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The Journal of Immunology, 2001, 167: 6092-6095.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Positive Selection Induced by a Self-Peptide with TCR Antagonist Activity1

Fabio R. Santori*, Stuart M. Brown{dagger}, Yun Lu{ddagger}, Thomas A. Neubert{ddagger} and Stanislav Vukmanovic2,*

* Michael Heidelberger Division of Immunology, Department of Pathology and Kaplan Cancer Center, {dagger} Department of Cell Biology, {ddagger} Skirball Institute of Biomolecular Medicine, Department of Pharmacology, New York University School of Medicine, New York, NY 10016


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Antagonist-like engagement of the TCR has been proposed to induce T cell selection in the thymus. However, no natural TCR ligand with TCR antagonist activity is presently known. Using a combination of bioinformatics and functional testing we identified the first self-peptide that can both deliver antagonist-like signals and promote T cell selection in the thymus. The peptide is presented by appropriate MHC class I molecules in vivo. Thus, endogenous antagonist peptides exist and may be involved in TCR repertoire selection.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Random rearrangement of TCR genes creates an enormous diversity of receptor specificities. Only a small fraction of the germline TCR repertoire is selected in the thymus. The selection is based on low avidity interactions of the TCRs with self MHC that promotes survival and differentiation of immature TCRlowCD4+CD8+ into mature TCRhighCD4-CD8+ or TCRhighCD4+CD8- thymocytes (1). The absence of TCR engagement or high avidity engagement leads to thymocyte death.

MHC-associated self-peptides have an important role in positive selection (2), but the characteristics of self-peptides that promote positive selection remain elusive. Peptides that are antagonists of mature T cell responses to Ag (3, 4) engage the TCR with relatively low avidity (5). Antagonist-like engagement of the TCR has been proposed as a basis for positive selection (6, 7, 8). In agreement with this hypothesis, several epitope analogs that antagonize mature T cell responses were able to induce positive selection in fetal thymus organ cultures (FTOC)3 (9, 10). In contrast, others have shown that the presence of an antagonist peptide not only failed to promote positive selection but also impaired functional response of mature T cells to Ags (11, 12). However, very few natural self-peptides that promote positive selection have been identified to date and none is an antagonist (13, 14, 15, 16, 17). In this report we present a new algorithm for identification of self-peptides that promote positive selection. Using this approach we identified the first self-peptide that both induces positive selection and acts as an antagonist of mature T cell proliferation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Self-peptide database assembly

All mouse protein sequences were retrieved from GenPept 114 using Batch Entrez (http://www.ncbi.nlm.nih.gov/entrez). The FINDPATTERNS program (Wisconsin Package, Version 10.1; Genetics Computer Group, Madison, WI) was used to collect a set of peptides containing binding motif for H-2Db = XXXXNXXX(L,M,I) (18). All redundant peptides were annotated because the same peptide fragment could be present in proteins with different expression patterns. This peptide set was converted into a Genetics Computer Group-formatted database containing 15,544 nonredundant entries. Similarity searches were performed with PROFILESEARCH (Genetics Computer Group). Profiles based on the epitope Smcy738–746(KCSRNRQYL), an Ag for the H-Y CD8+ T cells (19), were calculated by PROFILEMAKE (Genetics Computer Group) using a PAM250 matrix (20). Expression analysis was performed for the 100 highest scoring peptides by accessing the UniGene database at http://www.ncbi.nlm.nih.gov/UniGene/. One expressed sequence tag hit was considered sufficient to indicate expression in the thymus.

Peptide binding to MHC class I and proliferation assays

Peptide binding to H-2Db was verified by RMA-S stabilization assay (21). The half-life of MHC/peptide complexes was measured as described (22). Antagonist activity of peptides was tested by incubating irradiated splenocytes of C57BL/6 female mice (5 x 106/ml) for 1 h at 37°C with a suboptimal dose of Smcy738–746 peptide (100 nM). The cells were washed and plated (1 x 105 responders and 5 x 105 stimulators/well). Peptides tested for antagonism were added to cultures and proliferation was determined as described (23).

FTOC

The FTOCs were performed using gestation day-16 fetuses of H-Y TCR-transgenic mice (hereafter called H-Y) on the TAP1-/- background, as described (13, 14). Fetal thymus lobes were cultivated on sponge-supported filters (Millipore, Bedford, MA) in medium supplemented with 300 µM peptide. One lobe was treated as experimental, while the other lobe from the same fetus served as control. After 10 days, thymocytes were analyzed by triple staining with anti-mouse CD4-PE, CD8-CyChrome, and CD24-FITC (BD PharMingen, San Diego, CA).

Immunoprecipitation and identification of self-peptides

Normal mouse serum or anti-H-2Db-specific mAb (28-14-8.S) were bound to protein-A Sepharose 4B columns (Amersham Pharmacia Biotech, Piscataway, NJ). Each purification procedure used 1 x 1010 EL-4 T cell lymphoma cells, 3 x 109 cells derived from 427.1 thymic epithelial cell line, or 30 whole thymi from C57BL/6 mice. Cells were washed in PBS and resuspended in lysis buffer (1 x 108 cells/ml) (24). Whole lysates were applied first to normal mouse serum, followed by mAb affinity columns. Peptides were eluted using 10% glacial acetic acid (HPLC grade) and filtered on a 5000 m.w. cutoff membrane (Millipore, Bedford, MA).

Ten percent of the eluted peptides were separated by reversed phase HPLC on a Magic C18 column (Michrom BioResources, Auburn, CA) using a gradient of 2–55% acetonitrile in 0.1% trifluoroacetic acid. A new column was used for this analysis and synthetic peptide was never applied to it to avoid sample contamination. Five percent of each fraction was then dried and analyzed with a Micromass TofSpec2E matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometer using standard instrument settings and 10 mg/ml {alpha}-cyano-4-hydroxycinnamic acid (Sigma-Aldrich, St. Louis, MO) in 50% acetonitrile and 0.1% trifluoroacetic acid as matrix. Reflectron voltages varying between 1,098 V (segment 12) and 26,000 V (segment 1) and external calibration were used for postsource decay experiments.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Search for peptide(s) with biological activities

To date, biologically active self-peptides have been identified by purification and sequencing of peptides from complex mixtures containing up to thousands of different MHC-bound peptides, followed by testing in appropriate functional assays (13, 14, 24, 25). We have developed a "reverse" approach that uses bioinformatic tools to "predict" a limited number of candidate self-peptides with desired biological properties. The strategy is illustrated in Fig. 1Go. We built databases of all available mouse protein fragments that contain MHC anchor binding motifs (18). These databases were then subjected to profile similarity searches (26), and peptides were chosen based on similarity scores, predicted ability to bind MHC (27), and expression of the parent protein in the thymus. The top ten similarity scoring peptides were synthesized and tested for binding to H-2Db (Table IGo) and for their ability to induce positive selection. An increase in the percentage of CD4-CD8+ cells was detected in FTOCs treated with Ube1x509–517 (peptide 4; 31.6%) when compared with thymus lobes treated with the control peptide Uty246–254 (13.4%) (Fig. 2Gob). The CD4-CD8+ thymocytes in control-treated lobes were mostly immature CD24high cells, while a substantial proportion of CD4-CD8+ thymocytes in Ube1x509–517-treated lobes were mature CD24low thymocytes (Fig. 2Goc). Ube1x509–517 acted specifically on the H-Y TCR because no significant increase of CD4-CD8+ thymocytes was observed in TCR transgene-negative TAP1-/- lobes (data not shown). In addition, Rsk3670–678 (peptide 6) also consistently induced an increase in the proportion of mature CD4-CD8+ thymocytes compared with controls, albeit to a much lesser degree than Ube1x509–517 (data not shown). This increase was not observed in FTOCs treated with any of the remaining peptides.



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  		FIGURE 1. General strategy for identification of natural self-peptide/MHC complexes with biological activity. See text for explanation.

 

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  		Table I. Partial list of highest similarity scoring mouse self-peptides from the H-2Db peptide database.1

 


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  		FIGURE 2. Biologic activities of Ube1x509–517. a, Schematic representation of phenotypic changes associated with thymocyte maturation. b, H-Y TCR-transgenic, TAP1-/- thymic lobes were cultured for 10 days in the presence of 300 µM Ube1x509–517 or control Uty246–254 peptide and thymocytes were triple stained for CD4, CD8, and CD24. Shown are CD4 vs CD8 dot plots representative of at least 10 experiments. c, Expression of CD24 on the gated CD4-CD8+ subpopulations shown in b. d, Antagonist activity of Ube1x509–517 and control Psmd4199–207 (Table IGo; peptide 5) peptides to proliferation of H-Y-specific T cells in response to suboptimal dose of the Smcy738–746 peptide (100 nM). Shown are results representative of five experiments. e, Thymocytes from lobes cultured in the absence (mc, media control) or presence of Ube1x509–517 proliferate in response to Smcy738–746.

 
The next step was to test whether any of the selecting peptides could specifically inhibit proliferative response of mature T cells to Ag. Ube1x509–517 was a very potent inhibitor of H-Y-specific (Fig. 2God), but not of LCMV-specific, T cell proliferation (data not shown). In contrast, Rsk3670–678 showed no antagonist activity (data not shown). We next tested the functional potential of Ube1x509–517-selected thymocytes. Proliferation to the epitope Smcy738–746 was far more pronounced among peptide-treated than among control thymus lobes and equal to that of H-Y TAP1+/- thymocytes (Fig. 2Goe). Taken together, peptide Ube1x509–517 selects functional H-Y thymocytes and acts as an antagonist for H-Y responses to Ag.

Natural presentation of candidate peptides by MHC class I

Antagonist activity has previously been detected in putative self-peptides, but their in vivo presentation has not been assessed (28). To determine whether Ube1x509–517 is naturally presented, H-2Db molecules were immunopurified from EL-4 lymphoma cells (data not shown), total thymus extract, and the positively selecting thymic epithelial cell line 427.1 (29). The total mixture of eluted peptides was analyzed by MALDI-TOF mass spectrometry. A peptide of monoisotopic mass within the experimental error (± 25 ppm) of the predicted mass of m.w. 1118.62 for Ube1x509–517 was found in each sample (Fig. 3Go). Upon separation of eluate by reversed phase HPLC, we detected a peptide that corresponded in sequence to Ube1x509–517. None of the samples derived from precipitation using normal mouse serum (Fig. 3Go) or unrelated mAb (data not shown) contained Ube1x509–517. From MALDI-TOF peak intensities and UV absorbance at 214 nm during HPLC, we estimate that Ube1x509–517 accounted for ~3, 4.1, and 4.6% of the total peptide mass present in the original eluate of EL-4, 427.1, and thymus cell extract, respectively. In contrast to Ube1x509–517, Rsk3670–678 (m.w. 1189.36) was not detected in any of the samples, consistent with its poor binding to H-2Db (Table IGo). Thus, Ube1x509–517 is a natural self-peptide presented by H-2Db in vivo.



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  		FIGURE 3. MALDI-TOF mass spectrometry of H2-Db-associated peptides. Spectra of normal mouse serum or anti-H-2Db precipitated peptides from total thymus extract (a and b) or 427.1 thymic epithelial cell line (c and d). Peptides eluted from H2-Db show several peaks, including one with mass/charge ratio 1119.62 (Ube1x509–517). e, The postsource decay spectrum of synthetic Ube1x509–517. The amino acid sequence of the peptide based on the b ion series (35 ) is shown above the spectrum. f, The postsource decay spectrum, similar to that of synthetic Ube1x509–517, of a peptide with mass/charge ratio 1119.6 derived from total thymus extract.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this report we have demonstrated a new approach for the identification of MHC-bound self-peptides with biological activity. The power of this approach is best illustrated by the fact that the number of potential candidate peptides on the list was reduced to only 10, starting from a collection of 15,544 nonredundant peptides. The underlying assumption of this strategy is that similarity between self-peptides and Ags plays a role in TCR repertoire selection. A more comprehensive study is under way to test whether similarity to Ag indeed may be an important feature of selecting self-peptides. At present, we can conclude that the approach has allowed us to identify the first self-peptide that both promotes thymocyte positive selection and is an antagonist for mature T cell responses.

Some experimental evidence suggests a major role of antagonism in positive selection (9, 10, 30). In contrast, there are cases where antagonist ligands failed to promote selection, or even induced negative selection (11, 31). Furthermore, some studies support the role of agonist signals in positive selection (17, 32, 33). Discrepancies in these findings can at least partially be attributed to the possibility that antagonist-like signals may be selectively important for positive selection of the CD4-CD8+ lineage (30, 34). Perhaps it may be another quality shared by these functionally distinct groups of ligands, such as low avidity for the TCR, that may be important for promoting positive selection. We hope that our method will allow identification of multiple self-ligands involved in positive selection and that this knowledge will lead to a consensus about how self-peptides promote positive selection.

Antagonist activity can potentially affect peripheral responsiveness of T cells. The presence of endogenous antagonists seems to inhibit mature T cell responses in the CD4+ lineage (11, 12, 31). We have shown that Ube1x509–517 selects functional H-Y specific thymocytes (Fig. 2Go), suggesting that the presence of antagonist peptide on thymus epithelium does not inhibit the subsequent T cell response to Ag. Selection and inhibition of T cell responsiveness may occur sequentially; antagonist ligands may first select functionally capable T cells, but a frequent subsequent encounter results in inhibitory effects. We suspect this may be the case because peripheral H-Y CD8+ cells are hyporesponsive to Ag and the response is enhanced in milieu with reduced levels of MHC class I H-2Db (23). The effect of reducing the MHC class I possibly resulted from a reduction of levels of Ube1x509–517 peptide. Unfortunately, at present it is impossible to verify this directly as the Ube1x gene codes for a housekeeping protein (ubiquitin-activating enzyme E1) that is essential for cell survival.


   Acknowledgments
 
We thank Tirza Doniger from the Research Computing Resource for writing the computer routines, Stanley Wang for HPLC chromatography, Wenjun Mo for helpful discussions, John Hirst for FACS analysis, and Rose Zamoyska, Peter Cresswell, Dan Littman, David Levy, Jayne Raper, and Niel Stahl for reading the manuscript.


   Footnotes
 
1 This work was supported by National Institutes of Health Grant AI041573 (to S.V.), National Cancer Institute Core Support Grant 5P30 CA16087, and National Institutes of Health Shared Instrumentation (MALDI-TOF) Grant 1 S10 RR14662. Back

2 Address correspondence and reprint requests to Dr. Stanislav Vukmanovic, Michael Heidelberger Division of Immunology, Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016. E-mail address: vukmas01{at}med.nyu.edu Back

3 Abbreviations used in this paper: FTOC, fetal thymus organ culture; MALDI-TOF, matrix-assisted laser desorption ionization-time of flight. Back

Received for publication September 18, 2001. Accepted for publication October 12, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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