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The Journal of Immunology, 1999, 163: 1750-1754.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Dueling TCRs: Peptide Antagonism of CD4+ T Cells with Dual Antigen Specificities1

Jennifer M. Robertson and Brian D. Evavold2

Department of Microbiology and Immunology, Emory University, Atlanta, GA, 30322


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
T cells expressing two different TCRs were generated by interbreeding 3A9 and AND CD4+ TCR transgenic mice specific for the hen egg lysozyme (HEL) peptide 48–62:I-Ak and moth cytochrome c (MCC) peptide 88–103:I-Ek peptide:MHC ligands, respectively. Peripheral T cells in the offspring express two TCR Vß-chains and respond to HEL and MCC. We observed minimal or no additive effects upon simultaneous suboptimal stimulation with both agonist peptides; however, an antagonist peptide for the 3A9 TCR was able to inhibit the response of the dual receptor T cells to MCC, the AND TCR agonist. This HEL antagonist peptide did not affect AND single transgenic T cells, indicating that the antagonism observed in the dual TCR cells is dependent on the presence of the HEL-specific 3A9 TCR. In contrast, anti-TCR Abs mediate receptor-specific antagonism. These results demonstrate that peptide antagonism exerts a dominant effect.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A TCR can recognize a variety of peptide:MHC ligands, with the specific T cell responses evoked by each depending on the characteristics of the ligand. Partial agonists and antagonists have been identified for many receptor-ligand systems (1, 2, 3). TCR partial agonist and antagonist ligands are typically generated by making single amino acid substitutions of the immunogenic peptide at positions that contact the TCR, although peptides having very few amino acids in common with the immunogenic peptide can also act as partial agonist or antagonist ligands (2, 4). Partial agonists stimulate a subset of T cell responses, yet fail to achieve full activation (maximal T cell proliferation as compared with the immunogenic peptide) and have been useful in identifying the steps involved in T cell activation (2, 5). For instance, the weakest partial agonist ligands stimulate the earliest events in T cell activation, such as calcium flux, acid release, and TCR {zeta}-chain phosphorylation, while more potent partial agonist ligands stimulate later signaling events and effector cell functions like cytokine production and target cell lysis (2, 5, 6, 7). Some partial agonists have been shown to have antagonist activity, but most antagonist peptides stimulate minimal T cell responses on their own and are classified based on their ability to inhibit the T cell response to agonist ligand (1, 8).

3A9/AND dual transgenic mice were generated with CD4+ T cells expressing functional TCRs specific for hen egg lysozyme (HEL)3 and moth cytochrome c (MCC) peptides. We found that an antagonist peptide for the 3A9 TCR inhibits the proliferative response of the T cells to the agonist for the AND TCR. These findings indicate that two different TCR species can interact to deliver negative signals during antagonism.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

AND TCR transgenic mice [TgN(TcrAND)53Hed] (H-2b) mice were purchased from The Jackson Laboratory (Bar Harbor, ME) (9). 3A9 TCR transgenic mice [TgN(TcrHEL3A9)#Mmd] (H-2k) were a gift from Drs. Chris Larsen and Tom Pearson (Emory University, Atlanta, GA) (10). B10.A/Cr (H-2a) mice were purchased from the National Cancer Institute (Frederick, MD). 3A9 and AND mice were bred together to generate 3A9/AND F1 mice transgenic for two TCRs. All mice were housed and maintained in the Emory University Department of Animal Resources facility.

Cells and reagents

T cell lines were generated by stimulating splenic T cells of AND or 3A9 transgenic mice with either 5 µM MCC peptide 88–103 (ANERADLIAYLKQATK) or 1 µM HEL peptide 48–62 (DGSTDYGILQINSRW), respectively. 3A9/AND T cell lines from at least three different F1 mice were similarly generated by stimulation with either MCC or HEL. T cells (2 x 105/well) were restimulated every 2 wk in a 24-well plate with appropriate peptide and 5 x 106 {gamma}-irradiated splenocytes (2000 rad) from B10.A mice, along with 50 U of IL-2 obtained from the culture supernatants of IL-2-secreting P815 cells (11). Cell culture media consisted of RPMI 1640 supplemented with 2 mM L-glutamine, 0.01 M HEPES buffer, 100 µg/ml gentamycin (Mediatech, Herndon, VA), 10% FBS (Atlanta Biologicals, Norcross, GA), and 2 x 10-5 M 2-ME (Sigma, St. Louis, MO). All peptides were synthesized using F-moc chemistry on a Symphony/Multiplex Peptide Synthesizer and analyzed by HPLC (Rainin Instruments, Woburn, MA) and mass spectrometry by the Emory University Department of Chemistry Core Facility.

T cell proliferation assays

Proliferation assays were conducted by culturing T cells (3 x 104/well) with the indicated peptide and 5 x 105 {gamma}-irradiated B10.A spleen cells (2000 rad) in duplicate in a 96-well plate. Proliferating cells were labeled after 48 h with 0.4 µCi/well of [3H]thymidine, and after another 18 h the assays were harvested and analyzed on a Matrix 96 direct ß-counter (Packard Instruments, Meriden, CT).

For prepulsed antagonism assays, B10.A splenocytes were first incubated with agonist peptide for 2 h before being washed to remove any unbound peptide (12, 13). The APCs were irradiated (2000 rad), combined with T cells and additional peptides, and proliferation was determined as described above. Antagonism assays were also done with no prepulse step as the agonist and antagonist peptides are presented by different MHC molecules, a protocol we have previously used to analyze peptide antagonism of superantigen-stimulated T cells (12).

Ab inhibition experiments were conducted as described above with the addition of 50 µl of culture supernatant from either the KJ25 (anti-Vß3) or KJ16 (anti-Vß8.1, 8.2) B cell hybridomas grown in our laboratory.

Flow cytometry

An anti-Vß8.1, 8.2 (KJ16) Ab was grown, purified, and FITC-conjugated in our laboratory. PE-labeled anti-Vß3 (KJ25) Abs were purchased from PharMingen (San Diego, CA). All flow cytometry data were collected on a Becton Dickinson FACSCalibur (Bedford, MA) and analyzed using FlowJo software (Tree Star, San Carlos, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
3A9/AND dual receptor T cells

3A9 and AND TCR transgenic mice were bred to generate Th cells expressing two different TCRs with known Ag specificities. The 3A9 TCR transgenic mouse (H-2k) expresses a Vß8.2, V{alpha}3 TCR specific for the HEL peptide 48–62 presented by I-Ak MHC (10), and the AND TCR transgenic mouse (H-2b) expresses a Vß3, V{alpha}11 TCR specific for the MCC peptide 88–103 presented by I-Ek MHC (9). Neither T cell exhibits any cross-reactivity toward the other Ag, making the combination of these two TCR ideal for our purposes (data not shown). T cells from the resulting 3A9/AND F1 offspring were assayed for reactivity to the HEL and MCC peptides (Fig. 1GoA), with greatest proliferation observed at 1 µM HEL and 1 µM MCC regardless of the passage Ag. The peak proliferative response of the dual receptor T cells occurs at the same levels of Ag as compared with single transgenic 3A9 or AND T cells (data not shown). These results suggest that both the 3A9 and AND TCRs are expressed on T cells in the periphery of the 3A9/AND mice.



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  		FIGURE 1. 3A9/AND F1 T cells proliferate to both HEL and MCC Ags. A, 3A9/AND T cells maintained on 1 µM HEL peptide were stimulated with the indicated concentration of either HEL or MCC peptide presented by splenocytes from B10.A mice. B, 3A9/AND T cells maintained on 5 µM MCC peptide were labeled with a PE-conjugated anti-Vß3 Ab (KJ25) and a FITC-conjugated anti-Vß8.1, 8.2 Ab (KJ16). C, Levels of Vß8 expression on 3A9 single receptor T cells (black line) and 3A9/AND dual receptor cells (gray line) are compared. D, Vß3 levels on AND T cells (black line) are compared with 3A9/AND dual receptor T cells (gray line). Control staining for single and dual receptor cells in C and D is represented by the filled black and gray histograms, respectively. Data shown are representative of at least three independent experiments.

 
The surface expression of Vß8 and Vß3 TCRs on the 3A9/AND T cells was analyzed by flow cytometry. 3A9/AND T cells labeled with anti-Vß8.1, 8.2 and anti-Vß3 Abs were double positive, confirming that the T cells express both TCR Vß-chains simultaneously (Fig. 1GoB). The median fluorescence intensity (MFI) of the dual receptor cells was 355 for Vß8-FITC and 427 for Vß3-PE compared with the controls of 67 and 70, respectively. As expected, TCR levels are slightly lower on the 3A9/AND dual receptor T cells than on 3A9 (MFI for Vß8-FITC = 388, control = 124) and AND single transgenic T cells (MFI for Vß3-PE = 499, control = 133) (Fig. 1Go, C and D) (14, 15). Both Vß3 and Vß8 were expressed on freshly isolated 3A9/AND T cells, thymocytes, and T cell lines maintained on either HEL or MCC (Fig. 1Go, C and D, our unpublished observations).

Additive effects upon stimulation with HEL and MCC

The proliferation of 3A9/AND T cells was measured in response to simultaneous stimulation though both TCRs with agonist peptides. T cells were cultured with APCs expressing both I-Ak and I-Ek MHC molecules in the presence of various concentrations of both HEL and MCC peptides (Fig. 2Go). The combination of highly stimulatory doses of both agonists resulted in a decrease in T cell proliferation, consistent with the lessened proliferative response observed with high concentrations of Ag (16). For example, the maximal proliferative response induced with 1 µM HEL peptide (4796 cpm) was lessened by the addition of 10 µM MCC (8935 cpm alone, 3195 cpm together). At submaximal concentration combinations, it was expected that the proliferation of the T cells would be enhanced over the proliferation induced by either peptide alone. However, at most points very little effect was seen. The combination of 0.01 µM HEL (5535 cpm) and 1 µM MCC (6641 cpm) resulted in an intermediate level of proliferation (5793 cpm).



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  		FIGURE 2. Additive effects upon stimulation with HEL and MCC. 3A9/AND T cells maintained on 1 µM HEL peptide were stimulated with the indicated concentrations of MCC and HEL peptides presented by irradiated spleen cells from B10.A mice. The maximal T cell response obtained in this experiment was 10,074 cpm. Background proliferation was 633 cpm. These data are from one of at least six similar experiments performed.

 
MCC response of 3A9/AND T cells is inhibited by HEL antagonist

A panel of analogue peptides was generated for HEL48–62 in an effort to identify an antagonist peptide. Proliferation of single transgenic 3A9 T cells was measured in response to the analogue peptides, and those that induced little or no proliferation were tested in antagonism assays (data not shown). The analogue peptide 59I was found to be a potent inhibitor of 3A9 T cell proliferation in response to wild-type HEL peptide (89% inhibition at 100 µM 59I, 2804 cpm HEL prepulse) (Fig. 3GoA). In this peptide, an asparagine is replaced with an isoleucine at amino acid 59, which is position 8 of the peptide as identified by the crystal structure of HEL50–62 bound to I-Ak (17). This amino acid is a solvent-exposed TCR contact residue with minimal interactions with I-Ak (17).



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  		FIGURE 3. Dominant peptide antagonism of CD4+ dual receptor TCR cells. A, B10.A spleen cells were prepulsed with 1 µM HEL for 2 h and irradiated before being washed to remove any unbound peptide. APC were combined with 3A9 single transgenic T cells and the indicated analogue peptides. A concentration of 100 µM 59I inhibited the 1 µM HEL prepulse (2804 cpm) by 89%. B, 3A9/AND T cells maintained on 1 µM HEL were cultured with B10.A splenocytes prepulsed with 1 µM HEL peptide and the indicated analogue peptides. A dose of 100 µM 59I inhibited the 1 µM HEL prepulse (16,269 cpm) by 92%. C, 3A9/AND T cells maintained on 5 µM MCC were combined with B10.A splenocytes and the indicated concentrations of wild-type MCC and antagonist HEL peptides. A maximum inhibition of 71% was observed at 100 µM 59I plus 100 µM MCC. D, AND single receptor T cells were combined with B10.A spleen cells and various concentrations of MCC and 59I. These data are representative of at least three independent assays.

 
The effects of the HEL antagonist peptide on the proliferation of the dual receptor T cells were then examined. As expected, the response of the 3A9/AND T cells to HEL was antagonized by the HEL analogue peptide 59I (Fig. 3GoB). It was then of interest to determine whether the HEL antagonist could also inhibit the MCC response. It was not necessary to first prepulse the APC with MCC agonist peptide as described for the typical antagonism assay because MCC and HEL 59I are presented by different MHC molecules (12, 13). 3A9/AND T cells were cultured with APCs expressing both I-Ak and I-Ek, MCC wild-type peptide, and the HEL antagonist peptide 59I. Interestingly, the 3A9 antagonist peptide inhibited the MCC response of the dual receptor T cells in a dose-dependent manner (Fig. 3GoC). At a concentration of 1 µM, 59I did not significantly inhibit the MCC response; however, 10 µM 59I was able to cause 50% inhibition at 1 µM MCC, and 100 µM 59I blocked 71% of the response to 100 µM MCC. This is different from the high-dose inhibition observed in Fig. 2Go as the antagonist peptide induces no proliferation on its own. A similar result was also observed in traditional prepulse assays, where the APCs were cultured with MCC to ensure MHC loading before the addition of the antagonist peptide (data not shown). The HEL antagonist 59I does not inhibit proliferation of MCC-stimulated AND single receptor T cells, indicating that the antagonism is specific to cells expressing the 3A9 TCR (Fig. 3GoD). These results demonstrate that the inhibitory effect of an antagonist peptide dominates regardless of the TCR species with which the agonist peptide interacts.

Ab inhibition is TCR specific

Anti-TCR Abs can inhibit T cell responses and are therefore a form of TCR antagonist (18). To determine whether or not anti-TCR Abs act in a dominant negative manner, as seen above for the HEL antagonist 59I (Fig. 3GoC), the proliferation of the 3A9/AND T cells was measured in response to HEL and MCC in the presence or absence of anti-Vß8 and anti-Vß3 Abs. The HEL response was inhibited by anti-Vß8 Abs, but the anti-Vß3 Abs had minimal effects on the HEL response (Fig. 4GoA). Similarly, the MCC response was only inhibited by the anti-Vß3 Abs (Fig. 4GoB). These results suggest that Ab inhibition is strictly a cell-surface effect, which differs from the dominant peptide antagonism observed in Fig. 3Go.



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  		FIGURE 4. Ab inhibition of T cell proliferation is TCR specific. 3A9/AND T cells maintained on 1 µM HEL were stimulated with B10.A spleen cells and the indicated concentration of HEL (A) or MCC (B) peptide in triplicate. Culture supernatants (50 µl) from either KJ25, an anti-Vß3 Ab, or KJ16, an anti-Vß8.1, 8.2 Ab, were included where indicated. Proliferation is reported as {Delta} cpm, which is equal to experimental cpm - background cpm. These data are representative of at least four similar experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These experiments were initiated to determine whether TCRs with different Ag specificities could work in concert to deliver both positive and negative responses in a single cell. We have demonstrated by cell proliferation and flow cytometry that T cells bearing TCR reactive to HEL:I-Ak and MCC:I-Ek are generated by interbreeding TCR transgenic mice specific for these Ags. This finding is not unique as we have also generated mice with T cells specific for OVA and MCC using the same protocol (our unpublished observations). Under appropriate experimental conditions, we found that a HEL antagonist can negatively affect the response to MCC agonist.

There are no models of T cell activation and signaling that predict the segregation of TCR on the surface of a dual TCR cell. In the presence of both Ags, it is difficult to imagine that a T cell is able to differentiate one TCR species from another, making stimulation with two agonists equivalent to an increased level of one. However, the additive effects we have observed are less robust than expected despite the large dose matrices we have analyzed. Upon stimulation with both agonist peptides, the 3A9 and AND TCR should be recruited to a single signaling cap or immunological synapse at the T cell:APC junction (19, 20, 21, 22, 23). If the accumulation of signaling proteins and the consequent activation of signaling cascades is dependent on the number of TCR triggered (24), then the combination of 0.1 µM HEL and 0.1 µM MCC, which both stimulate half maximal proliferation on their own, results in only a small increase in dose. This difference does not greatly alter the overall strength of signal or the extent of proliferation of the cells. Thus, at the majority of concentration combinations T cell proliferation was very similar to that observed with the more potent of the two agonists.

Similarly, the 3A9 and AND TCR should be distributed equally at the initiation of an antagonism assay. Whether an interaction with an antagonist ligand prevents cap formation or transmits a dominant negative signal as the result of a buildup of negative-acting intermediate signaling cascade components and/or the recruitment and activation of phosphatases remains to be determined (23, 25). Our dual TCR system should allow for the analysis of the events occurring during peptide antagonism as each TCR can be independently activated and followed.

A powerful component of our dual TCR system is that the 3A9 and AND TCR are restricted by different MHC molecules, eliminating the need for prepulsing APC with agonist before adding antagonist peptide (12). As seen in Fig. 3Go, the HEL antagonist was able to inhibit the MCC response at a ratio of antagonist to agonist as low as 1:10 (44% inhibition at 100 µM MCC plus 10 µM 59I). These results demonstrate that antagonist peptides do not need to be in great excess to inhibit proliferation as suggested by prepulse antagonism assays (5). In traditional antagonism experiments, the agonist is incubated with APC before the addition of antagonist to minimize competition for MHC, relegating antagonist peptides to newly synthesized or freshly emptied MHC molecules (13). Most agonist peptides have high affinities for MHC and form very stable peptide:MHC complexes, suggesting that the number of MHC that become available for antagonists to bind is low (26). Therefore, even though antagonists greatly outnumber agonists in traditional prepulse assays, the numbers bound to MHC are expected to be more equal (5, 13).

Two recent reports have shown that the negative effects of antagonist peptides in CD8+ dual receptor T cells are not dominant, concluding that peptide antagonism is TCR specific (15, 27). The observed discrepancy between our systems could simply be due to the use of different classes of antagonist peptides. It has been shown that while some antagonist peptides induce no detectable signal transduction on their own, other antagonists possess partial agonist activity and can stimulate cell signals at select concentrations (1, 2, 3, 8, 12). Thus, it may be possible that in our system the HEL antagonist 59I is an active antagonist peptide able to deliver a negative-acting signal to the T cell, while the antagonist peptides used in the CD8+ systems act by competing with agonists for TCR engagement. This model predicts that both passive and active antagonist ligands could exist for a given TCR, such that further analysis of our system could yield a nondominant antagonist. Alternatively, inherent differences between CD4+ and CD8+ T cells may be responsible for the contradictory results obtained between these systems. CD8+ T cells are more sensitive to low levels of peptide, indicating that the activation thresholds for these T cells may be lower than for CD4+ cells. This could indicate that the kinetics of cap formation and T cell activation are different between CD4+ and CD8+ T cells, making the cells more or less sensitive to altered peptide ligands.

Pairing of TCR {alpha}- and ß-chains allow for as many as four different TCR species on the surface of the 3A9/AND T cells. In addition to 3A9 (Vß8.2, V{alpha}3) and AND (Vß3, V{alpha}11) TCR, hybrid receptors comprised of the ß-chain from one TCR and the {alpha}-chain from the other could also exist (Vß8.2, V{alpha}11 or Vß3, V{alpha}3). It is possible that one of these hybrid TCR could recognize both MCC:I-Ek and HEL:I-Ak ligands. However, our data show that most if not all of the HEL or MCC reactivity of the dual receptor cells was due to stimulation only through the Vß8- or Vß3-expressing TCR, respectively (Fig. 4Go). It is difficult to imagine that a hybrid molecule could be responsible for the 71% inhibition observed in Fig. 3Go. This is further supported by our other dual receptor T cells, which express the DO11.10 (Vß8.2, V{alpha} 1.1) and AND TCR. Quantitation of the DO11.10 TCR using an anti-TCR clonotypic Ab reveals TCR numbers similar to those measured using an anti-Vb8 Ab, indicating that Vß8 is exclusively paired with V{alpha}1.1. Similarly, Vß3 and V{alpha}11 are expressed at equivalent numbers, although at lower levels than Vß8 (our unpublished observations). These results indicate that there is preferential pairing between TCR {alpha}- and ß-chains, making the predominate TCR species on the T cells the two transgenic TCR.

In conclusion, we have described a method for the generation of T cells that possess multiple Ag specificities. Our system has allowed for the investigation of TCR antagonism and was used to demonstrate that antagonism can be a dominant effect.


   Acknowledgments
 
We thank the members of the Evavold lab for their support and Tracey M. Walden for technical assistance.


   Footnotes
 
1 This work was supported by National Institutes of Health Grant AI40549. B.D.E. is the recipient of a Junior Faculty Research Award from the American Cancer Society. Back

2 Address correspondence to Dr. Brian D. Evavold, Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, GA, 30322. E-mail address: Back

3 Abbreviations used in this paper: HEL, hen egg lysozyme; MCC, moth cytochrome C; MFI, median fluorescence intensity. Back

Received for publication May 3, 1999. Accepted for publication June 11, 1999.


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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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N. E. Kilgore, J. D. Carter, U. Lorenz, and B. D. Evavold
Cutting Edge: Dependence of TCR Antagonism on Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Activity
J. Immunol., May 15, 2003; 170(10): 4891 - 4895.
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W. Yang and H. M. Grey
Study of the Mechanism of TCR Antagonism Using Dual-TCR-Expressing T Cells
J. Immunol., May 1, 2003; 170(9): 4532 - 4538.
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 J. Immunol.Home page
L. K. McNeil and B. D. Evavold
TCR Reserve: A Novel Principle of CD4 T Cell Activation by Weak Ligands
J. Immunol., February 1, 2003; 170(3): 1224 - 1230.
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 J. Immunol.Home page
D. J. Topham, M. R. Castrucci, F. S. Wingo, G. T. Belz, and P. C. Doherty
The Role of Antigen in the Localization of Naive, Acutely Activated, and Memory CD8+ T Cells to the Lung During Influenza Pneumonia
J. Immunol., December 15, 2001; 167(12): 6983 - 6990.
[Abstract] [Full Text] [PDF]

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C. Chan, A. J. T. George, and J. Stark
Cooperative enhancement of specificity in a lattice of T cell receptors
PNAS, May 8, 2001; 98(10): 5758 - 5763.
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M. Garcia-Peydro, A. Paradela, J. P. Albar, and J. A. L. d. Castro
Antagonism of Direct Alloreactivity of an HLA-B27-Specific CTL Clone by Altered Peptide Ligands of Its Natural Epitope
J. Immunol., November 15, 2000; 165(10): 5680 - 5685.
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R. Kubota, S. S. Soldan, R. Martin, and S. Jacobson
An Altered Peptide Ligand Antagonizes Antigen-Specific T Cells of Patients with Human T Lymphotropic Virus Type I-Associated Neurological Disease
J. Immunol., May 15, 2000; 164(10): 5192 - 5198.
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 J. Exp. Med.Home page
E. N. Kersh, G. J. Kersh, and P. M. Allen
Partially Phosphorylated T Cell Receptor {zeta} Molecules Can Inhibit T Cell Activation
J. Exp. Med., December 6, 1999; 190(11): 1627 - 1636.
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