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The Journal of Immunology, 1999, 162: 3761-3764.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: A Test of the Dominant Negative Signal Model for TCR Antagonism1

Mark A. Daniels, Sonya L. Schober, Kristin A. Hogquist and Stephen C. Jameson2

Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The mechanism by which TCR antagonists interfere with T cell activation is unclear. One popular hypothesis is that incomplete early signaling events induced by these ligands dominantly inhibit the T cell’s ability to respond to a copresented agonist ligand. Here we test this "dominant negative" signal hypothesis by studying T cells expressing two distinct MHC class I-restricted TCRs (2C and OT-I). Although responses through each TCR can be efficiently inhibited by their specific antagonists, we found no evidence for "cross-antagonism" in which an antagonist for receptor "A" blocks responses through receptor "B." Such inhibition would have been expected were the dominant negative signaling hypothesis correct, and alternative models for TCR antagonism are discussed.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhibition of T cell activation by TCR antagonists is a well-established phenomenon (1, 2, 3), yet the mechanism by which this inhibition occurs remains obscure. Several groups have reported that antagonists bind the TCR with lower affinity and/or with faster off rates than agonist ligands (4, 5), which may prevent "full" activation of the TCR, as predicted by mathematical models (6, 7). In keeping with this data, there is evidence that both partial agonists and strict antagonists can induce some weak early signaling events, such as partial phosphorylation of TCR associated {zeta}-chains (8, 9, 10), and a recent study proposed that this partial phosphorylation pattern reflects the kinetics of TCR engagement (11). These data leave open the question of whether TCR antagonists inhibit a T cell response simply by competing with agonists for the attention of the TCR, or whether the partial signaling events induced by antagonists act to induce a global negative signal, crippling the cell’s ability to respond to a copresented agonist ligand.

In apparent support of a dominant negative signal model (also described as a "global" negative signal) of TCR antagonism, several reports describe antagonist ligands that appeared to inhibit responses even when presented at a lower density than the agonist ligand (12, 13, 14, 15). This data was interpreted to mean that such inhibition was not due to simple receptor competition, but rather that antagonists generate a negative signal that would block the activation cascade induced by agonists. Indirect support for this idea came from data demonstrating that TCR antagonists could partially inhibit responses to bystander APC presenting agonist ligands (12, 15, 16).

While consistent with a dominant negative model for antagonism, these data do not exclude mechanisms based on receptor competition, especially in light of T cell activation models involving serial triggering (17, 18) and data demonstrating antagonists with higher TCR affinity than weak agonists (19).

One direct prediction of a dominant negative signal model is that antagonism should occur even if the agonist and antagonist do not compete for the same TCR (see Fig. 1Go and Results below). To test this directly, we generated T cells bearing two different MHC class I-restricted TCRs with defined Ag reactivities. Using these cells, we found no evidence for such "cross-antagonism," indicating that a global negative signal is not the mechanism of TCR antagonism.



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  		FIGURE 1. Schematic of the system used to test for a dominant or global negative signal for TCR antagonism. A T cell bearing two distinct TCRs (A and B) is generated, and both agonist and antagonist ligands are defined for each receptor. In the situation shown, the T cell is stimulated using an agonist for TCR A, and the capacity of an antagonist for TCR B to block the response ("cross-antagonism") is determined. In model 1, cross-antagonism occurs, indicating that the TCR B antagonist induces a "dominant" (or "global") negative signal preventing activation through TCR A. In model 2, antagonism involves receptor competition, hence there is no global negative signal and interaction with an antagonist for TCR B has no effect on stimulation through TCR A.

 

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

OT-I (20) and 2C (21) TCR transgenic mice on a C57BL/6 background were crossed and double transgenic animals typed by flow cytometry. Spleen and lymph node cells from single and double TCR transgenic animals were stimulated using B6 spleen cells coated with either OVAp (SIINFEKL) or SIYp (SIYRYYGL) to stimulate through the OT-I and 2C receptors, respectively, or were stimulated using P815 tumor cells, which bear the 2C alloantigen Ld. The CTL lines lines studied were restimulated weekly for up to 5 wk using various combinations of these stimuli.

Peptides

Peptides were synthesized by Research Genetics (Huntsville, AL) and used either without further purification (purity, >80%) or after purification via reverse HPLC (purity, >90%) and were prepared as described previously (16, 20). The OT-I antagonists E1 and V-OVA have been described (16, 20). The SIY-A6 peptide was designed based on the data of Brock et al. (22).

51Cr-release assays for TCR antagonism

EL4 target cells were prepulsed with suboptimal doses of either the OVAp or SIYp agonist peptides during labeling with 51Cr, as described previously (16). After washing the target cells free of unbound agonist peptides, they were incubated briefly with the titrated control or antagonist peptide variants and CTL was added at an E:T ratio of 3:1. Lysis of target cells was determined by 51Cr release and calculated as described previously (23).

Flow cytometry

Expression of the OT-I TCR {alpha}-chain (V{alpha}2) was detected using B20 (PharMingen, San Diego, CA), and expression of the 2C receptor was detected using the clonotypic Ab 1.B2 (a kind gift of Dr. Matthew Mescher, University of Minnesota, Minneapolis, MN) as phycoerythrin or biotin conjugates. For negative control staining, biotinylated T3.70 (24) and CD4-phycoerythrin were used. Biotinylated Abs were detected using avidin-tricolor (Caltag, Burlingame, CA), and cells were counterstained with FITC-CD8 (PharMingen).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
To test for a dominant negative signal in TCR antagonism, we generated T cells bearing two TCRs of known specificity. The logic of this approach is summarized in Fig. 1Go. The two TCRs (A and B) have nonoverlapping Ag specificities. If antagonism is induced by a negative signal (model 1), agonist stimulation through TCR-A would be blocked by antagonists for receptor A ("direct antagonism") but also by antagonists for receptor B ("cross-antagonism"), because both sets of antagonists would induce a negative signal. The same would, of course, be true for stimulation through receptor B. In contrast, if antagonism operates through receptor competition (model 2), cross-antagonism would not be seen, because the receptors act independently of each other. Thus stimulation through, e.g., receptor A would be blocked by antagonists for TCR-A but not TCR-B.

We derived such T cells by crossing the 2C and OT-I TCR transgenic mice (20, 21). Both TCRs are restricted by the MHC class I molecule Kb, but they recognize distinct Ags: OT-I recognizes OVAp/Kb (16, 20), while 2C recognizes the complex SIYp/Kb (25). There is no cross-reactivity between the receptors for these Ags (Ref. 19 and data not shown).

CD8+ T cells in the blood, spleen, and lymph nodes of these mice express both TCRs as determined by staining with specific mAbs (Fig. 2GoA and data not shown). Expression of both the OT-I and 2C receptors was reproducibly lower on the double transgenic mice than on either parent (Fig. 2GoA), yet T cells from the double transgenic mice could be stimulated with ligands for either receptor and CTL lines established (data not shown). TCR expression on representative CTL lines is shown in Fig. 2Go, B and C. In general, these CTL lines had slightly lower expression levels of OT-I vs 2C receptor (Fig. 2GoB), similar to the freshly isolated cells. Double staining with Abs to each receptor revealed coordinate expression of both receptors (Fig. 2GoC), making them suitable for our purposes.



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  		FIGURE 2. The expression of OT-I and 2C receptors on T cells from single and double TCR transgenic mice. A, Fresh lymph node T cells from OT-I, 2C and 2C x OT-I mice were prepared and stained for CD4, CD8, and biotinylated Abs to B20 (anti-V{alpha}2, part of the OT-I receptor), 1.B2 (specific for the 2C receptor), or T3.70 (negative control). Staining for CD8+ cells is shown. B, TCR expression on line 13SPOP. This CTL line was induced by stimulation four times in vitro (sequentially with SIY peptide, P815 cells, OVA peptide, and SIY peptide). C, TCR double staining of line 13SP was as in B, except the cells were simultaneously stained for B20-phycoerythrin and 1.B2-biotin as indicated. This line was stimulated twice in vitro, using SIY peptide and P815 cells, respectively.

 
A6 is an antagonist specific for the 2C TCR, while V-OVA and E1 are antagonists specific for the OT-I TCR

We have characterized several TCR antagonists for the OT-I TCR (16, 20) and chose two well defined variants, E1 and V-OVA. To identify antagonists for the 2C receptor, variants of the SIY peptide were tested, based on their ability to bind Kb and their failure to stimulate a 2C cytolytic response (Ref. 22 and data not shown). The peptide variants were screened for antagonism of cytolysis by 2C effector CTL, using our standard approach (16). An antagonist variant bearing a mutation of Tyr -> Ala at position 6 (SIY-A6) was defined in this way (data not shown and Fig. 3Goa).



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  		FIGURE 3. Fine specificity of TCR antagonists used. a, EL4 cells pulsed with 50 pM SIYp were used as targets for a 2C CTL line. b, EL4 cells pulsed with 150 pM OVAp were used as targets for an OT-I receptor bearing CTL clone (clone 2, Ref. 26 ). Lysis in the absence or presence of titrated P815p, E1, V-OVA, or SIY-A6 peptides was determined using a 51Cr release assay. Percent specific lysis is plotted on the y-axis, and molar concentration of the agonist and antagonist variant peptides is plotted on the x-axis. The horizontal black line represents the level of lysis in the absence of secondary peptide addition.

 
To use 2C x OT-I dual reactive T cells to in the system outlined in Fig. 1Go, it was essential that each TCR did not cross-react with antagonist ligands for the other. Hence, we tested TCR antagonism of "parental" OT-I and 2C single TCR transgenic T cells by various Kb binding peptides. As shown in Fig. 3Go, CTL bearing the OT-I TCR were antagonized by E1 and V-OVA but not by the SIY-A6 peptide. Reciprocally, CTL with the 2C TCR were antagonized by SIY-A6, but not by E1 (Fig. 3Go) or V-OVA (data not shown) peptides. As expected, neither CTL population was antagonized by P815p, an efficient Kb binding peptide (27, 28) with little homology to either OVAp or SIYp.

Absence of cross-antagonism in 2C x OT-I T cells

2C x OT-I dual reactive CTL lines were established from two separate mice (#13 and #14) and tested for direct- and cross-antagonism, as described above. Direct antagonism could easily be seen for both the 2C and OT-I receptors, using the same antagonist ligands defined for the parental T cells, but there was no evidence for cross-antagonism (Fig. 4Go, A and B). For example, when stimulated through the OT-I receptor, line 13-SPOP was antagonized by E1 and V-OVA as expected, whereas SIY-A6 failed to inhibit the response. In contrast, when this line was stimulated through the 2C receptor, the SIY-A6 peptide caused the expected antagonism while E1 and V-OVA had no effect. CTL line 14S showed comparable responses (Fig. 4GoB), and similar results were obtained using several different suboptimal agonist doses for lines from both animals (data not shown). Furthermore, these results were not significantly affected by differences in the TCR stimuli used to generate or maintain the CTL lines (data not shown). Thus, our data indicate that a global negative signal is not a mechanism for TCR antagonism in our system.



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  		FIGURE 4. Absence of cross-antagonism using 2C x OT-I cells. Antagonism assay using 2C x OT-I lines 13-SPOP (A) and 14-S (B). EL4 target cells were pulsed with SIYp (10 pM) (a) or OVAp (37.5 pM for line 13SPOP and 150 pM for line 14/S) (b). Target cell lysis was determined in the presence or absence of titrated P815p, SIY-A6, V-OVA, or E1 peptides. Data are plotted as for Fig. 3Go.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Through generation of CD8+ T cells bearing two non-cross-reactive TCRs, we were able to test whether TCR antagonism involves a global (dominant) negative signal. The specificity and efficiency of direct-antagonism was very similar between the 2C x OT-I dual TCR-expressing CTL and each parental CTL, indicating that expression of both TCRs did not affect the signaling capacity or agonist/antagonist specificity of either receptor. However, we found no evidence for cross-antagonism between these receptors, in either direction. Hence, our data argues against the global negative signal model.

How then can we account for TCR antagonism? As described in Fig. 1Go, model 2, there are two likely possibilities. One is that antagonists induce no signal and act simply by direct competition for the TCR, preventing its engagement with agonist ligands. This idea has been criticized by various authors (19, 29) by the argument that the antagonist would need to engage nearly all the cell surface TCRs to effectively compete: an unlikely situation given both the low density of antagonist ligand and high numbers of TCRs, plus the low TCR affinity for antagonists. However, such reasoning may not be valid for T cells interacting with physiological ligands, where both the TCR and its ligands are cell-surface bound. Rather than competing for all TCRs, antagonists need only compete for TCRs in the vicinity of an agonist ligand on the APC cell surface, i.e., in the initial T cell-APC contact cap. From this viewpoint, a simple excess of antagonist vs agonist ligands would be sufficient to block activation. An additional factor is the capacity of ligands to interact with multiple TCRs, in the process termed serial triggering (17, 18). A key feature of this process is that the TCR should release the ligand fairly rapidly after activation: thus, a low-affinity TCR ligand (i.e., a typical antagonist) would serially trigger more TCRs than a higher-affinity ligand, per unit time. Hence, ironically, an antagonist may efficiently out-compete an agonist in the T cell-APC contact zone as a direct consequence of the former ligands’ lower affinity.

A second, more interesting possibility is that TCR antagonists induce an abortive signal, i.e., one that acts locally to "inactivate" a specific TCR, rather than globally to inactivate the T cell. For example, partial phosphorylation of TCR {zeta}-chain immunoreceptor tyrosine-based activation motifs, observed with many TCR antagonists and partial agonists (8, 9, 10, 11), might incapacitate the TCR, preventing its ability to signal following any subsequent interaction with an agonist. This effect would be TCR specific, i.e., it would not affect the signaling capacity of other TCRs expressed on the same T cell, as is observed in our system. Again, if serial triggering occurs, this may allow low-affinity antagonist ligands to interact with and "inactivate" multiple TCRs rapidly.

Reports that certain TCR antagonists inhibit when at molar inferiority vs the agonist (12, 13, 14, 15) are hard to reconcile with the absence of a global negative signal proposed here. Of course, our data do rule out the existence of other "types" of TCR antagonist that might use a dominant negative signal, but we think a more likely explanation concerns subtle differences in the categorization of suboptimal TCR ligands. Specifically, there is a risk that TCR "antagonists" defined by their capacity to inhibit individual T cell response, might actually be partial agonists. Such ligands may induce a specific response that distracts the T cells from their normal function, but are not strict antagonists. Interestingly, all the "dominant" antagonists so far reported were isolated from pathogens (12, 13, 14, 15), and this might suggest they are selected for a role in immune evasion.

In contrast to our data, Evavold’s group observed cross-antagonism using a similar system, involving dual TCR cells with MHC class II-restricted receptors (B. Evavold, unpublished observations). This discordance might again result from distinctions between strict antagonist and partial agonist ligands or could be a real difference in the mechanism of CD4 vs CD8 T cell antagonism. Additional experiments with other systems will be needed to resolve this interesting question.


   Acknowledgments
 
We thank Dawn Erlandson for maintaining and typing the mice, Matt Mescher for various reagents, Brian Evavold for communicating unpublished data and stimulating discussions, and members of the Jameson and Hogquist labs for practical and intellectual contributions to this work.


   Footnotes
 
1 This work was supported in part by the American Cancer Society (IN-13-35-19 and JFRA-639) and U.S. Public Health Service Grant AI-38903 (to S.C.J.). M.A.D. was supported by the University of Minnesota graduate program in Microbiology, Immunology, and Molecular Pathobiology. Back

2 Address correspondence and reprint requests to Dr. Stephen C. Jameson, Department of Laboratory Medicine and Pathology, Box 334 FUMC, University of Minnesota Medical School, 420 Delaware St. SE, Minneapolis, MN 55455. E-mail address: Back

Received for publication December 7, 1998. Accepted for publication January 25, 1999.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
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