansion and Activation of CD8+ T Cells Ex Vivo

et al. 2008

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Artificial antigen-presenting constructs efficiently stimulate minor histocompatibility antigen–specific cytotoxic T lymphocytes

Cited by 37 publications

References 23 publications

Allogeneic HLA-A*02–Restricted WT1-Specific T Cells from Mismatched Donors Are Highly Reactive but Show Off-Target Promiscuity

Allogeneic HLA-A*02–Restricted WT1-Specific T Cells from Mismatched Donors Are Highly Reactive but Show Off-Target Promiscuity

Investigation of Peptide Involvement in T Cell Allorecognition Using Recombinant HLA Class I Multimers

Establishment and Characterization of a Cell Based Artificial Antigen-Presenting Cell for Expansion and Activation of CD8+ T Cells Ex Vivo

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