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Presentation of a T cell receptor antagonist peptide by immunoglobulins ablates activation of T cells by a synthetic peptide or proteins requiring endocytic processing.

Legge KL, Min B, Potter NT, Zaghouani H - J. Exp. Med. (1997)

Bottom Line: Free PLP-LR abolishes T cell activation when the stimulator is free PLP1 peptide, but has no measurable effect when the stimulator is the native PLP or Ig-PLP1.Free PLP-LR coadministered with Ig-PLP1 has no effect on the T cell response to PLP1.Efficient endocytic presentation of antagonist peptides, which is the fundamental event for either mechanism, may be critical for reversal of spontaneous T cell-mediated autoimmune diseases where incessant endocytic antigen processing could be responsible for T cell aggressivity.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Tennessee, Knoxville 37996, USA.

ABSTRACT
T cell receptor (TCR) antagonism is being considered for inactivation of aggressive T cells and reversal of T cell-mediated autoimmune diseases. TCR antagonist peptides silence aggressive T cells and reverse experimental allergic encephalomyelitis induced with free peptides. However, it is not clear whether free antagonist peptides could reverse natural disease where the antigen is presumably available for endocytic processing and peptides gain access to newly synthesized class II MHC molecules. Using an efficient endocytic presentation system, we demonstrate that a proteolipid protein (PLP) TCR antagonist peptide (PLP-LR) presented on an Ig molecule (Ig-PLP-LR) abrogates the activation of T cells stimulated with free encephalitogenic PLP peptide (PLP1), native PLP, or an Ig containing PLP1 peptide (Ig-PLP1). Free PLP-LR abolishes T cell activation when the stimulator is free PLP1 peptide, but has no measurable effect when the stimulator is the native PLP or Ig-PLP1. In vivo, Ig-PLP1 induces a T cell response to PLP1 peptide. However, when coadministered with Ig-PLP-LR, the response to PLP1 peptide is markedly reduced whereas the response to PLP-LR is normal. Free PLP-LR coadministered with Ig-PLP1 has no effect on the T cell response to PLP1. These findings indicate that endocytic presentation of an antagonist peptide by Ig outcompete both external and endocytic agonist peptides whereas free antagonist hinders external but not endocytic agonist peptide. Direct contact with antagonist ligand and/or trans-regulation by PLP-LR-specific T cells may be the operative mechanism for Ig-PLP-LR-mediated downregulation of PLP1-specific T cells in vivo. Efficient endocytic presentation of antagonist peptides, which is the fundamental event for either mechanism, may be critical for reversal of spontaneous T cell-mediated autoimmune diseases where incessant endocytic antigen processing could be responsible for T cell aggressivity.

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In vivo priming of PLP1-specific T cells by Ig-PLP1. Mice  were immunized subcutaneously with 50 μg of Ig-PLP1 in CFA as described in Materials and Methods, and after 10 d, cells from the lymph  nodes (a) and spleen (b) were tested for specific proliferation to PLP1. The  indicated results are those obtained with 4 × 105 lymph node cells/well  and 10 × 105 spleen cells/well. The stimulators PLP1 and PLP2 were  used at 15 μg/ml and PPD was used at 5 μg/ml. Each value represents  the mean ± SD of triplicates after deduction of BG cpms obtained with  no stimulator in the media. The cpm values obtained with PPD for each  mouse exceeded the cpm values obtained with PLP1 by 20–60% dependent upon each mouse. Similar results were obtained when mice were  immunized with 150 μg of Ig-PLP1 per mouse (not shown). Note that  some mice show proliferation with PLP2. This may be because this peptide is presented by I-As, like PLP1, and low affinity cells could bind to it.
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Figure 7: In vivo priming of PLP1-specific T cells by Ig-PLP1. Mice were immunized subcutaneously with 50 μg of Ig-PLP1 in CFA as described in Materials and Methods, and after 10 d, cells from the lymph nodes (a) and spleen (b) were tested for specific proliferation to PLP1. The indicated results are those obtained with 4 × 105 lymph node cells/well and 10 × 105 spleen cells/well. The stimulators PLP1 and PLP2 were used at 15 μg/ml and PPD was used at 5 μg/ml. Each value represents the mean ± SD of triplicates after deduction of BG cpms obtained with no stimulator in the media. The cpm values obtained with PPD for each mouse exceeded the cpm values obtained with PLP1 by 20–60% dependent upon each mouse. Similar results were obtained when mice were immunized with 150 μg of Ig-PLP1 per mouse (not shown). Note that some mice show proliferation with PLP2. This may be because this peptide is presented by I-As, like PLP1, and low affinity cells could bind to it.

Mentions: As demonstrated in Fig. 7, when individual mice were immunized with Ig-PLP1, they developed strong PLP1-specific T cell responses in the lymph nodes (Fig. 7 a) and even significant proliferation in the spleen (Fig. 7 b). Consequently, Ig-PLP1, which is presumably processed in endocytic vacuoles like autoantigens, provides a relevant system to assay the antagonists Ig-PLP-LR and PLP-LR peptide for in vivo T cell antagonism.


Presentation of a T cell receptor antagonist peptide by immunoglobulins ablates activation of T cells by a synthetic peptide or proteins requiring endocytic processing.

Legge KL, Min B, Potter NT, Zaghouani H - J. Exp. Med. (1997)

In vivo priming of PLP1-specific T cells by Ig-PLP1. Mice  were immunized subcutaneously with 50 μg of Ig-PLP1 in CFA as described in Materials and Methods, and after 10 d, cells from the lymph  nodes (a) and spleen (b) were tested for specific proliferation to PLP1. The  indicated results are those obtained with 4 × 105 lymph node cells/well  and 10 × 105 spleen cells/well. The stimulators PLP1 and PLP2 were  used at 15 μg/ml and PPD was used at 5 μg/ml. Each value represents  the mean ± SD of triplicates after deduction of BG cpms obtained with  no stimulator in the media. The cpm values obtained with PPD for each  mouse exceeded the cpm values obtained with PLP1 by 20–60% dependent upon each mouse. Similar results were obtained when mice were  immunized with 150 μg of Ig-PLP1 per mouse (not shown). Note that  some mice show proliferation with PLP2. This may be because this peptide is presented by I-As, like PLP1, and low affinity cells could bind to it.
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Related In: Results  -  Collection

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Figure 7: In vivo priming of PLP1-specific T cells by Ig-PLP1. Mice were immunized subcutaneously with 50 μg of Ig-PLP1 in CFA as described in Materials and Methods, and after 10 d, cells from the lymph nodes (a) and spleen (b) were tested for specific proliferation to PLP1. The indicated results are those obtained with 4 × 105 lymph node cells/well and 10 × 105 spleen cells/well. The stimulators PLP1 and PLP2 were used at 15 μg/ml and PPD was used at 5 μg/ml. Each value represents the mean ± SD of triplicates after deduction of BG cpms obtained with no stimulator in the media. The cpm values obtained with PPD for each mouse exceeded the cpm values obtained with PLP1 by 20–60% dependent upon each mouse. Similar results were obtained when mice were immunized with 150 μg of Ig-PLP1 per mouse (not shown). Note that some mice show proliferation with PLP2. This may be because this peptide is presented by I-As, like PLP1, and low affinity cells could bind to it.
Mentions: As demonstrated in Fig. 7, when individual mice were immunized with Ig-PLP1, they developed strong PLP1-specific T cell responses in the lymph nodes (Fig. 7 a) and even significant proliferation in the spleen (Fig. 7 b). Consequently, Ig-PLP1, which is presumably processed in endocytic vacuoles like autoantigens, provides a relevant system to assay the antagonists Ig-PLP-LR and PLP-LR peptide for in vivo T cell antagonism.

Bottom Line: Free PLP-LR abolishes T cell activation when the stimulator is free PLP1 peptide, but has no measurable effect when the stimulator is the native PLP or Ig-PLP1.Free PLP-LR coadministered with Ig-PLP1 has no effect on the T cell response to PLP1.Efficient endocytic presentation of antagonist peptides, which is the fundamental event for either mechanism, may be critical for reversal of spontaneous T cell-mediated autoimmune diseases where incessant endocytic antigen processing could be responsible for T cell aggressivity.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Tennessee, Knoxville 37996, USA.

ABSTRACT
T cell receptor (TCR) antagonism is being considered for inactivation of aggressive T cells and reversal of T cell-mediated autoimmune diseases. TCR antagonist peptides silence aggressive T cells and reverse experimental allergic encephalomyelitis induced with free peptides. However, it is not clear whether free antagonist peptides could reverse natural disease where the antigen is presumably available for endocytic processing and peptides gain access to newly synthesized class II MHC molecules. Using an efficient endocytic presentation system, we demonstrate that a proteolipid protein (PLP) TCR antagonist peptide (PLP-LR) presented on an Ig molecule (Ig-PLP-LR) abrogates the activation of T cells stimulated with free encephalitogenic PLP peptide (PLP1), native PLP, or an Ig containing PLP1 peptide (Ig-PLP1). Free PLP-LR abolishes T cell activation when the stimulator is free PLP1 peptide, but has no measurable effect when the stimulator is the native PLP or Ig-PLP1. In vivo, Ig-PLP1 induces a T cell response to PLP1 peptide. However, when coadministered with Ig-PLP-LR, the response to PLP1 peptide is markedly reduced whereas the response to PLP-LR is normal. Free PLP-LR coadministered with Ig-PLP1 has no effect on the T cell response to PLP1. These findings indicate that endocytic presentation of an antagonist peptide by Ig outcompete both external and endocytic agonist peptides whereas free antagonist hinders external but not endocytic agonist peptide. Direct contact with antagonist ligand and/or trans-regulation by PLP-LR-specific T cells may be the operative mechanism for Ig-PLP-LR-mediated downregulation of PLP1-specific T cells in vivo. Efficient endocytic presentation of antagonist peptides, which is the fundamental event for either mechanism, may be critical for reversal of spontaneous T cell-mediated autoimmune diseases where incessant endocytic antigen processing could be responsible for T cell aggressivity.

Show MeSH
Related in: MedlinePlus