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The Journal of Immunology, 2000, 165: 6791-6795.
Copyright © 2000 by The American Association of Immunologists

Functional Equivalency of B7-1 and B7-2 for Costimulating Plasmid DNA Vaccine-Elicited CTL Responses1

Sampa Santra*, Dan H. Barouch*, Shawn S. Jackson*, Marcelo J. Kuroda*, Joern E. Schmitz*, Michelle A. Lifton*, Arlene H. Sharpe{dagger} and Norman L. Letvin2,*

* Department of Medicine, Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and {dagger} Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
A costimulatory signal in addition to an Ag-specific stimulus is required for optimal activation of T lymphocytes. CD28, the primary positive costimulatory receptor on T cells, has two identified ligands, B7-1 and B7-2. Whether B7-1 and B7-2 have identical, overlapping, or distinct functions remains unresolved. In this study, we show that mice lacking B7-2 were unable to generate CTL responses following immunization with a plasmid DNA vaccine. The ability of these B7-2-deficient mice to generate CTL responses following plasmid gp120 DNA vaccination was fully reconstituted by coadministering either a plasmid expressing B7-2 or B7-1. Moreover, the ability to generate CTL responses following plasmid DNA vaccination in mice lacking both B7-1 and B7-2 could be reconstituted by administering either plasmid B7-1 or plasmid B7-2 with the vaccine construct. These data demonstrate that either B7-1 or B7-2 administered concurrently with a plasmid DNA vaccine can fully costimulate vaccine-elicited CTL responses. Functional differences between B7-1 and B7-2 observed in vivo therefore may not reflect inherent differences in the interactions of CD28 with these ligands.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The full activation of T cells requires both an Ag-specific stimulus provided by an MHC-peptide complex and a costimulatory signal (1, 2). Engagement of CD28 on the surface of T cells by B7-1 (CD80) (3, 4) or B7-2 (CD86) (5, 6, 7) expressed by APCs provides a potent costimulatory signal. CD28-B7 interactions lead to T cell proliferation, differentiation, and cytokine secretion. In contrast, engagement of CTLA-4 on activated T cells by B7-1 or B7-2 results in inhibition of T cell responses (8). The identification of two similar B7 molecules that both interact with CD28 and CTLA-4 has spurred considerable recent interest in defining any functional differences that might exist between these molecules.

Some investigators have suggested that B7-1 and B7-2 provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL (9, 10). However, others have reported significant biological differences between these molecules, including differences in their ability to induce IL-4 production (11), maturation toward polarized Th1 or Th2 phenotypes (12), antitumor immunity (13, 14), and immune responses following viral infection (15). Using mice genetically deficient for either B7-1 or B7-2, we have shown that the functions of these two molecules in the generation of Ab responses are largely overlapping (16). However, B7-2 was demonstrated to have an independent critical role in the initiation of Ab responses elicited by a protein Ag in the absence of adjuvant. We have also shown that either B7-1 or B7-2 is sufficient for the generation of Ab and CTL responses against vesicular stomatitis virus (17).

Whether the observed functional differences between B7-1 and B7-2 reflect inherent differences in their biological functions or result from their distinct temporal expression patterns has not yet been fully investigated. Both B7-1 and B7-2 have a high affinity for CTLA-4 and a lower affinity for CD28. However, B7-2 exhibits faster dissociation kinetics than B7-1 in interactions with both CD28 and CTLA-4 (18), suggesting a possible mechanism by which these molecules may exert different biological effects. Alternatively, the different expression patterns of B7-1 and B7-2 may account for their functional differences. B7-2 is constitutively expressed on monocytes and dendritic cells, whereas B7-1 is inducible (4, 7, 19). The expression of both B7-1 and B7-2 is up-regulated following activation of B cells and monocytes, but B7-2 is up-regulated more quickly than B7-1 (20, 21). The constitutive and early expression of B7-2 has led to the hypothesis that B7-2 may be important for initiating an immune response, whereas B7-1 may be important for maintaining the response (6).

In the present study, we have explored the relative importance of the contributions of B7-1 and B7-2 to the generation of HIV-1 envelope-specific CTL responses elicited by a plasmid DNA vaccine. The experiments show that, although B7 expression is critical for the generation of this vaccine-elicited immune response, either B7-1 or B7-2 alone can mediate this costimulatory function.


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

The plasmid DNA vaccine expressing HIV-1 IIIB gp120 (pV1J-gp120) was obtained from John Shiver (Merck Research Laboratories, West Point, PA) (22, 23, 24). The sham plasmid was the empty pV1J vector. Plasmid-encoded B7-1 and B7-2 were constructed in the pV1J backbone, as described previously (25). Plasmids were prepared from large-scale bacterial cultures, as described elsewhere (24).

Mice and immunizations

Eight- to 12-wk-old wild-type BALB/c mice were purchased from Charles River Breeding Laboratories (Wilmington, MA). B7-1-/-, B7-2-/-, and B7-1-/-/B7-2-/- BALB/c mice on backcross generation 10 were bred for these studies (5, 16). Mice were immunized by the i.m. route by injecting 50 µg of pV1J-gp120 plasmid in normal saline without adjuvant using a 100-µl injection volume. Half the dose of plasmid was delivered to each quadriceps muscle. For reconstitution experiments, 50 µg of pV1J-gp120 plasmid was mixed with 50 µg of either pV1J, pV1J-B7-1 or pV1J-B7-2 plasmid DNA before injection. In some experiments, a lower dosage of B7 plasmid was used.

CTL assays

CTL responses specific for the immunodominant gp120 P18 peptide (26) were assessed in vaccinated mice, as reported previously (24, 25). Spleens were aseptically removed 3 wk after immunization, and RBC were removed from single-cell splenocyte suspensions using a hypotonic NH4Cl-KCl lysis buffer. A total of 8 x 106 washed splenocytes was then stimulated with 20 µg/ml of the HIV-1 IIIB V3 loop P18 epitope peptide RIQRGPGRAFVTIGK (26) in RPMI 1640 medium containing 10% FBS, 20 U/ml penicillin, 20 µg/ml streptomycin, and 50 µM 2-ME (Life Technologies, Rockville, MD). IL-2 (10 U/ml; Sigma, St. Louis, MO) was added on day 2. On day 7, the cultured splenocytes were harvested and used as effector cells in standard 51Cr release cytotoxicity assays with P815 mastocytoma cells (American Type Culture Collection, Manassas, VA) as target cells. A total of 1 x 106 P815 cells, pulsed overnight with 20 µg/ml P18 peptide and 250 µCi of 51Cr, was washed, and 104 target cells were added to varying concentrations of effector cells in 200-µl reaction volumes. Spontaneous and maximum release were measured by incubating target cells with media and 2% Triton X-100, respectively. After a 5-h incubation, 50 µl of supernatant was harvested, mixed with scintillation fluid, and assayed for radioactivity using a Wallac 1450 Microbeta liquid scintillation counter (Wallac, Gaithersburg, MD). Spontaneous release was <10% of maximum release. Percent specific cytotoxicity was measured as ((experimental release - spontaneous release)/(maximum release - spontaneous release)) x 100.

Tetramer staining

Tetrameric H-2Dd/P18 tetramers were prepared essentially as described previously (27, 28). A total of 0.1–0.2 µg of PE-labeled tetrameric H-2Dd–P18 complexes in conjunction with APC-labeled anti-mouse CD8{alpha} (Ly-2; Caltag, South San Francisco, CA) mAb was used to stain P18-specific CD8+ T cells, as described elsewhere (28). Mouse blood was collected in unsupplemented RPMI 1640 containing 40 U/ml heparin. Following lysis of the RBC, the lymphocytes were stained with the above reagents, washed in PBS containing 2% FBS, and fixed in 0.5 ml of PBS containing 1.5% paraformaldehyde. Samples were analyzed by two-color flow cytometry on a FACScalibur (Becton Dickinson, Mountain View, CA) system. Gated CD8+ T cells were examined for staining with tetrameric H-2Dd–P18 complexes.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To examine the costimulatory requirements for a vaccine-elicited CTL response, we examined the ability of the plasmid DNA vaccine pV1J-gp120 to elicit CTL in wild-type, B7-1-/-, and B7-2-/- mice. This DNA vaccine elicited potent gp120 epitope-specific CTL responses in wild-type mice, and lower, but readily detectable responses in B7-1-/- mice. However, no CTL responses were detected in similarly vaccinated B7-2-/- mice (Fig. 1Go). This confirms our earlier observation (25) that B7-2 is critical for generating CTL responses following plasmid DNA immunization. B7-1 appears not to be required for developing these CTL responses, but is required for generating maximal CTL responses.



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  		FIGURE 1. Requirement for B7-2 in generating CTL responses following plasmid DNA vaccination. Wild-type, B7-1-/-, and B7-2-/- BALB/c mice (n = 4 mice per group) were immunized with 50 µg of pV1J-gp120. Specific CTL activity was measured in splenocytes from each mouse in duplicate after 3 wk by chromium release assays. The mean responses for each group with SEs are shown and are representative of independent experiments performed at least twice.

 
We reasoned that there were two possible explanations for the critical requirement of B7-2 but not B7-1 in costimulating CTL responses elicited by immunization with this DNA vaccine. B7-2 may mediate critical biological functions that cannot be mediated by B7-1. Alternatively, the B7-1 and B7-2 proteins may not have inherent functional differences, but an apparent selective requirement for B7-2 may reflect the different expression patterns of B7-1 and B7-2. For example, B7-2, but not B7-1, is expressed constitutively by APCs and is rapidly up-regulated following activation, and is therefore selectively present early in an immune response (7, 19, 20). To differentiate between these two possibilities, we explored the ability of B7-2-deficient mice to develop CTL responses following plasmid gp120 DNA vaccination when these mice were concurrently inoculated with a plasmid expressing B7-1 or B7-2.

As shown in Fig. 2GoA, coinoculation of plasmid B7-2 with the plasmid gp120 DNA vaccine in B7-2-/- mice reconstituted the vaccine-elicited CTL responses to wild-type levels. Coinoculation of 50 µg of a sham plasmid control with the DNA vaccine, however, did not reconstitute these CTL responses. As shown in Fig. 2GoB, injection of the plasmid B7-2 2 days before or 2 days after the gp120 DNA vaccine led to only a partial reconstitution of the CTL responses. Thus, plasmid B7-2 inoculated concurrently with the vaccine was able to correct, at least transiently, this immunological defect in B7-2-/- mice. The requirement for concurrent inoculation of plasmid B7-2 and the DNA vaccine most likely reflects a requirement for close temporal and spatial expression of B7-2 and Ag for optimal costimulation.



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  		FIGURE 2. Coadministration of plasmid B7-2 can reconstitute the ability of B7-2-/- mice to generate CTL responses following DNA vaccination. A, Wild-type and B7-2-/- BALB/c mice (n = 4 mice per group) were immunized with 50 µg of pV1J-gp120. In addition, 50 µg of pV1J sham plasmid or 50 µg of pV1J-B7-2 was administered concurrently with the DNA vaccine. B, B7-2-/- BALB/c mice (n = 4 mice per group) were immunized with 50 µg of pV1J-gp120. In addition, 50 µg of pV1J-B7-2 was administered on day -2 or day +2 relative to vaccination. In both experiments, specific CTL activity was measured in splenocytes from each mouse in duplicate after 3 wk by chromium release assays. The mean responses for each group with SEs are shown and are representative of independent experiments performed at least twice.

 
If B7-1 and B7-2 are, in fact, functionally equivalent, and the apparent differences in requirements for these molecules in specific immune responses simply reflect differences in the kinetics of their expression by particular cells, then B7-1 might be able to replace B7-2 in reconstituting CTL responses in the B7-2-/- mice vaccinated with the plasmid DNA. To investigate this possibility, we coinoculated B7-2-/- mice with plasmid B7-1 and gp120 DNA vaccine. We reasoned that this might lead to B7-1 expression at a time when B7-1 expression is typically low or absent. As shown in Fig. 3Go, inoculation of plasmid B7-1 together with the gp120 DNA vaccine reconstituted the capacity of B7-2-/- mice to generate CTL responses to gp120 as effectively as did the inoculation of plasmid B7-2. Inoculation of plasmid B7-1 4 days before the DNA vaccine or coinoculation of a sham plasmid concurrently with the DNA vaccine, however, did not reconstitute the ability of the mice to develop these CTL responses. Thus, the defective CTL responsiveness in B7-2-/- mice could be corrected in the absence of B7-2 by expressing B7-1 in combination with the Ag. This result suggests that either B7-1 or B7-2 can costimulate wild-type level CTL responses if expressed concurrently with Ag.



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  		FIGURE 3. Coadministration of plasmid B7-1 can reconstitute the ability of B7-2-/- mice to generate CTL responses following DNA vaccination. B7-2-/- BALB/c mice (n = 4 mice per group) were immunized with 50 µg of pV1J-gp120. In addition, groups of mice received 50 µg of pV1J sham plasmid, 50 µg of pV1J-B7-1, or 50 µg of pV1J-B7-2 concurrently with the DNA vaccine in three groups of mice. A total of 50 µg of pV1J-B7-2 was administered on day -4 relative to vaccination in another group of mice. Specific CTL activity was measured in splenocytes from each mouse in duplicate after 3 wk by chromium release assays. The mean responses for each group with SEs are shown and are representative of independent experiments performed at least twice.

 
Finally, we investigated whether either B7-1 or B7-2 alone could costimulate vaccine-elicited CTL by comparing CTL responses in B7-1/B7-2-/- mice following immunization with HIV-1 gp120 plasmid and reconstitution with either B7-1 or B7-2 plasmid DNA. The double knockout B7-1/B7-2-/- mice were unable to generate CTL responses following gp120 DNA vaccination. However, as shown in Fig. 4Go, coinoculation of either plasmid B7-1 or plasmid B7-2 along with the gp120 DNA vaccine reconstituted the ability of the mice to generate CTL responses comparable with wild-type mice. Coinoculation of both the B7-1 and B7-2 plasmids had a similar effect, whereas injection of a sham plasmid control was not able to reconstitute the ability to generate these CTL responses. The CTL responses in the B7-1/B7-2-/- mice that received the B7-2 plasmid were actually higher than those in the B7-1-/- mice (Fig. 1Go). This may have occurred as a result of higher local concentrations of B7-2 expressed from the B7-2 plasmid than seen in mice expressing their own B7-2 gene. Overall, this experiment directly demonstrates that only one B7 molecule is necessary, and either B7-1 or B7-2 molecule is sufficient, for full costimulation of CTL responses elicited by this gp120 DNA vaccine.



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  		FIGURE 4. Coadministration of plasmid B7-1 or plasmid B7-2 can reconstitute the ability of B7-1/B7-2-/- mice to generate CTL responses following DNA vaccination. Wild-type or B7-1/B7-2-/- BALB/c mice (n = 4 mice per group) were immunized with 50 µg of pV1J-gp120. In addition, groups of mice received 50 µg of pV1J sham plasmid, 50 µg of pV1J-B7-1, 50 µg of pV1J-B7-2, or 50 µg pV1J-B7-1 + 50 µg pV1J-B7-2 concurrently with the DNA vaccine. Specific CTL activity was measured in splenocytes from each mouse in duplicate after 3 wk by chromium release assays. The mean responses for each group with SEs are shown and are representative of independent experiments performed at least twice.

 
Since traditional functional CTL assays are done by expanding Ag-specific splenocyte populations in cell culture, these assays are imprecise quantitatively. We therefore also used tetramer staining technology to quantitate CTL epitope-specific CD8+ T cell responses in the blood of these mice. Staining freshly isolated PBLs with fluorochrome-labeled tetrameric MHC class I-peptide complexes with subsequent analysis by flow cytometry has recently proven to be an accurate method of quantitating Ag-specific CD8+ T cells in vivo in a number of experimental systems (27, 28, 29, 30). As shown in Fig. 5Go, staining of whole blood from plasmid gp120 DNA-vaccinated wild-type mice using the H-2Dd/P18 tetramer demonstrated that ~1% of circulating CD8+ T cells are specific for this peptide following a single inoculation of the DNA vaccine. Comparable levels of circulating tetramer-binding CD8+ T cells were observed in B7-1/B7-2-/- mice inoculated with the DNA vaccine plus plasmid B7-1 or plasmid B7-2, whereas no tetramer-binding CD8+ T cells were detected in B7-1/B7-2-/- mice inoculated with the DNA vaccine alone. These results further demonstrate that B7-1 and B7-2 are independently capable of costimulating CD8+ T cell responses to the level seen in wild-type mice.



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  		FIGURE 5. Detection of P18 tetramer-positive CD8+ T cells in the fresh whole blood of B7-1/B7-2-/- mice following coadministration of a plasmid gp120 DNA vaccine and plasmid B7-1 or plasmid B7-2. Wild-type (WT+sham) (n = 4) or B7-1/B7-2-/- (n = 3 mice per group) BALB/c mice were immunized with 50 µg of pV1J-gp120. In addition, groups of mice received 50 µg of pV1J sham plasmid (DKO+sham), 50 µg of pV1J-B7-1 (DKO+B7-1), or 50 µg of pV1J-B7-2 (DKO+B7-2). After 3 wk, tetramer-binding CD8+ T cell responses were measured directly in freshly isolated whole blood from each mouse by using an H-2Dd/P18 tetramer. Percent tetramer binding on gated CD8+ lymphocytes for each mouse was determined by flow cytometry.

 
In summary, in this study, we have investigated whether the distinct roles of B7-1 or B7-2 in eliciting CTL responses to gp120 plasmid DNA vaccination are related to distinct temporal expression of B7-1 and B7-2. We have found 1) either B7-1 or B7-2 plasmid DNA when given at the time of immunization with gp120 plasmid DNA can restore CTL responses of B7-2-/- mice to the level elicited in wild-type mice; and 2) either B7-1 or B7-2 plasmid DNA can restore CTL responses of mice lacking both B7-1 and B7-2 to wild-type levels. Taken together, these data show that B7-1 and B7-2 can compensate for each other, and that either can fully costimulate effector CTL responses when expressed concurrently with Ag. This observation extends our previous findings that B7-1 and B7-2 are largely overlapping in function. B7-1-/- mice and B7-2-/- mice both can generate Ab responses to protein Ags administered with adjuvant, as well as Ab and CTL responses to vesicular stomatitis virus and recombinant vaccinia virus infection (16, 17, 25). However, B7-2-/- mice cannot generate effective immune responses to protein Ags administered without adjuvant or following plasmid DNA vaccination, suggesting that B7-2 may be critical for the initiation of these immune responses (16, 25). It has been suggested that adjuvants and viral infections lead to a rapid up-regulation of B7-1 expression that can compensate for an absence of B7-2, and that the requirement for B7-2 for generating immune responses in the absence of adjuvant reflects its constitutive expression on APCs. The results in this report strongly support this model. The present findings, therefore, are consistent with the notion that apparent functional differences between B7-1 and B7-2 disappear when they are placed under similar transcriptional control.


   Acknowledgments
 
We thank Dr. Gordon Freeman for providing murine B7-1 and B7-2 genes, Dr. John Shiver for the pV1J vaccine vector and pV1J-gp120 construct, Dr. Paul McKay for assistance with computer graphics, and Baolin Chang for superb technical assistance.


   Footnotes
 
1 This work was supported by Grants CA-50139, AI-26507, and AI-20729 (to N.L.L.) and AI-38310 (to A.H.S.). Back

2 Address correspondence and reprint requests to Dr. Norman L. Letvin, Department of Medicine, Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, RE113, P.O. Box 15732, Boston, MA 02215. Back

Received for publication August 1, 2000. Accepted for publication September 18, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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