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* T Cell Laboratory, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia;
Laboratory of Viral Diseases, National Institute for Allergy and Infectious Diseases, Bethesda, MD 20892; and
Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-, 
-, etc.) defined by the frequencies of responding TCD8+. In this paper, we study the mechanistic basis for place-swapping between - (acid polymerase (PA)224–233) and -determinants (nuclear protein 366–374) in primary vs secondary anti-influenza A virus (IAV) responses in mice. This phenomena was recently correlated with the inability of IAV-infected nondendritic cells (DCs) to generate PA224–233, and it was proposed that secondary TCD8+ are principally activated by IAV-infected epithelial cells, while primary TCD8+ are activated by IAV-infected DCs. In this study, we show that the inability of non-DCs to generate PA224–232 is relative rather than absolute, and that the preferential use of cross-priming in secondary anti-IAV responses can also account for the revised hierarchy. We further show that immunodomination of PA224–233-specific TCD8+ by nucleoprotein 366–374-specific TCD8+ plays a critical role in the phenomena, and that this is unlikely to be mediated by TCD8+ lysis of APCs or other cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunodominance results from a complex combination of factors that encompass all aspects of TCD8+ biology, including: 1) positive and negative selection of the TCR repertoire in the thymus and periphery, 2) signaling for TCD8+ activation, 3) interaction of TCD8+ with professional APCs in lymphoid organs, 4) interaction of TCD8+ with peripheral cells, 5) protease generation class I peptide ligands or their immediate precursors, 6) TAP-dependent or -independent transport of peptides into the endoplasmic reticulum, 7) peptide binding to class I molecules, and 8) "immunodomination": the propensity of TCD8+ to immunodominant determinants to suppress responses of subdominant determinant-specific TCD8+.
Therefore, understanding immunodominance is key to understanding and manipulating the cellular immune response to viruses, particularly with regards to developing vaccines that elicit effective anti-viral TCD8+ responses.
The TCD8+ response of B6 mice to influenza A virus (IAV) provides an excellent model system to dissect the relative importance of the factors that govern immunodominance (7, 8). In addition to the numerous strains of B6 background mice with targeted deletions in myriad genes involved in the TCD8+ response, there are seven well-defined determinants restricted by Kb or Db that constitute a well-defined immunodominance hierarchy following infection with IAV. These determinants can be ranked -, -, 
-, etc. (9) based on the numbers of responding TCD8+ as quantitated using MHC-class I peptide complex tetramers (10) or intracellular cytokine staining (ICS; Ref. 11). Interestingly, the -determinant, acid polymerase (PA)224–233 in primary responses to IAV, is supplanted in the secondary response to virus challenge by the -determinant, nucleoprotein (NP)366–374 (8). This phenomena points to differences between the activation of primary vs memory TCD8+, which is an area of intense current interest due to it’s implication for designing vaccines that induce effective TCD8+ responses to pathogens and tumors. In the present study, we have examined the mechanisms underlying this interesting phenomenon.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MC57G fibroblast cells (H-2b), EL-4 thymoma cells (H-2b), TAP-2-deficient cell RMA-S cells (an EL-4 subline; H-2b; Ref. 12), DC-like DC2.4 cells (H-2b; Ref. 13), and LTA-5 fibroblast cells (H-2d) were all cultured in RPMI 1640 containing 10% FBS), 50 µM 2-ME, antibiotics, and 2 mM glutamine (RP-10). For culturing TCD8+ lines, briefly, 3 x 107 splenocytes were cultured with irradiated (100 Gy) 1.5 x 105 peptide-pulsed (at 10–9 M) EL-4 cells, in 6-well plates with RP-10 containing 10 U/ml recombinant human IL-2. Media were changed every 2–3 days. Activated viable cells were collected through Ficoll-Hypaque gradients. TCD8+ cell lines were generally used after a single round of in vitro stimulation.
Mice, tetramers, mAbs, and viruses
We used the following mouse strains: C57BL/6j (B6; WEHI, Kew, Australia), generalized lymphoproliferative diseases (gld) and perforin (pfp)–/– mice (Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia), B6.Ly5.1 (originally purchased from WEHI and then bred at the Ludwig Institute, Melbourne branch, Victoria, Australia), Low molecular mass polypeptide (LMP)2–/– mice were originally generated by van Kaer et al. (14) and imported from Taconic Farms National Institute of Allergy and Infectious Diseases colony (Germantown, NY). Nude mice on B6 background (B6NU-M, Taconic Farms). Animals were 8- to 12-wk-old at the start of the experiments, and females were used exclusively. Fluorescein-labeled anti-IFN-, CyChrome-labeled anti-CD8-chain, and purified anti-B220 were purchased from BD Biosciences Australia (North Ryde, New South Wales, Australia). MHC class I-peptide complexes complexed to PE-labeled streptavidin ("tetramers") were provided by the National Institute of Allergy and Infectious Diseases tetramer facility (Emory University, Atlanta, GA). Tetramers were diluted 1/200 and 100 µl was used for staining 1–2 million splenic cells at room temperature for 45 min. All mAb were used at 1/200 dilution in PBS. Purified B220 Ab was used to coat M450 Dynal beads (Dynal Biotech, Brown Deer, WI) for depleting B220+ cells as described (9) in T cell cultures. The H2-Db-conformational-specific mAb, B22.249, was used as a hybridoma tissue culture supernatant. FITC-conjugated secondary rat-anti-mouse Ab was purchased from Selinus (Selinus/Amrad, Melbourne, Australia). IAV PR8 (Puerto Rico/8/34, H1N1), X31 (reassortant with H3N2 glycoprotein gene segments with the remainder from PR8), and E61-13-H17 (all genes identical with X31 except NP from NT60) and were propagated in 10-day-old embryonated chicken eggs and used as infectious allantoic fluid.
Measuring Db affinity for synthetic peptides
These methods have been described elsewhere (15). Briefly, both assays use RMA-S cells cultured at 26°C overnight to increase cell surface peptide-receptive class I molecules. For the binding assay, aliquots of the induced RMA-S cells were incubated with peptides at the concentrations indicated for 60 min in a 96-well plate before being shifted to 37°C for 2 h. For the complex decay assay, RMA-S cells were pulsed with 1 µM of indicated peptides for 60 min at 26°C in the presence of BFA at 10 µg/ml. Cells were then washed to remove excess peptides and shifted to 37°C. Aliquots were removed to 0°C at the intervals indicated. Samples were then stained with B22.249 followed with FITC-conjugated rat anti-mouse (Selinus/Amrad), and were analyzed by flow cytometry.
TCD8+ induction and adoptive transfer
For in vivo priming and challenge, mice were injected i.p. with 
600 hemagglutinating units IAV. Mice were also challenged with virus mixed with 100 µl of neat H28-E23 ascites fluid, (16). For challenge with cells, mice were injected i.p. with 5 x 106 peptide-pulsed or IAV-infected cells. Cells were irradiated (100 Gy) just before injection. For IAV-infection, cells were infected for 4 h, washed to remove free virus, and resuspended in 0.5 ml of PBS. The cells were then injected i.p. Adoptive transfers were performed by i.v. injection using the numbers of splenocytes indicated.
Intracellular cytokine staining
Peptides were procured and characterized by the Biologic Resource Branch, National Institute of Allergy and Infectious Diseases (Rockville, MD). In each case, substances with the predicted mass constituted >95% of the material analyzed. Peptides were dissolved in DMSO at 1 mM and stored at –20°C. For ICS, splenic and peritoneal cells from primed animals were suspended in 200 µl of RP-10 at 1.5–2x 106 per well in round-bottom 96-well plates. Peptides were added to wells to a final concentration of 0.5 µM. Cells were incubated initially for 2 h at 37°C and then for 4 h with brefeldin A (BFA; Sigma-Aldrich, St. Louis, MO) at 10 µg/ml. When TCD8+ lines were used, the 2-h preincubation step was omitted. Cells were then stained with CyChrome anti-CD8 mAb on ice for 30 min, washed, and fixed with 1% paraformaldehyde in PBS at room temperature for 20 min, then further stained with fluorescein-anti-IFN- in PBS containing 0.2% saponin (Sigma-Aldrich). Stained cells were analyzed on a FACSCalibur (BD Biosciences, Sunnyvale, CA) with live-gate on the CD8+ cells. A total of 100,000 cells were normally acquired and analyzed with FlowJo software (TreeStar, Ashland, OR).
Ag-processing kinetics assessment with ICS
Briefly, 105 of various cell lines or cultured bone marrow-derived DCs (bmDCs) were infected with PR8 for 60 min and aliquoted into 96-well round-bottom plates. An equal number of TCD8+ were then added (time zero), and BFA was added to prevent additional Ag processing and presentation. Cells were incubated for an additional 4–6 h in the presence of BFA to enable TCD8+ accumulation of IFN-, which was analyzed as described above.
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Results |
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Following primary infection of B6 mice with PR8, the -, -, and -determinants recognized by TCD8+ are PA224–233, NP366–374, and PB1-F262–70 (8, 17). To determine the immunodominance hierarchy following secondary challenge, it is necessary to re-infect mice with a virus that is not neutralized by Abs specific for the HA or neuraminidase glycoproteins of the priming virus. We minimized the sequence differences between other genes in the priming and boosting viruses, by using the X31 reassortant virus for secondary challenge. X31 derives serologically noncross reactive glycoproteins from a H3N2 strain and its other genes from PR8. Seven days following i.p. boosting, we determined the frequency of local and splenic TCD8+ responding to the -, -, and - determinants using ICS to measure the percentage of TCD8+ expressing IFN- following exposure of freshly isolated cells to APCs sensitized with the corresponding synthetic peptide.
As first reported by Belz et al. (8), PA224–233 is dominant/codominant in the central (spleen) and local (in our case, peritoneal, in their case, lung) primary responses but subdominant to NP366–374 in secondary responses (Fig. 1, A–D). The relative magnitude of the TCD8+ responses to PB1-F262–70, the -determinant, is similar between primary and secondary responses. To examine the relationship between the magnitude of secondary responses and the number of memory TCD8+, we performed ICS on splenocytes from IAV-primed mice ex vivo without boosting the animals (Fig. 1E). This recapitulated the primary immunodominance hierarchy, which is consistent with the quantitation Belz et al. (8) of memory TCD8+ populations by ELISPOT analysis.
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In vitro presentation of immunodominant determinants
Why are PA224–233 TCD8+ activated relatively poorly in secondary responses? To begin to answer this question, we characterized the interaction between the respective peptides and Db molecules by measuring the ability of peptides to stabilize peptide receptive Db molecules on RMA-S cells. Incubating cells overnight at 26°C generates thermolabile class I molecules that can be stabilized by peptide binding. The peptide concentration required to stabilize half of the peptide-receptive molecules to thermal denaturation after raising the temperature to 37°C provides a good approximation of the dissociation constant of the peptide interaction. As seen in Fig. 3A, NP366–374 and PB1-F262–70 demonstrate half maximal binding at 10–7.5 M, while PA224–233 demonstrates half-maximal binding at 10–8 M. Although the curves in Fig. 3A are somewhat nonclassical for a first order association reaction, the higher affinity of PA224–233 for Db is supported by the 3-fold greater stability of its complexes compared with NP366–374 and PB1-F262–70 complexes (Fig. 3B). Linear regression of a semilog plot of mean channel fluorescence vs time reveals that the t1/2 of unprotected Db molecules is 34 min while binding of PB1-F262–70, NP366–374, or PA224–233, respectively, prolongs the t1/2 to 202, 230, and 985 min.
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3-fold more of Db-PA224–232 complexes.
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(Fig. 4B). Although IFN- is known to enhance expression of all of the various components of the class I Ag-processing pathway, it had little effect on the susceptibility of PR8-infected cells to lysis by NP366–374- or PB1-F262–70-specific TCD8+ (Fig. 4, C and D). This suggests that enhanced recognition of PA224–233 is due to the induction of immunoproteasomes by IFN-. Because DCs are believed to constitutively express immunoproteasomes (20), we tested the capacity of the DC-like cell line, DC 2.4 and bmDCs to present PA224–233. EL-4 cells served as a control for nonprofessional APCs in this experiment. As in the previous experiment, the TCD8+ populations used to demonstrate similar sensitivity to peptide-sensitized target cells (Fig. 5A). To increase the resolution of the assay to detect differences in the expression of class I peptide complexes, we measured the kinetics of presentation by using BFA to prevent export of newly created complexes from the endoplasmic reticulum following IV infection. This experiment revealed that both DC preparations tested were able to activate each the TCD8+ populations more rapidly than EL-4 cells (Fig. 5, B–D). Notably, bmDCs exhibited enhanced presentation of PA224–233 relative to the other cells tested, though presentation of PA224–233 still lagged behind the presentation of the other determinants and never reached saturating levels achieved using synthetic PA224–233.
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Contribution of immunodomination to the secondary immunodominance hierarchy
Immunodomination can play an important role in creating primary immunodominance hierarchies. To examine the role of immunodomination in the demotion of PA224–233 in secondary responses, we selectively reduced the number of primed NP366–374-specific TCD8+ by boosting PR8-primed mice with X31 or with a reassortant IAV (E61-13-H17) that differs from X31 by containing the NT60 NP gene segment in place of the PR8 gene. Due to two alterations in the NP366–374 determinant (ASNENMETM (PR8) vs ASNENMDAM (NT60)), the NT60 NP activates only a subpopulation of TCD8+ induced by the PR8 NP. Boosting with E61-13-H17induced a response in which PA224–233-specific TCD8+ were now codominant (Fig. 7), while X31 boosting yielded the expected NP366–374-dominated response. This finding is consistent with the idea that immunodomination by NP366–374-specific memory TCD8+ plays a role in establishing the dominance of NP366–374 over PA224–233 in secondary responses.
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Role of TCD8+-mediated lysis in establishing the secondary immunodominance hierarchy
Given the important role of immunodomination in the secondary response, it was of interest to examine whether destruction of APCs by TCD8+ (presumably NP366–374-specific TCD8+) is required for the demotion of PA224–233 TCD8+ in secondary responses. TCD8+ principally destroy APCs in a pfp-dependent manner, while they use Fas-Fas ligand (FasL) to destroy other T cells. To this end, we use ICS to measure local (Fig. 9) and splenic (not shown, but similar to local responses) secondary TCD8+ responses to NP366–374 and PA224–233 in mice with a targeted deletion in the pfp gene (pfp–/–) and in gld mice, which fail to express FasL.
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Together, these findings demonstrate that neither pfp nor Fas-based lysis is required to maintain immunodominance hierarchies in primary or secondary IAV-specific TCD8+ responses in B6 mice. These data are consistent with the idea that these immunodominance hierarchies are created independently of direct elimination of APCs or competing TCD8+ by TCD8+ specific for immunodominant determinants.
Evidence for a key role of cross-presentation in secondary responses
The relative contributions of cross-presentation vs direct presentation to induction of TCD8+ in anti-viral responses is uncertain (24). We recently showed that IAV-infected cells are able to induce robust responses in which NP366–374-specific responses equal or exceed PA224–233-specific responses (16). To examine the potential role of cross-presentation in secondary responses, we boosted PR8-primed mice with PR8-infected LTA-5 cells, which are derived from H-2d mice (Fig. 10). PR8-infected LTA-5 cells induced an extremely robust response, particularly the local peritoneal response, which outstripped the response induced by virus challenge (compare with Fig. 1, B and D). Importantly, as with virus-boosting, the response to infected cells was dominated by NP366–374-specific TCD8+ at the expense of PA224–233-specific TCD8+. Immunization with other IAV-infected allogeneic and syngeneic cells (MC57G) gave similar results (not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we extend the findings of Crowe et al. (25) by demonstrating that the reversal in immunodominance is highly conditional, as it is dependent on the nature of boosting Ag. PA224–233-specific TCD8+ maintain their -status following immunization with peptide-pulsed nonprofessional APCs expressing similar amounts of PA224–233- and NP366–374-Db complexes or if mice are boosted with an IAV-expressing NP that stimulates only a subpopulation of the primed NP366–374-specific TCD8+. Further, the position of PA224–233-specific TCD8+ in the secondary hierarchy is strengthened if limited numbers of memory TCD8+ are adoptively transferred to naive recipients. We interpret these experiments to indicate that hierarchy can be influenced by increasing the relative number of PA224–233 complexes on APCs or by decreasing the number of responding NP366–374 TCD8+, either by limiting activation to subpopulation of memory cells or by decreasing the absolute number of responding cells. The latter two conclusions point to an important role of immunodomination by secondary NP366–374-specific TCD8+ in the phenomena, which does not appear to require either pfp or Fas-mediated killing of APCs or responding TCD8+, as determined using mice defective in these killing pathways.
In contrast to our findings, Crowe et al. (25), found that adoptively transferred memory TCD8+ faithfully recapitulated the typical immunodominance hierarchy observed in unmanipulated animals. This discrepancy seems to be unlikely to be attributed to the numbers transferred cell population. Although Crowe et al. (25) transferred 2.5 x 105 memory TCD8+ (CD44high) vs 107 unfractionated splenocytes in case, given that TCD8+ constitute 10% of splenocytes, and 30% of these are CD44high, the number of transferred CD8+ CD44high cells are highly similar. Therefore, it is likely the different findings are due either to the method of virus priming (intranasal vs i.p.), modulatory effect of other memory cells transferred in splenocyte population, or differences in cell preparation. Additional experiments are required to sort out the contributions of these differences.
Another discrepancy between the studies is that Crowe et al. (25) failed to detect presentation of PA224–233 by non-DCs. We show that this is likely due to the insensitivity of the assays used rather than an absolute defect in the capacity of non-DCs to generate the determinant. We found that both EL-4 cells and MC57G cells were able to generate a sufficient number of complexes to activate some PA224–233-specific TCD8+. Similarly, Zhong et al. (27) demonstrated PA224–233-specific TCD8+ recognition of IAV-infected EL-4 cells. Inasmuch as MC57G cells required exposure to IFN-, and EL-4 cells are a T cell lymphoma that could well express immunoproteasomes (based on the predominant expression of immunoproteasomes in spleen, which presumably extends to each of the major cell populations, including T cells), these findings are consistent with the idea that PA224–233 generation is greatly enhanced by immunoproteasomes. Extending our previous observations using LMP2–/– mice (19), we now show directly that bmDCs from these mice demonstrate a compromised capacity to generate PA224–233.
The abilities of non-DCs to generate PA224–233 argues against but ultimately does not eliminate the mechanism favored by Crowe et al. to explain the ascension of NP366–374 in the secondary immunodominance hierarchy: secondary TCD8+ are activated by IAV-infected non-DCs. Crowe et al. (25) are careful to point out that they could not eliminate the possible contribution of cross-presentation to the phenomena. The caution is well taken because we show that boosting PR8-infected with X31-infected allogeneic cells results in a similar immunodominance hierarchy as boosting with infectious X31virus and further, that the dominance of NP366–374 is reduced in parallel when using E61-13-H17 virus and infected cells to limit activation to strain specific NP366–374-specific TCD8+.
How could cross-presentation play a more important role in secondary vs primary responses?
First, inasmuch as cross-presentation appears to require help from TCD4+ (28), help may be less limiting in secondary infections, either because there is an enhanced TCD4+ response or because memory TCD8+ require less help than naive TCD8+. This sort of mechanism requires that TCD8+ be preferentially activated by cross-presenting cells vs direct-presenting cells when help is not a limiting factor.
Second, memory TCD8+ may have better anatomic access to cross-presenting APCs due to their altered trafficking properties relative to naive TCD8+. This mechanism requires that cross-presenting and direct presenting APCs be located in different compartments; an important question that has not been addressed experimentally. It is conceivable that TCD8+ first must pass through a gauntlet of cross-presenting DCs before they have access to direct-presenting DCs. Given the poor (but not zero) cross-presentation of PA224–233, this may provide optimal conditions for NP366–374 to dominate the PA224–233 response.
This latter possibility points to the fact that detailed understanding of this phenomena (and for that matter, immune responses in general), will require visualizing the interactions of TCD8+ with APCs in lymphoid tissue via "vital" microscopy, which is now becoming a reality due to advances in cell labeling methods and light microscopy (29).
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Acknowledgments |
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Footnotes |
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1 W.C. is a Senior International Fellow supported by the Wellcome Trust (066646/Z/01/Z). K.P. is supported by the National Health and Medical Research Council (Australia) with a Postgraduate Research Scholarship 234711. This project is supported in part by National Health and Medical Research Council (Australia) Project Grant 234710. 
2 Address correspondence and reprint requests to Dr. Jonathan Yewdell, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Room 211, Building 4, 4 Center Drive, Bethesda, MD 20892-0440. E-mail address: jyewdell{at}niaid.nih.gov
3 Abbreviations used in this paper: TCD8+, CD8+ T cells; IAV, influenza A virus; FasL, Fas ligand; PR8, IAV Puerto Rico/8/34; ICS, intracellular cytokine staining; NP, nucleoprotein; gld, generalized lymphoproliferative disease; pfp, perforin; BFA, brefeldin A; bmDC, bone marrow-derived DC; wt, wild type; PA, acid polymerase; LMP, low molecular mass polypeptide.
Received for publication March 2, 2004. Accepted for publication August 10, 2004.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J. Exp. Med. 189:371. (IFN-)-inducible subunits. J. Exp. Med. 187:97.-subunits into the 20 S proteasome complex. J. Mol. Biol. 288:117.[Medline]
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