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Making the most of major histocompatibility complex molecule multimers: applications in type 1 diabetes.

Gojanovich GS, Hess PR - Clin. Dev. Immunol. (2012)

Bottom Line: The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations.Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease.This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences and Immunology Program, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USA.

ABSTRACT
Classical major histocompatibility complex (MHC) class I and II molecules present peptides to cognate T-cell receptors on the surface of T lymphocytes. The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations. In type 1 diabetes (T1D), CD8+ cytotoxic T lymphocytes, in conjunction with CD4+ T helper cells, destroy the insulin-producing β cells within the pancreatic islets of Langerhans. Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease. By administering pMHC multimers coupled to fluorophores, nanoparticles, or toxic moieties, researchers have demonstrated the ability to enumerate, track, and delete diabetogenic T-cell clonotypes that are, at least in part, responsible for insulitis; some studies even delay or prevent diabetes onset in the murine model of T1D. This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.

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Schematic representation of the effects of toxic pMHCI tetramer administration to NOD mice. Clockwise from upper left: toxic moieties, such as saporin, can be linked to pMHCI multimers that are specific for diabetogenic CTL before being delivered to prediabetic NOD mice. Toxic pMHCI tetramers can access inflamed islets where cognate CTLs are present. Insulitis involves numerous autoreactive immune cell subsets that act in concert to potentiate diabetogenic CTL and destroy β cells. However, pMHCI multimers can deliver saporin to diabetogenic CTL clonotypes and induce apoptosis in an antigen-specific manner. Cognate TCR interacting with saporin-conjugated pMHCI results in uptake of the tetramer into the lysosome of the CTL. In the lysosome, the toxic pMHCI tetramer is disassociated, allowing the freed saporin molecules to escape these organelles. Saporin is a potent ribosome-inactivating toxin that can perform multiple rounds of ribosome disabling, ultimately leading to apoptosis of the CTL and therein preventing further β cell damage by the targeted diabetogenic clonotype.
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fig1: Schematic representation of the effects of toxic pMHCI tetramer administration to NOD mice. Clockwise from upper left: toxic moieties, such as saporin, can be linked to pMHCI multimers that are specific for diabetogenic CTL before being delivered to prediabetic NOD mice. Toxic pMHCI tetramers can access inflamed islets where cognate CTLs are present. Insulitis involves numerous autoreactive immune cell subsets that act in concert to potentiate diabetogenic CTL and destroy β cells. However, pMHCI multimers can deliver saporin to diabetogenic CTL clonotypes and induce apoptosis in an antigen-specific manner. Cognate TCR interacting with saporin-conjugated pMHCI results in uptake of the tetramer into the lysosome of the CTL. In the lysosome, the toxic pMHCI tetramer is disassociated, allowing the freed saporin molecules to escape these organelles. Saporin is a potent ribosome-inactivating toxin that can perform multiple rounds of ribosome disabling, ultimately leading to apoptosis of the CTL and therein preventing further β cell damage by the targeted diabetogenic clonotype.

Mentions: While pMHCI-mediated expansion of islet-specific suppressor CTL appears to hold great promise for recent-onset T1D treatment, it is plausible that such therapies would be ineffective for modulating all islet-specific CTL, such as memory-like CTL clonotypes found in long-term diabetics. Therefore, the use of pMHCI multimers to specifically ablate diabetogenic clonotypes may be advantageous for islet transplantation, since islet antigen-specific CTL clonotypes mediate recurrence of T1D [61–65]. The first description of a toxic pMHCI multimer was published by Yuan et al. [46] and utilized tetramers conjugated to a radionuclide, which eliminated antigen-specific CTL in vitro. Using saporin as a toxic agent, we demonstrated the ablation of transgenic CD8+ T cells in an antigen-specific manner in vitro and in vivo [66]. Our group then demonstrated that toxic pMHCI administration killed IGRP-reactive CTL transferred into T-cell deficient NOD.scid recipients [53]. Toxic tetramer treatment also resulted in the rapid reduction of cognate CTL (>75% eliminated 72 hours post treatment) from the spleens of lymphoreplete NOD recipients. Furthermore, toxic tetramer-treated WT NOD mice showed delayed onset of T1D (3 of 10 treated animals were euglycemic at study completion, compared to none among the PBS-injected mice), and lasting depletion (for 44 weeks after treatment) of cognate CTL from the islets. Lastly, treatment was initiated at 8 weeks of age, a time point when the autoimmune response is well underway in NOD mice, indicating that this strategy may be applicable to the prevention of disease progression. Figure 1 depicts parenteral administration of pMHCI tetramers, conjugated to the ribosome-inactivating molecule saporin, which can diffuse into pancreatic tissues and interact with diabetogenic CTL at the site of inflammation. Binding of toxin-linked pMHCI to the cognate TCR results in the uptake of the multimer into the lysosomes of the T cell, where the toxin is then cleaved from the tetramer. Released saporin escapes into the cytosol, inactivating ribosomes and thereby killing the CTL, which prevents β cell destruction. Thus, immunomodulation and ablation strategies utilizing pMHCI multimers may be suitable for preventing progression or recurrence of T1D.


Making the most of major histocompatibility complex molecule multimers: applications in type 1 diabetes.

Gojanovich GS, Hess PR - Clin. Dev. Immunol. (2012)

Schematic representation of the effects of toxic pMHCI tetramer administration to NOD mice. Clockwise from upper left: toxic moieties, such as saporin, can be linked to pMHCI multimers that are specific for diabetogenic CTL before being delivered to prediabetic NOD mice. Toxic pMHCI tetramers can access inflamed islets where cognate CTLs are present. Insulitis involves numerous autoreactive immune cell subsets that act in concert to potentiate diabetogenic CTL and destroy β cells. However, pMHCI multimers can deliver saporin to diabetogenic CTL clonotypes and induce apoptosis in an antigen-specific manner. Cognate TCR interacting with saporin-conjugated pMHCI results in uptake of the tetramer into the lysosome of the CTL. In the lysosome, the toxic pMHCI tetramer is disassociated, allowing the freed saporin molecules to escape these organelles. Saporin is a potent ribosome-inactivating toxin that can perform multiple rounds of ribosome disabling, ultimately leading to apoptosis of the CTL and therein preventing further β cell damage by the targeted diabetogenic clonotype.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368179&req=5

fig1: Schematic representation of the effects of toxic pMHCI tetramer administration to NOD mice. Clockwise from upper left: toxic moieties, such as saporin, can be linked to pMHCI multimers that are specific for diabetogenic CTL before being delivered to prediabetic NOD mice. Toxic pMHCI tetramers can access inflamed islets where cognate CTLs are present. Insulitis involves numerous autoreactive immune cell subsets that act in concert to potentiate diabetogenic CTL and destroy β cells. However, pMHCI multimers can deliver saporin to diabetogenic CTL clonotypes and induce apoptosis in an antigen-specific manner. Cognate TCR interacting with saporin-conjugated pMHCI results in uptake of the tetramer into the lysosome of the CTL. In the lysosome, the toxic pMHCI tetramer is disassociated, allowing the freed saporin molecules to escape these organelles. Saporin is a potent ribosome-inactivating toxin that can perform multiple rounds of ribosome disabling, ultimately leading to apoptosis of the CTL and therein preventing further β cell damage by the targeted diabetogenic clonotype.
Mentions: While pMHCI-mediated expansion of islet-specific suppressor CTL appears to hold great promise for recent-onset T1D treatment, it is plausible that such therapies would be ineffective for modulating all islet-specific CTL, such as memory-like CTL clonotypes found in long-term diabetics. Therefore, the use of pMHCI multimers to specifically ablate diabetogenic clonotypes may be advantageous for islet transplantation, since islet antigen-specific CTL clonotypes mediate recurrence of T1D [61–65]. The first description of a toxic pMHCI multimer was published by Yuan et al. [46] and utilized tetramers conjugated to a radionuclide, which eliminated antigen-specific CTL in vitro. Using saporin as a toxic agent, we demonstrated the ablation of transgenic CD8+ T cells in an antigen-specific manner in vitro and in vivo [66]. Our group then demonstrated that toxic pMHCI administration killed IGRP-reactive CTL transferred into T-cell deficient NOD.scid recipients [53]. Toxic tetramer treatment also resulted in the rapid reduction of cognate CTL (>75% eliminated 72 hours post treatment) from the spleens of lymphoreplete NOD recipients. Furthermore, toxic tetramer-treated WT NOD mice showed delayed onset of T1D (3 of 10 treated animals were euglycemic at study completion, compared to none among the PBS-injected mice), and lasting depletion (for 44 weeks after treatment) of cognate CTL from the islets. Lastly, treatment was initiated at 8 weeks of age, a time point when the autoimmune response is well underway in NOD mice, indicating that this strategy may be applicable to the prevention of disease progression. Figure 1 depicts parenteral administration of pMHCI tetramers, conjugated to the ribosome-inactivating molecule saporin, which can diffuse into pancreatic tissues and interact with diabetogenic CTL at the site of inflammation. Binding of toxin-linked pMHCI to the cognate TCR results in the uptake of the multimer into the lysosomes of the T cell, where the toxin is then cleaved from the tetramer. Released saporin escapes into the cytosol, inactivating ribosomes and thereby killing the CTL, which prevents β cell destruction. Thus, immunomodulation and ablation strategies utilizing pMHCI multimers may be suitable for preventing progression or recurrence of T1D.

Bottom Line: The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations.Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease.This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences and Immunology Program, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USA.

ABSTRACT
Classical major histocompatibility complex (MHC) class I and II molecules present peptides to cognate T-cell receptors on the surface of T lymphocytes. The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations. In type 1 diabetes (T1D), CD8+ cytotoxic T lymphocytes, in conjunction with CD4+ T helper cells, destroy the insulin-producing β cells within the pancreatic islets of Langerhans. Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease. By administering pMHC multimers coupled to fluorophores, nanoparticles, or toxic moieties, researchers have demonstrated the ability to enumerate, track, and delete diabetogenic T-cell clonotypes that are, at least in part, responsible for insulitis; some studies even delay or prevent diabetes onset in the murine model of T1D. This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.

Show MeSH
Related in: MedlinePlus