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The Journal of Immunology, 1999, 163: 2363-2367.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: N-Hydroxy Peptides: A New Class of TCR Antagonists1

Sascha Hin*, Claus Zabel*, Alberto Bianco2,{dagger}, Günther Jung{dagger} and Peter Walden3,*

* Department of Dermatology, Medical Faculty Charité, Humboldt University, Berlin, Germany; and {dagger} Institute for Organic Chemistry, University of Tübingen, Tübingen, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
TCR antagonists are altered T cell epitopes that specifically inactivate T cells. Commonly, they are derived from agonists by amino acid side chain replacement at positions accessible to the TCR. In this paper we report for the first time that a main chain N-hydroxylation, which is not exposed at the surface of the MHC peptide complex, renders an agonist into an antagonist. These mimotopes are a new, yet undescribed class of TCR antagonists. The antagonists are about 100 times more potent than an unrelated peptide that competes for binding to the MHC molecule. The novel main chain modification enhances biostability and maintains side chain constitution and thus opens new prospects for the use of TCR antagonists in the treatment of pathological immune reactions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Aberrant immune reactions such as allergies or autoimmune diseases are often mediated by T lymphocytes. The immune suppressive drugs frequently used to alleviate the symptoms have severe side effects such as increased susceptibility toward infectious diseases or even malignancies. Such side effects occur especially after prolonged treatment (1). Reagents that specifically inhibit the pathologic T cells but do not affect the immune system in general would provide new options for the treatment of such diseases. TCR antagonists have great potentials in this direction (2, 3, 4, 5). These antagonists are specifically recognized by the T cells but block their activation even in the presence of the agonist, i.e., the cognate epitope.

The initial event leading to the activation of T cells is the recognition of complexes of peptides and MHC molecules by the TCR (6). Antagonists are usually derived from known epitopes by amino acid replacements (7) that introduce charge or bulky size modification of peptide side chains accessible to the TCR. A recent report shows that modifications in haptens covalently attached to the peptide’s side chain can also create antagonists (8). In this paper we describe an antagonist that was created by a single main chain N-hydroxylation of a known epitope. In our search for epitope mimetics, we tested N-hydroxylated peptide derivatives of the T cell epitope SIINFEKL for their potential to bind to and stabilize the MHC molecule and to stimulate T cells. Such compounds can become highly valuable for clinical applications as the N-hydroxylation of the peptide bond confers enhanced stability to enzymatic degradation (9) and increased bioavailability. Low resistance to proteolysis has so far limited the application of peptides in vivo. Because the side chain constitution of the N-hydroxy peptides remain unaltered, a high specificity of the antagonists is expected.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Peptides and N-hydroxy peptides

SIINFEKL (OVA257–264) (10) and RGYVYQGL (VSV-8; VSV-NP52–59) (11), SIINFEDL (7), and the glycine variants of SIINFEKL and the N-hydroxy peptides were synthesized in our laboratories at the University of Tübingen, or by ECHAZ Microcollections (Tübingen, Germany), as described previously (9).

Cell lines

The SIINFEKL-specific cytotoxic T cell clone 4G3 (12) was cultured in DMEM and 10% FCS, the usual supplements, and 4% conditioned medium of Con A (5 µg/ml) stimulated rat spleen cells as a source of growth factors. The cells were restimulated biweekly with irradiated OVA expressing EG7.OVA cells (13), RMA (14), and RMA-S (15) T lymphoma cells were cultured in DMEM and 5% FCS. Short-term SIINFEKL-specific cytotoxic T cell lines were established from spleen cells of C57BL/6 mice primed by i.p. injection with 10 µg SIINFEKL, 20 µg Pam3-Cys-Ser Lys4, and 100 µg keyhole limpet hemocyanin (KLH; Calbiochem, Schwalbach, Germany) 9 days before, as described previously (16). The spleen cells were restimulated in vitro with 5 µg/ml SIINFEKL and 100 µg/ml KLH in {alpha}MEM without nucleotides (Life Technologies, Karlsruhe, Germany) for 5 days. Lymphoblast were harvested by Ficoll-Paque (Pharmacia, Freiburg, Germany) density centrifugation and cultured in the same medium without Ags for additional 9 days and then used for the assays.

Cytotoxicity assay

51Cr release assays were used to measure the stimulation of the T cell clone 4G3 (16). The thymoma cell line RMA used as target was labeled with 51Cr for 1 h, washed five times, and incubated in DMEM containing BSA (0.1%) with the peptides or peptide analogues for 1 h at 26°C in 96-well U-bottom plates. 4G3 cells were added at an E:T ratio of 5:1. After an incubation time of 5 h at 37°C, 51Cr released from the target cells was measured. Spontaneous release was below 10% in all experiments. Percent specific lysis was calculated as: [(experimental release - spontaneous release)/(total release - spontaneous release)] x 100. The effects of potential antagonist peptides on the activation of the CTL were tested by incubating the 51Cr-labeled target cells with a fixed concentration of agonist SIINFEKL (10 nM) together with the indicated concentrations of either glycine or N-hydroxy-glycine substituted peptide derivatives as described previously (9). The inhibitory capacity of antagonists was calculated from the oligomer concentration required for half-maximal inhibition of the T cells in relation to the corresponding concentration for the MHC competitor RGYVYQGL corrected for the different concentrations of these compounds required for half-maximal MHC stabilization.

MHC stabilization assay

H-2Kb binding of the oligomers was tested with stabilization assays as described in detail elsewhere (17). Briefly, peptide transporter-deficient RMA-S cells were incubated over night at 26°C to allow for the accumulation of peptide-free MHC class I molecules at the cell surfaces. These "empty" MHC molecules are only stable at 26°C and denature at 37°C. The peptides and N-hydroxy peptides were dissolved in DMSO at a concentration of 50 mM and diluted in DMEM with BSA (0.1%) to 50 or 500 µM, then titrated in serial dilutions and incubated with the RMA-S cells at 26°C. After 30 min, the cultures were exposed to 37°C for 45 min to induce denaturation of unligated MHC. Stable H-2Kb expressed on the cell surfaces served as an indicator for bound oligomer and was quantified by flow cytometry (FACScan, Becton Dickinson, Heidelberg, Germany) using the conformation sensitive monoclonal H-2Kb-specific Ab B8.24.3 (18) and a FITC-labeled goat anti-mouse Ab (Jackson ImmunoResearch, West Grove, PA). Ligand concentrations required for half-maximal H-2Kb stabilization were calculated after linearization of the data and linear regression as described earlier (17). All the assays included the original peptide SIINFEKL as control.

IFN-{gamma} assay

The T cells were incubated for 16 h at 37°C in a humidified atmosphere with 8% CO2 in the above-described culture medium with the peptides or peptide analogues. After this time the supernatants of the cultures were analyzed for IFN-{gamma} employing a sandwich ELISA with the mAb R4-6A2 as capture Ab and biotinylated AN-18.17.24 for detection. Recombinant mouse IFN-{gamma} was used as standard.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Main chain N-hydroxylated variants of the T cell epitope SIINFEKL

The effects of positional glycine substitutions and the corresponding main chain N-hydroxy modifications of the natural H-2Kb-restricted SIINFEKL (10) epitope on the activation of the CTL clone 4G3 were tested in cell-mediated cytolysis assays (Fig. 1Go). The peptides and peptidomimetics used are shown in Fig. 2Go. These oligomers are representatives of a complete positional glycine and N-hydroxy glycine scan. N-Hydroxy glycine was tolerated in all but one position (9). Of particular interest were positions 1, 4, 6 and 7 at which the side chains are exposed to the TCR (17, 19). P1G and P1G-OH both stimulated the T cell clone with about the same efficiency as the cognate peptide SIINFEKL. Similar results were obtained with P7G and P7G-OH (data not shown). The replacement of glutamate with glycine at position 6 abolished the stimulatory capacity of the peptide thus emphasizing the importance of the side chain at this position (19). The corresponding N-hydroxy derivative was equally inefficient. At position 4 divergent results were obtained with P4G being capable of inducing cytolysis efficiently, but its N-hydroxy variant was completely ineffective. The results indicate that the side chains at positions 1 and 4 are not directly involved in the activation of clone 4G3 in contrast to the side chain at position 6.



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  		FIGURE 1. Response of the H-2Kb-restricted CTL clone 4G3 to the main chain hydroxylated variants of its epitope SIINFEKL. Lysis of 5000 51Cr-labeled RMA cells was induced by peptides or peptide analogues in a 51Cr release assay. The tested oligomers were added at a concentration of 250 pM and titrated by serial 2-fold dilutions. The oligomers were: SIINFEKL (•), P1G ({square}), P1G-OH ({blacksquare}), P4G ({triangleup}), P4G-OH ({blacktriangleup}), P6G ({diamond}), and P6G-OH ({diamondsuit}). The E:T ratio was 5:1. The data are representative for four independent experiments and mean values of triplicates.

 


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  		FIGURE 2. Peptides and N-hydroxy peptides.

 
Stabilization of the MHC -I molecule by the N-hydroxylated peptides

To rule out the possibility that the lack of T cell stimulation by P4G-OH is caused by a decreased capacity to bind to H-2Kb, binding of the peptides and peptide analogues to the MHC molecule was analyzed with stabilization assays (Table IGo) (15, 17). P1G-OH binds to H-2Kb with about the same efficiency as SIINFEKL, whereas P1G is about 10 times less potent. P6G and P6G-OH both require the same concentration for half maximal stabilization of the MHC molecule and are 2-fold more potent than SIINFEKL. At position 4 the asparagine to glycine change does not alter the capacity of the peptide to bind to H-2Kb. P4G-OH binds even six times more efficiently. Thus, neither the lack of the side chain (Fig. 1Go) nor possible differences in presentation of the peptide analogue by the MHC molecule (Table IGo) can explain the failure of P4G, P6G, and P6G-OH to stimulate clone 4G3. These findings raise the possibility that P4G-OH confers a negative signal to the T cell.


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  		Table I. Binding of peptides and N-hydroxy derivatives to the MHC class I molecule H-2Kb

 
Antagonistic capacity of main chain N-hydroxylated peptides

To test the above possibility, the effects of the glycine containing peptides and their hydroxylated counterparts on SIINFEKL-induced cytolysis of target cells by 4G3 were investigated (Fig. 3Go). SIINFEDL, an established antagonist (7), was used as a control and compared with the unrelated H-2Kb binding peptide RGYVYQGL (11) which acts as a competitor for binding to the MHC molecule. Both inhibited 4G3 activation by SIINFEKL (Fig. 3GoA). SIINFEDL is 100 times more potent than RGYVYQGL, indicating that the inhibitory effect of SIINFEDL is not only due to competition for binding sites on the MHC molecules. Because P1G and P1G-OH act as agonists, no antagonistic effect can be seen (Fig. 3GoB). P6G and P6G-OH on the other hand are both antagonists with an inhibitory capacity of 210 and 100 in comparison to RGYVYQGL (Fig. 3GoD). P4G is an agonist and behaved like the position 1 variants. P4G-OH, however, was a potent antagonist and had the same efficiency as SIINFEDL (Fig. 3GoC). The inhibitory capacities were calculated on the basis of the concentration of the oligomer required for half-maximal inhibition of SIINFEKL-induced cytolysis of target cells (Fig. 3Go) corrected by the concentrations required for half-maximal stabilization of H-2Kb by the same oligomer (Table IGo). Compared with the MHC competitor peptide RGYVYQGL, higher inhibitory capacities of the antagonists SIINFEDL, P4G-OH, P6G, and P6G-OH indicate that these peptides and peptide analogues induced a negative signal in the T cell clone 4G3. The antagonistic effects of the oligomers were tested in the presence of 10 nM SIINFEKL, which is a saturating concentration for the induction of cytolysis by 4G3. For half maximal activation of 4G3 about 70 fM peptide is required (Fig. 1Go). Half-maximal inhibition of SIINFEKL-induced cytolysis is achieved at concentrations of 400 nM for SIINFEDL, 200 nM for P6G, 600 nM for P6G-OH, or 200 nM for P4G-OH. SIINFEDL appears to be about 5 times more potent in these experiments than reported earlier (7) when a 200-fold molar excess over the agonist was required for half-maximal inhibition. This difference may be due to differences in the T cell clones used or, very likely, by the different designs of the experiments. Whereas here, agonists and antagonists were premixed before the target cells were added to allow for free competition, in the earlier experiments the target cells were prepulsed with the agonist and the antagonists added thereafter, thus providing a kinetic advantage for the former.



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  		FIGURE 3. Antagonistic capacity of main chain N-hydroxylated variants of 4G3 epitope SIINFEKL. 5000 51Cr-labeled RMA target cells were incubated with 10 nM of SIINFEKL (arrow), the glycine variants of SIINFEKL, or their N-hydroxylated derivatives or the control peptides SIINFEDL and RGYVYQGL: A, SIINFEDL ({circ}) or as a control for competitive effects RGYVYQGL (•); B, P1G ({square}) or P1G-OH ({blacksquare}); C, P4G ({triangleup}) or P4G-OH ({blacktriangleup}); D, P6G ({diamond}) or P6G-OH ({diamondsuit}). All oligomers were titrated in a serial dilution. The E:T ratio was 5:1. The data are representative for three independent experiments and mean values of triplicates.

 
To confirm these results, a short-term SIINFEKL-specific cytotoxic T cell line was incubated with either 10 ng/ml of SIINFEKL, P4G, P4G-OH, or SIINFEDL alone (Fig. 4Go, left panel, controls) or with 10 ng/ml SIINFEKL in the presence of 100 ng, 1 µg and 10 µg per ml of P4G, P4G-OH, or SIINFEDL (Fig. 4Go, right panels). P4G induced about 20% less IFN-{gamma} secretion than SIINFEKL, whereas only marginally enhanced IFN levels were detect in the P4G-OH and SIINFEDL-stimulated cultures. In admixing experiments, P4G-OH was an efficient antagonist of SIINFEKL with a 65% reduction of the IFN at a 10-fold excess of the antagonist already. P4G-OH appeared to be more efficient than SIINFEDL in these assays, which caused a reduction of SIINFEKL-induced IFN secretion by about 30% at the same molar excess. In contrast to the assays done with the CTL clone 4G3, a significant amount of IFN-{gamma} was still detectable at a 1000-fold excess of antagonists. Also P4G cause some reduction of SIINFEKL-induced IFN secretion which, however, still was above the level obtained with P4G alone.



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  		FIGURE 4. Inhibition of SIINFEKL-induced IFN-{gamma} secretion N-hydroxy peptides. Left panel, T cells of a short-term SIINFEKL-specific cytotoxic T cell line were stimulated with 10 ng/ml SIINFEKL, P4G, P4G-OH, SIINFEDL, or no oligomer. Right panel, The T cells were stimulated with 10 ng/ml SIINFEKL in the presence of 100 ng/ml, 1 µg/ml, or 10 µg/ml of P4G, P4G-OH, or SIINFEDL. The assays was done in triplicates with 50,000 cells/well and 200 µl culture medium without additional stimulator cells. Supernatants were harvested after 16 h and analyzed for IFN-{gamma} in a standard sandwich ELISA assay.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A novel class of antagonists is created by main chain hydroxylation. Here for the first time we present an example for a TCR antagonist that was generated by main chain modification. The main chain N-hydroxylation affects a site of the peptide that is not exposed to and not directly accessible by the TCR (19, 20, 21). It is buried inside the peptide binding groove. The hydroxy group should point down- and sidewards away from the molecular surface of the MHC peptide complex. Thus, in contrast to the anta-gonists described so far (22), no direct effect on the recognition by the TCR is possible. The effect must be indirect, mediated by conformational changes in either the peptide, the MHC molecule, or both. The exact structural basis for the complete reversal of the biological effects of the peptide caused by the hydroxylation of one peptide bond nitrogen atom remains to be investigated.

This report shows that the incorporation of nonpeptide backbone elements into a natural T cell epitope generates MHC ligand complexes with antagonistic properties. Systematic modifications of the main chain via N-hydroxylation is a new rational approach for the development of TCR antagonists. Leaving the side chain constitution of the molecule intact will improve the specificity of the antagonist. Clonotypic variations between T cell clones in the response to agonists and antagonists have been described for cases where exposed potential TCR contact residues were altered (7, 8). In addition, main chain N-hydroxylated peptides are resistant to enzymatic degradation and thus exhibit improved biostability and bioavailability (9). A high stability in vivo is pivotal for a clinical application. The main chain N-hydroxylated antagonists described in this report are active in the nanomolar range even in the presence of saturating amounts of the agonist. Their capacity to bind to the MHC molecule compares favorably with the best-known natural epitopes and their antagonistic potency with the best known peptide antagonists. With these properties, this novel class of antagonists could help the development of specific therapies of T cell-mediated disorders.


   Acknowledgments
 
The technical assistance of Karin Kälberer, and the secretarial support by Patricia Zambon and Rodion Demine, are gratefully acknowledged.


   Footnotes
 
1 This work was supported in part by the Deutsche Forschungsgemeinschaft and the Charité Research Student Fund. A.B. was an Alexander von Humboldt Foundation postdoctoral fellow. Back

2 Current address: Institute for Molecular and Cell Biology, UPR 9021 Immunochemistry of Peptides and Viruses, 15 Rue René Descartes, 67084 Strasbourg Cedex, France. Back

3 Address correspondence and reprint requests to Dr. Peter Walden, Department of Dermatology, Medical Faculty Charité, Humboldt University, Schumannstrasse 20/21, D-10117 Berlin, Germany. E-mail address: Back

Received for publication March 17, 1999. Accepted for publication June 24, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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