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The Journal of Immunology, 2003, 170: 1224-1230.
Copyright © 2003 by The American Association of Immunologists

TCR Reserve: A Novel Principle of CD4 T Cell Activation by Weak Ligands 1

Lisa K. McNeil and Brian D. Evavold2

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


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Some ligand-receptor systems have a receptor reserve where a maximal response can be achieved by occupation of a fraction of available receptors. An implication of a receptor reserve is the expansion of the number of ligands for response. To determine whether T cells follow receptor reserve, we have characterized the effect of reducing TCR levels on CD4 T cell responses elicited by altered peptide ligands that vary in potency. Agonist peptide is unaffected by a 90% reduction in TCR level while proliferation to weak agonists is significantly inhibited when TCR expression is reduced by 40%. Thymocyte-negative selection similarly demonstrates a differential requirement of TCR for response to agonist, weak agonist, and partial agonist. Therefore, our data demonstrate receptor reserve as a novel principle of T cell activation in which excess TCRs expand the antigenic repertoire to include less potent ligands.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Several groups have demonstrated that only a small percentage of the ~30,000–100,000 TCRs are needed for response to agonist. For example, a child with a mutation in CD3{epsilon}, which caused a reduction in TCR/CD3 levels, responded to tetanus toxin and alloantigen (1, 2). In CD8+ T cells, ligands with a high affinity for the TCR require only 500-1000 TCRs for cytolysis or proliferation (3, 4). Together, these observations suggest an excess expression of TCR by T cells for response to agonist and raise questions on the utility of spare Ag receptors.

Receptor reserve was proposed to explain the observations of alkyl triethylammonium ions on the contraction of the guinea pig ileum (5). Some of the analogs were able to achieve a maximal response whereas others had only partial activity, achieving a reduced maximal response. To account for the apparent differential response to analogs of varying potency, the spare receptor theory proposes that a full agonist need not occupy all receptors to achieve the maximal response (5). The less potent partial/weak agonists make use of the spare receptors and occupy more receptors to respond. Experimental evidence for the existence of spare receptors came from work with irreversible antagonists, which allows for the identification of the fractional occupancy of the receptor (6, 7). An advantage of receptor reserve is that it provides a mechanism to expand the potential number of ligands for a receptor.

TCRs interact with multiple ligands of differing potency to mediate thymocyte selection, T cell survival, alloreactivity, and autoimmunity in addition to responses against pathogens. Analysis of the T cell response to altered peptide ligands (APLs)3 further underscores the potential of TCR interaction with ligands of differing potency. APLs are analogs of the immunogenic peptide that typically have substitutions at TCR contact residues (8). APLs can be divided into different classifications based on the potency of response they elicit from T cells (9). Agonists and weak agonists can maximally stimulate all effector functions of a T cell, although weak agonists require a higher concentration of peptide. Partial agonists cannot induce proliferation of T cells, yet they can stimulate other effector functions such as cytokine production or cytolysis. In light of receptor reserve, we wanted to determine whether manipulating the TCR level would affect T cell responses to ligands of different potency.

Although few TCRs appear necessary for T cell activation to strong agonists, we extend this analysis to include less potent ligands. Reducing TCR levels ablates the T cell and thymocyte responses to a weak agonist but has no effect on the effector functions induced by full agonists. Our data illustrate that receptor reserve is essential to expand the repertoire of TCR ligands to less optimal ligands such as weak and partial agonists.


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

AND TCR-transgenic mice (TgN(TcrAND)53Hed) (H-2b) and B10.A/Cr (H-2a) mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and the National Cancer Institute (Frederick, MD), respectively (10). 3A9 TCR-transgenic mice were a gift from Drs. C. Larsen and T. Pearson (Emory University, Atlanta, GA) (11). 3A9 and AND mice were bred together to generate (3A9 x AND)F1 mice transgenic for two TCRs (12). All mice were housed and maintained at the Department of Animal Resources Facility (Emory University).

Peptides

Peptides were synthesized using standard F-moc (9-fluorenylmethyloxycarbonyl) chemistry on a Symphony/Multiplex Peptide Synthesizer and analyzed by HPLC (Ranin Instruments, Woburn, MA) and mass spectrometry at the Department of Chemistry Core Facility (Emory University). The sequences of the peptides used were as follows: MCC88–103 (ANERADLIAYLKQATK), 97F (ANERADLIAFLKQATK), 102Q (ANERADLIAYLKQAQK), and 99G (ANERADLIAYLGQATK).

Cells and reagents

Transgenic T cell lines were obtained by stimulating AND splenocytes with 1 µM MCC88–103. T cell lines were restimulated every 7 days in a 24-well plate with MCC and 5 x 106 gamma-irradiated spleen cells (2000 rad) from a B10.A mouse. Cell culture medium consisted of RPMI 1640 supplemented with 10% FBS (Mediatech, Herndon, VA), 2 mM L-glutamine, 0.01 M HEPES buffer, 100 µg/ml gentamicin (Mediatech), and 2 x 10-5 M 2-ME (Sigma-Aldrich, St. Louis, MO). The following Abs were used: CD8, CD4 (Caltag Laboratories, Burlingame, CA), CD69, and V{beta}3 (BD PharMingen, San Diego, CA). Supernatants from the B cell hybridoma KJ25 were harvested and anti-V{beta}3 molecules were collected on a protein IgG column. V{beta}3 Fab were generated using the Immunopure Fab Preparation kit (Pierce, Rockford, IL). SDS-PAGE confirmed that the Fab were >95% pure.

TCR quantitation

Quantum R-PE microbeads 500–50(500–50,000 molecular equivalents of fluorescein; Bangs Laboratories, Fishers, IN) carrying known numbers of PE molecules were used as fluorescent standards to directly quantitate the absolute numbers of TCR on AND T cells and thymocytes. The AND T cells and thymocytes were incubated with anti-V{beta}3 Fab molecules at 37°C for 30 min, then V{beta}3-PE was added and flow cytometry was performed. The data were analyzed using the calibration platform from the FlowJo software (Tree Star, San Carlos, CA), based on a fluorescence:protein ratio for PE:Ab of 1:1 and monovalent binding of the Ab when used at binding at saturating levels.

Proliferation assay

AND x B10.A or 3A9 x AND splenocytes (3 x 105/well) were incubated with the indicated peptide in a 96-well plate. After 72 h in culture, cells were labeled with 0.4 µCi/well [3H]thymidine and after another 18 h, the plates were harvested and analyzed on a Matrix 96 Direct Beta Counter (Packard Instruments, Meriden, CT). In some assays, various concentrations of V{beta}3 Fab were added for the entire culture period to mask TCR.

Dulling assay

Transgenic thymocytes (1 x 105) were cultured with B10.A peritoneal exudate cells (5 x 105), the indicated concentrations of peptide, and various concentrations of V{beta}3 Fab in a flat-bottom 96-well plate. After 16–20 h of incubation, the cells were stained with CD4, CD8, and V{beta}3, and surface expression of the Abs was assessed by flow cytometry on a BD Biosciences FACSCalibur (Mountain View, CA). The data are expressed as percent dulling or percent deletion of thymocytes, which is calculated as (1- (DPpeptide/DPno peptide)) x 100.

CD69 up-regulation

CD69 up-regulation was performed as described by Davey et al. (13). Exactly 5 x 105 thymocytes or purified CD4+ splenocytes from AND mice, 105 CH27 cells, various concentrations of peptide, and V{beta}3 Fab were incubated for 3 h at 37°C in a round-bottom 96-well plate. Following incubation, the cells were stained for CD4, CD8, V{beta}3, and CD69 expression. The CD69 levels at 100 µM MCC were set at 100% and the data were normalized by dividing the mean fluorescence intensity at the experimental peptide dilution by the mean fluorescence intensity at 100 µM MCC and multiplying by 100.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Dual TCR T cells demonstrate a receptor reserve

AND TCR-transgenic mice express a V{alpha}11,V{beta}3 TCR specific for MCC88–103 peptide presented by IEk MHC while 3A9 TCR-transgenic mice express a V{alpha}3,V{beta}8.2 TCR specific for HEL48–62 presented by IAk MHC. When these two transgenic mice are bred together, the F1 offspring have CD4+ T cells that express both TCRs, dual TCR T cells (12). However, although 3A9 x AND T cells express both TCRs, the AND TCR is lower on the dual T cells (1,590 V{beta}3 TCR) as compared with AND single-transgenic T cells (47, 815 V{beta}3 TCR) (Fig. 1A).



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  		FIGURE 1. Proliferation of AND vs 3A9 x AND splenocytes to a weak agonist. A, Splenocytes from AND mice (shaded) and 3A9 x AND dual transgenic mice (black line) were stained with V{beta}3 and gated on CD4+ T cells. The number above each histogram corresponds to the molecules of V{beta}3 TCR expressed on each cell population as quantified by microbeads. AND-transgenic splenocytes (B) and 3A9 x AND dual TCR-transgenic splenocytes (C, 3 x 105) were incubated with the indicated doses of peptides for 72 h and proliferation was measured by [3H]thymidine incorporation.

 
To determine whether TCR reserve is important for recognition of weaker ligands, we examined the ability of the single and dual TCR-transgenic T cells to proliferate to APLs. MCC88–103, the wild-type peptide, is a full agonist for AND T cells as is 97F, an APL with a conservative substitution at the P3 secondary TCR contact residue. 102Q substitutes a glutamine for a threonine at the P7 TCR contact residue and is classified as a weak agonist (Fig. 1B and our unpublished observations). The two agonist peptides, MCC and 97F, induced maximal proliferation of both the AND T cells and the 3A9 x AND dual T cells (Fig. 1, B and C). However, the weak agonist 102Q was unable to stimulate proliferation of 3A9 x AND dual T cells. Although the dual T cells are slightly less sensitive, the half-maximal response to agonist is very similar on the single (0.1 µM) and dual (0.5 µM) transgenic T cells. In contrast, the half-maximal response to the 102Q weak agonist is 10 µM for single AND T cells and undefined (>100 µM) for the 3A9 x AND dual T cells. Although the dual TCR cells are not appreciably less sensitive to agonists, as shown by half-maximal value, the dual TCR cells lose response to weaker ligands.

Decreased TCR expression ablates proliferation

To address whether the lower TCR levels on 3A9 x AND dual T cells is responsible for the inability to respond to a weak agonist, the TCR level was decreased on AND T cells using Fab specific for V{beta}3. V{beta}-specific Fab essentially behave as an irreversible antagonist by binding to the TCR and effectively blocking the TCR from ligation by antigenic peptide-MHC complexes (14). As shown in Fig. 2, the number of V{beta}3 molecules on AND CD4+ splenocytes can be blocked with 15 µg/ml Fab to 9%, or 4175 TCRs. The AND T cell response stimulated by MCC is not affected by any concentration of V{beta}3 Fab, even when the TCR level was masked by 90% (Fig. 3A). Proliferation to 97F, a full agonist, is also unaffected by blocking of the TCR (data not shown). Fifteen micrograms of Fab per milliliter Fab was chosen as our maximal because a complete blockade of TCR would require extreme amounts of Fab (500 TCR = 1300 µg/ml Fab; 10 TCR = 1.2 x 107 µg/ml Fab, see equation in Fig. 2A). In contrast, the proliferative response to 102Q, the weak agonist, is significantly inhibited when TCR expression is blocked by 40% and the response is completely abrogated at 0.15 µg/ml Fab when 15% of the TCR remain (Fig. 3B). Based on analysis of the proliferative response, AND T cells express a huge receptor reserve for responses to agonists. Weak agonists, on the other hand, have a higher fractional receptor occupancy for response. Thus, the excess TCRs increase the repertoire of T cell Ags to include less potent ligands.



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  		FIGURE 2. Quantitation of V{beta}3 molecules on AND CD4+ splenocytes and DP thymocytes. A, A best-fit curve of the data correlates Fab concentration vs the number of V{beta}3 molecules. The equation of the line is y = 10627.613x-0.428, r2 = 0.954. B, A table demonstrating the number of V{beta}3 molecules remaining on splenocytes and thymocytes after incubation with various concentrations of V{beta}3 Fab. AND CD4+ T cells and AND DP thymocytes were analyzed by flow cytometry for V{beta}3 expression after incubation with various concentrations of V{beta}3 Fab. R-PE microbeads carrying known numbers of PE molecules were used to directly quantitate the absolute numbers of V{beta}3 molecules on the T cells and thymocytes.

 


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  		FIGURE 3. Blocking TCR on AND splenocytes ablates the proliferative response to the weak agonist, 102Q. AND-transgenic splenocytes (3 x 105) were incubated with the indicated doses of MCC (A) or 102Q and various concentrations of V{beta}3 Fab (B) for 72 h and proliferation was measured by [3H]thymidine incorporation.

 
Decreasing the TCR on thymocytes prevents negative selection

We have suggested that negative selection of thymocytes is also dependent on TCR levels (15). The dulling assay is an in vitro model for negative selection and TCR triggering that measures the down-regulation of the CD4 and CD8 coreceptors on double-positive (DP) thymocytes induced by Ag (16, 17). Previous reports have demonstrated that APLs, including antagonists, weak agonists, and partial agonists are able to induce negative selection of CD4+ T cells (17, 18). MCC (agonist), 97F (agonist), 102Q (weak agonist), and 99G (partial agonist) induce dulling, or negative selection, of AND thymocytes (Fig. 4A). Blocking of the V{beta}3 TCR has no effect on negative selection at any concentration of the agonists MCC and 97F (Fig. 4, B and C). DP dulling in response to the partial agonist 99G is inhibited by 50% when TCR levels are masked by almost 80% (Fig. 4D). Similarly, the weak agonist 102Q is unable to stimulate negative selection when 85% of the TCRs are blocked (Fig. 4E). Therefore, weak agonists and partial agonists are inhibited from mediating negative selection of AND thymocytes when TCR levels are reduced, extending the concept of a receptor reserve to include thymocyte selection.



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  		FIGURE 4. Blocking the TCR prevents negative selection of AND thymocytes in response to APLs. AND-transgenic thymocytes (5 x 105) and B10.A peritoneal exudate cells (105) were incubated with various concentrations of the indicated peptides (A) or with V{beta}3 Fab and 100 µM MCC (B), 100 µM 97F (C), 100 µM 99G (D), and 100 µM 102Q (E) for 16–20 h. Cells were analyzed by flow cytometry for expression of CD4 and CD8. Percent dulling is calculated as (1 - (DPpeptide/DPno peptide)) x 100.

 
CD69 up-regulation

T cells and thymocytes may be differentially sensitive to TCR levels, yet T cell proliferation and thymocyte negative selection are difficult responses to compare directly. Accordingly, CD69 up-regulation, a very early event in the activation of both thymocytes and T cells, was measured in response to the ligands (13, 19, 20). CD4+ splenocytes and DP thymocytes demonstrate similar expression of CD69 after 3 h of incubation with MCC and 97F (Fig. 5). The APLs, 102Q and 99G, induced considerable up-regulation of CD69 on mature T cells and thymocytes, although at lower levels than for MCC. Since all of the peptides have the same affinity for IEk, the same dose of each peptide (100 µM) was used with various concentrations of Fab, allowing comparison of responses to equivalent number of peptide-MHC complexes.



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  		FIGURE 5. CD69 up-regulation on AND CD4+ splenocytes and DP thymocytes. CH27 APCs and AND CD4+ T cells (A) or AND DP thymocytes (B) were incubated with the indicated concentrations of peptide for 3 h. The cells were analyzed by flow cytometry for CD69 expression. The data have been normalized such that CD69 up-regulation was defined as 100% for 100 µM MCC for each cell population.

 
Addition of V{beta}3 Fab to mask TCR expression had no effect on the CD69 levels on CD4+ T cells and DP thymocytes induced by either agonist, MCC or 97F (Fig. 6A). CD69 up-regulation on splenocytes was inhibited at 15 and 5 µg/ml Fab for 102Q and 99G, corresponding to an ~90% reduction in TCR number (Fig. 6B). Comparable to the splenocytes, the weak agonist 102Q and the partial agonist 99G displayed reduced expression of CD69 on DP thymocytes at higher concentrations of V{beta}3 Fab (Fig. 6B). Although the data presented are at a single peptide concentration (100 µM), CD69 up-regulation to lower doses of peptide was not more sensitive to the addition of Fab (data not shown). In summary, CD69 expression was inhibited by reducing TCR levels on thymocytes and splenocytes demonstrating an equal dependence on receptor reserve for response to APLs.



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  		FIGURE 6. Blocking the TCR inhibits CD69 up-regulation by APLs on splenocytes and thymocytes. CH27 APCs and CD4+ T cells ({square}, {circ}, {triangleup}, {diamond}) or AND thymocytes ({blacksquare}, •, {blacktriangleup}, {diamondsuit}) were incubated with the indicated concentrations of V{beta}3 Fab and 100 µM MCC or 100 µM 97F (A), or 100 µM 102Q or 100 µM 99G (B) for 3 h, then stained for CD69 expression.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In ligand-receptor systems governed by receptor reserve, the repertoire of ligands is expanded by virtue of maximal receptor expression. Originally described by Stephenson (5) in muscarinic receptors, receptor reserve has also been observed in other systems such as G protein-coupled receptors, CCR3, and dopamine receptors (21, 22). Our data demonstrate the application of receptor reserve to T cells. First, T cells have an excess of TCRs or a receptor reserve, as the full agonist MCC can still induce maximal proliferation when 90% of the TCRs are blocked (Figs. 2 and 3). Second, the spare receptors increase the flexibility of the T cell and thymocyte to respond to weaker ligands (Figs. 3 and 4). This is the first report demonstrating the distinct TCR levels required for CD4+ T cell responses to ligands differing in potency. Thus, the data support a spare receptor model of T cell activation where the reserve TCRs are needed, not for response to agonist, but to expand the antigenic repertoire of T cells to include less potent ligands.

More than applying a new term to T cell biology, receptor reserve redefines the mechanism of T cell activation. Receptor reserve is not simply an extension of the law of mass action in which a higher concentration of engaged TCRs equates to an increase in the magnitude of the response, as agonist ligands achieve maximal activation irrespective of whether 4,000 or 48,000 TCRs are expressed. Instead, the spare Ag receptor allows for increased response to weaker ligands. In this study, we demonstrated this property for weak and partial agonists but we would expect a similar requirement for spare receptors in antagonism. Unlike TCRs, not all ligand-receptor systems have spare receptors or have flexible ligand recognition to allow different levels of response. For example, cytokine receptors, such as IL-4, IL-2, and IL-12, only interact with one ligand and follow the law of mass action, i.e., the more receptors bound by cytokine, the higher the magnitude of response (23).

Although DP thymocytes have a lower overall level of TCR as compared with peripheral CD4+ T cells, they both appear to make use of the receptor reserve for responses to weak ligands (24). How much TCR is required for T cell responses in the periphery vs the thymus? CD69 up-regulation directly compares the peripheral T cell and thymocyte response to ligand and similar dose-response curves are generated for MCC and the analog peptides for both cell types (Fig. 5). Masked TCR levels inhibit CD69 expression to similar levels with 99G and 102Q for CD4+ T cells and DP thymocytes but this equates to 5000 TCRs on splenocytes and only 2000 TCRs on DP thymocytes (Figs. 2 and 6). Since thymocytes have a lower activation threshold than mature T cells, they can compensate for the lower amount of TCRs on their surface (25). Thus, thymocytes require fewer TCRs and are more sensitive to ligands with TCR contact substitutions than mature T cells, indicating that the excess TCRs may play an important role in negative selection of thymocytes that are weakly reactive to self-ligands. This is in contrast to our studies using MHC variant peptides where we have demonstrated that elevated TCR in the periphery increases the response to less stable peptide-MHC complexes (15).

Based on our data, we propose receptor reserve as a model of TCR triggering and activation in response to ligands of differing potency. Other models of T cell activation have been proposed to explain TCR response to ligands differing in potency and include serial engagement, kinetic proofreading/discrimination, and the immunological synapse (26, 27, 28, 29, 30, 31, 32). However, these models are all based on the presence of excess TCR and do not specifically consider TCR density as a limiting factor for activation. In addition, they fail to adequately describe responses to weak ligands. For example, weak agonists initiate responses in the absence of TCR internalization and significant serial engagement (27, 33, 34). Kinetic models rely on the half-life of the TCR-peptide-MHC complex to achieve the activation threshold, yet no provision is given for weak/partial agonists to reach this threshold by interacting with more TCR (28, 29). Finally, the role of the immunological synapse in initial TCR triggering and activation is probably limited (32, 35). As the number of TCR molecules is essential for T cell activation elicited by weak ligands to overcome the activation threshold barrier, receptor reserve more accurately models and describes T cell activation.

Although our analysis of TCR reserve and ligand potency made use of APLs, the relationship between TCR expression level and response to less potent ligands should also explain recognition of peptide-MHC complexes during selection, survival, autoimmunity, transplantation, and infection. For example, could this flexible recognition of ligand provide a mechanism for T cells to combat immune evasion strategies? Pathogens can mutate their immunodominant T cell epitopes by forming natural APLs in an attempt to evade recognition by the cells of the immune system (36, 37). If only a few TCRs are necessary to initiate the expansion phase of the immune response, maintenance of a receptor reserve would allow for response to mutations in the immunodominant epitope that arise later in the life cycle of the pathogen and are weaker in potency. In fact, a naturally occurring mutant of the CTL epitope of lymphocytic choriomeningitis virus can elicit cytolysis of targets, behaving as a weak agonist, presumably through interaction with excess receptors (25, 38). Other viral escape mutants that attenuate the T cell response have been identified, including mutations of HIV, hepatitis C virus, hepatitis B virus, and influenza (39, 40, 41, 42, 43, 44). Thus, excess expression of TCRs could have evolved for T cells to combat the immune evasion strategy of mutations in the immunodominant epitope.

In summary, our data indicate that T cells and thymocytes possess a receptor reserve to increase the flexibility of T cells to respond to ligands of weaker potency. This view of T cell activation impacts on all recognition of weaker ligands by T cells and may have direct implications for T cell survival, selection, and autoimmunity.


   Acknowledgments
 
We thank Mandy L. Ford for critical reading of this manuscript and the members of the Evavold laboratory for their support.


   Footnotes
 
1 This work was supported by American Cancer Society Grant RPG-00-314 and National Institutes of Health Grant R29A40549. Back

2 Address correspondence and reprint requests to Dr. Brian D. Evavold, Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, GA 30322. E-mail address: evavold{at}microbio.emory.edu Back

3 Abbreviations used in this paper: APL, altered peptide ligand; DP, double positive. Back

Received for publication August 13, 2002. Accepted for publication November 22, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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