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Journal of Virology, September 2008, p. 9293-9298, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00749-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Differential Antigen Presentation Kinetics of CD8+ T-Cell Epitopes Derived from the Same Viral Protein{triangledown}

Jonah B. Sacha,1 Matthew R. Reynolds,1 Matthew B. Buechler,1 Chungwon Chung,1 Anna K. Jonas,1 Lyle T. Wallace,1 Andrea M. Weiler,1 Wonhee Lee,1 Shari M. Piaskowski,1 Taeko Soma,1 Thomas C. Friedrich,1 Nancy A. Wilson,1 and David I. Watkins1,2*

Wisconsin National Primate Research Center (WNPRC), Madison, Wisconsin 53715,1 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 537152

Received 4 April 2008/ Accepted 25 June 2008


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ABSTRACT
 
The kinetics of peptide presentation by major histocompatibility complex class I (MHC-I) molecules may contribute to the efficacy of CD8+ T cells. Whether all CD8+ T-cell epitopes from a protein are presented by the same MHC-I molecule with similar kinetics is unknown. Here we show that CD8+ T-cell epitopes derived from SIVmac239 Gag are presented with markedly different kinetics. We demonstrate that this discrepancy in presentation is not related to immunodominance but instead is due to differential requirements for epitope generation. These results illustrate that significant differences in presentation kinetics can exist among CD8+ T-cell epitopes derived from the same viral protein.


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TEXT
 
Multiple factors contribute to the antiviral efficacy of CD8+ T cells, including functional avidity (3), killing efficiency (14), polyfunctionality (4), evolutionary constraints on the epitope sequences (8, 12, 17), and the kinetics of antigen presentation (1, 15). Antigen presentation kinetics may be important because the earlier that an epitope is present on the surface of an infected cell, the greater the window of opportunity for CD8+ T cells to recognize and eliminate the infected cell before release of progeny virus. The kinetics of CD8+ T-cell epitope presentation, however, remain poorly defined.

We recently demonstrated that penetration of virion-associated proteins into the cytoplasm was sufficient to generate CD8+ T-cell epitopes early after infection of a target cell (15). However, a previous study showed that presentation of an immunodominant CD8+ T-cell epitope derived from another viral structural protein, lymphocytic choriomeningitis virus nucleoprotein, depended upon de novo protein synthesis (10). To determine if all CD8+ T-cell epitopes derived from a viral protein are presented with similar kinetics, we investigated the ontogeny of several CD8+ T-cell epitopes derived from the simian immunodeficiency virus (SIV) structural protein SIVmac239 Gag.

Gag-specific CD8+ T cells recognize an epitope only after de novo protein synthesis. We previously demonstrated that early presentation of incoming, virion-derived Gag epitopes was maximal at 6 h postinfection, while presentation of epitopes due to de novo synthesis of Gag occurred between 18 and 24 h postinfection (15). To determine whether all Gag CD8+ T-cell epitopes could be presented early after infection, we performed the kinetic intracellular cytokine staining (KICS) assay as described previously (15, 16) using major histocompatibility complex class I (MHC-I)-matched CD4+ T-cell targets and CD8+ T cells specific for four different epitopes in Gag (Table 1). We examined two time points to determine if the Gag epitopes present on the surface of infected cells were derived from incoming (6-h-postinfection) or newly synthesized (24-h-postinfection) Gag proteins.


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  		TABLE 1. CD8+ T-cell clones used in KICS assay

As previously observed, the immunodominant Mamu-A*02-restricted Gag71-79 GY9 and Mamu-A*01-restricted Gag181-189 CM9 CD8+ T-cell epitopes were efficiently presented by SIV-infected cells at both 6 and 24 h postinfection, indicating that these epitopes could be derived from both incoming and newly synthesized Gag proteins (Fig. 1A and B). Next, we investigated the kinetics of the Mamu-A*01-restricted subdominant Gag epitope Gag254-262 QI9, which is derived from the same mature protein as Gag181-189 CM9, Gag p27CA. Surprisingly, the Gag254-262 QI9 epitope was absent from the surface of infected cells early after infection, even though the epitope was efficiently presented to CD8+ T cells late in the viral replication cycle (Fig. 1C). We confirmed late-only presentation of Gag254-262 QI9 by using 23 different CD8+ T-cell clones and polyclonal cell lines (Table 1).


Figure 1
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  		FIG. 1. The subdominant epitope Gag QI9 is not presented early by SIV-infected CD4+ T cells. (A to D) CD4+ T cells from macaques positive for the allele Mamu-A*01, -A*02, or -B*48 were either mock or synchronously infected with SIVmac239 and used at the time points indicated in the KICS assay as antigen-presenting cells for CD8+ T cells specific for Gag71-79 GY9 (A), Gag181-189 CM9 (B), Gag254-262 QI9 (C), or Gag276-283 RI8 (D). Dot plots were generated by gating on live CD8+ T cells, and percentages of tumor necrosis factor alpha (TNF-{alpha})- and gamma interferon (IFN-{gamma})-positive cells are shown. Data are representative of at least four independent assays. No CD8+ T cells responded to infected CD4+ T cells that were MHC-I mismatched (data not shown). p.i., postinfection. (E) Amino acid sequence and positions of {alpha}-helices in the first 150 residues of the N terminus of SIVmac239 Gag p27CA. CD8+ T-cell epitopes are highlighted by boxes and shown in bold.

Although both Mamu-A*01-restricted Gag epitopes are derived from the N-terminal domain of Gag p27CA, they map to separate areas in the secondary structure of the mature protein. Gag181-189 CM9 is located predominantly within {alpha}-helix 3 while Gag254-262 QI9 is situated partially inside {alpha}-helix 7 in mature Gag p27CA (Fig. 1E). To determine if the location of Gag254-262 QI9 in Gag p27CA was responsible for the inability of infected cells to present the epitope early after infection, we mapped a new epitope contained at the end of {alpha}-helix 7 in Gag p27CA, Mamu-B*48-restricted Gag276-283 RI8 (Table 1; Fig. 1E). Infected cells efficiently presented Gag276-283 RI8 at both time points after infection, indicating that this new Gag epitope was generated from both virion-associated and newly synthesized Gag (Fig. 1D). Therefore, it appeared that the location of Gag254-262 QI9 near {alpha}-helix 7 of Gag p27CA was likely not responsible for late presentation of this epitope.

Immunodominance is not responsible for the inability of Gag254-262 QI9 to be recognized early. Gag181-189 CM9 is the immunodominant epitope presented by Mamu-A*01 and binds to the MHC-I molecule with a higher affinity than does Gag254-262 QI9 (Fig. 2A). A recent study demonstrated that immunodominant epitopes are more efficiently liberated from polypeptide precursors than subdominant epitopes (11). Therefore, we hypothesized that the earlier presentation of Gag181-189 CM9 was due to more efficient production of this epitope. This would enable Gag181-189 CM9 to outcompete Gag254-262 QI9 for access to MHC-I molecules in the endoplasmic reticulum. To test this hypothesis, we constructed a molecularly cloned mutant virus, SIVmac239-CM9(T2A), which contains a threonine-to-alanine alteration at the secondary anchor position of the Gag181-189 CM9 epitope together with two compensatory substitutions outside the epitope that restore fitness of the epitope mutant virus. This escape mutation has previously been shown to reduce binding to the MHC-I molecule by >90% while minimally affecting the infectivity or replication kinetics of the virus (9) (Fig. 2A). By drastically reducing the binding of Gag181-189 CM9 to the MHC-I molecule, we hypothesized that Gag254-262 QI9 would then be more likely to bind MHC-I and be presented early after infection.


Figure 2
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  		FIG. 2. Immunodomination by Gag181-189 CM9 is not responsible for lack of early QI9 presentation. (A) Amino acid sequences and 50% inhibitory concentrations (IC50) for the Gag181-189 CM9, mutant Gag181-189 CM9 (CM9-T2A), and Gag254-262 QI9 CD8+ T-cell epitopes. (B to D) CD4+ T cells from a macaque positive for both Mamu-A*01 and -A*02 alleles were either mock or synchronously infected with SIVmac239-CM9(T2A) and used at the time points indicated in the KICS assay as antigen-presenting cells for CD8+ T cells specific for Gag71-79 GY9 (B), Gag181-189 CM9 (C), or Gag254-262 QI9 (D). Dot plots were generated by gating on live CD8+ T cells, and percentages of tumor necrosis factor alpha (TNF-{alpha})- and gamma interferon (IFN-{gamma})-positive cells are shown. Data are representative of at least three independent assays.

The Mamu-A*02-restricted Gag71-79 GY9 epitope lies in Gag p17MA and was unaffected by the CM9(T2A) mutation. Therefore, it was still efficiently presented both early and late by cells infected with the mutant virus (Fig. 2B). The Gag181-189 CM9-specific CD8+ T cells failed to recognize CD4+ T cells infected with SIVmac239-CM9(T2A) at any time point during the assay, indicating that the escape mutation completely ablated presentation of the epitope (Fig. 2C). Although Gag181-189 CM9 presentation was abolished, Gag254-262 QI9 was still not presented early (Fig. 2D). These data indicate that the immunodominance of Gag181-189 CM9 over Gag254-262 QI9 does not play a role in the late-only presentation of the Gag254-262 QI9 epitope.

Gag254-262 QI9 presentation requires de novo Gag protein synthesis. Gag181-189 CM9-specific CD8+ T cells exhibit a higher functional avidity (~13.3 nM) than do those specific for Gag254-262 QI9 (~574 nM) (13). Similar values were obtained for the CD8+ T-cell clones used in the present study (data not shown). This difference might account for the inability of Gag254-262 QI9-specific CD8+ T cells to recognize infected cells early after infection, especially if the epitope were poorly processed from incoming Gag proteins. To explore this hypothesis, we infected CD4+ T cells with increasing amounts of virus and examined the early time point for Gag254-262 QI9 presentation. While increasing the input virus to as high as a multiplicity of infection of 10 boosted early presentation of Gag181-189 CM9, we detected no presentation of Gag254-262 QI9 at 6 h postinfection (data not shown). These data suggest that differences in functional avidity and epitope processing rates are likely not responsible for the lack of early Gag254-262 QI9 presentation.

A previous study demonstrated that macrophages, but not CD4+ T cells, were able to present CD8+ T-cell epitopes derived from Gag proteins in the incoming virus particle (5). It remained possible, therefore, that CD4+ T cells lack the antigen processing machinery required to derive the Gag254-262 QI9 epitope from virion-associated Gag. We generated macrophages from CD14+ monocytes cultured in the presence of 5 ng/ml macrophage colony-stimulating factor for 5 days. We synchronously infected these macrophages with the macrophage-tropic virus SIVmac316E and examined presentation of the Mamu-A*01-restricted Gag epitopes. Similarly to CD4+ T cells, infected macrophages presented Gag254-262 QI9 only late in the viral replication cycle, even though they presented Gag181-189 CM9 both early and late (Fig. 3A and B).


Figure 3
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  		FIG. 3. Presentation of Gag QI9 requires de novo protein synthesis. Monocyte-derived macrophages were synchronously infected with SIVmac316E and used at the time points indicated in the KICS assay as antigen-presenting cells for CD8+ T cells specific for Gag181-189 CM9 (A) or Gag254-262 QI9 (B). CD4+ T cells from macaques positive for the allele Mamu-A*01, -A*02, or -B*48 were either mock or synchronously infected with AT-2 inactivated SIVmac239 and used at the time points indicated in the KICS assay as antigen-presenting cells for CD8+ T cells specific for Gag71-79 GY9 (C), Gag181-189 CM9 (D), Gag276-283 RI8 (E), or Gag254-262 QI9 (F). Similar results were obtained with CD4+ T cells infected with SIVmac239 in the presence of tenofovir (data not shown). Data are representative of at least three independent assays. p.i., postinfection.

Finally, we examined the ability of CD4+ T cells to present Gag-derived epitopes under conditions in which synthesis of viral proteins is blocked. CD4+ T cells pulsed with the chemically inactivated virus AT-2 SIVmac239 still efficiently presented the Gag71-79 GY9, Gag181-189 CM9, and Gag276-283 RI8 epitopes early after infection (Fig. 3C to E). Residual presentation of these epitopes still occurred at 24 h postinfection, but the robust second wave of antigen presentation due to de novo protein synthesis of Gag observed previously was abolished (compare Fig. 1 with Fig. 3). Interestingly, blocking viral protein synthesis completely eliminated presentation of Gag254-262 QI9 (Fig. 3F). Similar results were obtained using CD4+ T cells infected with SIVmac239 in the presence of tenofovir (data not shown). These experiments indicate that de novo Gag protein synthesis is required for generation of Gag254-262 QI9.

One possible explanation for Gag254-262 QI9's dependence upon de novo protein synthesis is provided by the defective ribosomal product (DRiP) hypothesis, which posits that epitope generation is tightly linked to protein translation (20). Since Gag254-262 QI9 epitope generation is tied to synthesis of Gag, this epitope may be derived from a DRiP. In support of this explanation, a previous study demonstrated that human immunodeficiency virus (HIV) Gag is a rich source of DRiPs in infected cells (18). However, we cannot exclude the possibility that generation of the Gag254-262 QI9 epitope from mature, virion-associated Gag p27CA is blocked due to posttranslational protein modifications. The precursor Gag p55 polyprotein is proteolytically cleaved to liberate mature Gag proteins such as Gag p27CA, which undergoes dramatic conformational changes during maturation of the virus particle. These conformational rearrangements of Gag p27CA during maturation of the virion may preclude proteasomal degradation of the region in virion-associated Gag p27CA containing Gag254-262 QI9. Furthermore, because maturation of the Gag proteins does not occur until after the virion buds from the cell (7), the inability of the antigen processing machinery to liberate the Gag254-262 QI9 epitope from mature Gag would not become apparent until the virus particle infected a new cell.

HLA-B*57 and HLA-B*27 are associated with slow disease progression in HIV type 1 infections and are overrepresented in cohorts of elite controllers (6). These MHC-I molecules also restrict immunodominant CD8+ T-cell epitopes in Gag p27CA, Gag240-249 TW10 and Gag262-271 KK10, respectively. These two responses may be important for establishing low viremia in elite controllers, as recent studies have indicated that these epitopes dominate the acute-phase CD8+ T-cell response in HIV type 1 infection (2, 19). Interestingly, these epitopes map to the same area of the Gag capsid protein as does Gag254-262 QI9, the epitope that required de novo Gag synthesis for presentation. It would be of interest, therefore, to investigate the requirements for epitope generation of these two HLA-B*57- and HLA-B*27-restricted CD8+ T-cell epitopes.

While the direct relationship between epitope presentation kinetics and antiviral efficacy in CD8+ T cells remains poorly defined, the kinetics of epitope expression on the surface of virally infected cells contribute to the antiviral capacity of CD8+ T cells. The results presented here, therefore, imply that not all CD8+ T cells directed at the same protein will be equally effective due to differences in epitope ontogeny. Additionally, these results suggest that caution must be applied when extending the characteristics of individual epitope-specific CD8+ T-cell responses to all of the CD8+ T-cell responses directed against the same viral protein.


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ACKNOWLEDGMENTS
 
This work was supported by NIH grants RO1 AI076114 and R01 AI049120 to D.I.W. This publication was also made possible in part by NCRR grant P51 RR000167. This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01.

We gratefully acknowledge Ronald Desrosiers for providing SIVmac316E and Jeffrey Lifson for providing AT-2 inactivated SIVmac239. The following reagent was obtained through the AIDS Research and Reference Reagent Program, NIAID, NIH: tenofovir disoproxil fumarate. We thank Laura Valentine and Buck Magnus for helpful discussions. We thank Louise Sacha for ongoing support.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, 555 Science Drive, Madison, WI 53711. Phone: (608) 265-3380. Fax: (608) 265-8084. E-mail: watkins{at}primate.wisc.edu Back

{triangledown} Published ahead of print on 2 July 2008. Back


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Journal of Virology, September 2008, p. 9293-9298, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00749-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Sacha, J. B., Giraldo-Vela, J. P., Buechler, M. B., Martins, M. A., Maness, N. J., Chung, C., Wallace, L. T., Leon, E. J., Friedrich, T. C., Wilson, N. A., Hiraoka, A., Watkins, D. I. (2009). Gag- and Nef-specific CD4+ T cells recognize and inhibit SIV replication in infected macrophages early after infection. Proc. Natl. Acad. Sci. USA 106: 9791-9796 [Abstract] [Full Text]  

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