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CORRESPONDENCE David A. Price: dprice1{at}mail.nih.gov OR Daniel C. Douek: ddouek{at}mail.nih.gov
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© 2009 The Rockefeller University Press
The global HIV pandemic demands an effective vaccine. However, while immunogenic vectors enter advanced clinical trials, the parameters on which to base measurements of efficacious immunity in a prospective manner remain unclear. Indeed, the recent Merck STEP trial failure has exposed our rudimentary understanding of protective determinants within the adaptive T cell response to HIV (1–3). It is established that specific CD8+ T cell immunity suppresses HIV replication in vivo and that certain patterns with respect to antigen targeting and MHC class I restriction are consistently associated with low levels of virus load (4–6). However, simple quantitative correlates, at least in peripheral blood, have proved elusive (7, 8). This paradox is exemplified by the SIV model, in which CD8+ T cell responses to the structurally constrained Gag CM9 epitope restricted by Mamu-A*01 are protective yet insufficient in terms of magnitude alone to define outcome (9, 10).
In the absence of consistent numerical correlates of immune control, recent observational studies have focused on functional profiling in attempts to identify the properties that demarcate effective HIV-specific CD8+ T cell responses (11–15). Indeed, a broad consensus indicates that polyfunctionality within pathogen-specific T cell populations, which is related to the sensitivity of antigen recognition among other parameters, correlates with improved outcome measures (3, 16). However, the qualitative properties of CD8+ T cell populations are clearly affected by viral replication, and the extent to which such functional associates reflect deterministic attributes remains uncertain. Similarly, phenotypic analyses of HIV-specific CD8+ T cell populations have yet to provide definitive indicators of immune control (3). At a more fundamental level, a given cognate T cell response is defined by the nature of its constituent clonotypes, which are defined on the basis of their expressed TCRs and can be considered the elemental units of any antigen-specific T cell population. Thus, the primary interface between the virus and adaptive T cell immunity occurs at the level of TCR-mediated recognition of peptide-MHC antigen; these signal transduction events, in turn, dictate the ontogeny and biological characteristics of individual cognate T cells in vivo. Given the seminal importance of clonotype-dependent TCR-mediated recognition events, it is not unreasonable to propose that the potential efficacy of a composite virus-specific CD8+ T cell population might depend on the idiosyncrasies with which individual cognate TCRs engage the targeted viral antigen.
In a previous study, we examined the clonotypic composition of immunodominant CD8+ T cell populations in acute SIV infection to illuminate the role of TCR usage in the process of mutational immune escape (17). In the present study, we conducted a detailed prospective study of vaccine-induced SIV-specific CD8+ T cell responses to the same immunodominant epitopes to establish whether the mobilized antigen-specific TCR repertoire can influence virologic outcome.
RESULTS
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RESULTS
DISCUSSION
MATERIALS AND METHODS
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Disparate outcomes after vaccination and challenge despite induction of potent SIV-specific CD8+ T cell responses
Eight Mamu-A*01+/B*17– rhesus macaques were vaccinated with SIVmac239-derived immunogens using a DNA prime/adenovirus serotype 5 (Ad5) boost regimen and subsequently exposed to repeated intrarectal challenges with homologous virus until infection occurred (Fig. 1 A). Longitudinal CD4+ T cell trajectories and plasma virus load (pVL) dynamics are summarized for all participant macaques in Fig. 1 B. Consistent with a previous report that indicated a central role for vaccine-induced CD8+ T cell responses in the outcome of subsequent infection (9), the vaccinated macaques in this study developed lower peak and postprimary set point pVL levels and maintained memory CD4+ T cells to a greater extent compared with control nonvaccinated macaques infected under identical conditions (18). Furthermore, although potent SIV-specific CD8+ T cell responses were induced by vaccination in all cases, virus-specific humoral responses were not a confounding factor; no env gene-derived products were incorporated in the vaccine formulations, and neutralizing antibodies were detected after infection only in the vaccinee with the least favorable course (r97111; Fig. 1 B). However, no significant correlations were observed between the magnitude of the vaccine-induced CD8+ T cell response to SIV and the degree of virologic control after infection; this held for the classically immunodominant Mamu-A*01–restricted CD8+ T cell responses specific for the Tat SL8 (STPESANL; residues 28–35) and Gag CM9 (CTPYDINQM; residues 181–189) epitopes, as well as for subdominant responses induced to other viral products (18). Notably, these latter CD8+ T cell responses conferred no additional protection in the acute and early chronic phases of SIV infection when compared with Gag vaccination alone using the same platform (9, 18). Thus, this cohort encapsulates the conundrum that while the presence of a response is clearly beneficial, the precise attributes of the induced CD8+ T cell populations that confer protection remain obscure.
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and TNF-
production were triggered in response to antigen with almost identical peptide sensitivities for the former effector function (Fig. 5, A–C). Screening for additional soluble factors released on antigen encounter yielded similarly uniform results overall, although PBMCs from r96133 failed to produce significant levels of MIP-1 and were comparatively meager with respect to lymphotoxin A secretion (Fig. 5 B). Furthermore, these vaccine-induced CD8+ T cell populations exhibited indistinguishable effector memory (CD28–CD45RA+CD95+) phenotypic profiles (Fig. 5 D); interestingly, this suggests that the impaired maturational profile characteristic of HIV-specific CD8+ T cells in infected individuals arises as a consequence of virus exposure (33, 34). Thus, consistent with the findings of a recent mouse study (35), no major disparities were apparent in the interactions of these constitutively distinct CM9-specific CD8+ T cell populations with cognate wild-type antigen. Functional and phenotypic homogeneity irrespective of clonotypic composition was also observed in multiparametric analyses of CM9-specific CD8+ T cell populations at the PI time point (n = 6; Fig. S2 and not depicted). Collectively, these data suggest that such approaches are insufficient in isolation to monitor the efficacy of T cell responses with respect to biological outcome.
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ELISPOT analysis of PBMCs from the prechallenge time point (Fig. 6); importantly, the discrete but related parameter of activation threshold per se was not a confounder in these experiments because recognition sensitivities for wild-type antigen were almost identical (Fig. 5 C). All possible amino acid substitutions were tested at positions 1, 7, and 8 in the CM9 peptide; these are potential TCR contact residues that have previously been shown by alanine scanning experiments to be the only intraepitopic sites tolerant of variability within the confines of viral fitness, although replication competence is affected to a substantial extent in the case of P7 mutations (26). Notably, a greater degree of recognition flexibility was apparent in the public clonotype–dominated CM9-specific CD8+ T cell population from macaque r97113 (Fig. 6). Similar results were observed in additional macaques with diametrically opposed patterns of CM9-specific clonotype usage (Fig. S3 and not depicted); interestingly, some public clonotype–rich CM9-specific CD8+ T cell populations exhibited enhanced recognition of variants relative to wild-type antigen. The extent to which individual variants were recognized by public versus private clonotypes could not be assessed in these experiments due to limiting cell numbers. However, CD8+ T cells specific for the CM9 variants L1 and M8 sorted from macaque r97113 with pMamu-A*01 tetrameric complexes refolded around the relevant peptides demonstrated almost identical clonotypic compositions to the corresponding wild-type CM9-specific population; these data exclude the possibility that the observed cross-reactivity was mediated by clonotypically distinct CD8+ T cell populations (unpublished data). Thus, public clonotype usage is associated with enhanced cross-reactivity to potentially relevant antigenic variants.
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Mechanistically, the observed association between public clonotype usage and enhanced cross-reactivity profiles is somewhat at odds with the finding that the contingent protective effect is apparent immediately after infection. The CM9 epitope is generally stable throughout the early periods of infection, with escape mutants appearing late and variably; indeed, no CM9 mutations were detected within the course of this study (macaques r00060 and r01008; unpublished data). How can we explain this apparent discrepancy? One possibility is that emerging escape mutations below the level of detection or at anatomically disparate sites are quelled more effectively by public clonotypes and that these imperceptible events favorably influence other facets of host immunity and, hence, the subsequent outcome of infection. Alternatively, public clonotype usage might be linked to a distinct determinant of virologic control, with enhanced variant recognition simply representing an epiphenomenon. For example, the kinetics with which cognate T cells are mobilized from the naive pool in response to incoming virus could dramatically modify the massive pathological damage that can occur during acute SIV infection (46), and thereby associate better downstream virologic outcomes with more pronounced public clonotype content if the latter are preferentially recruited into earlier and more robust CM9-specific CD8+ T cell populations. Mechanistically, such a selective priming bias could occur as a function of precursor frequency, and it does appear that public clonotypes are generated more often as a consequence of convergent recombination (20, 47–49). Indeed, it is tempting to speculate that this process establishes an "immunological homunculus" (50) within the naive T cell pool comprising highly prevalent public T cell clonotypes with a proclivity for cross-reactivity that can expand rapidly in response to a substantial number of antigenic assaults and thereby provide an early protection system against many pathogens. This scenario is consistent with several observations. First, it could explain the classical early immunodominance of the SL8/TL8 epitope in Mamu-A*01+ macaques during acute SIV infection (19); SL8/TL8-specific CD8+ T cell populations are dominated by public clonotypes bearing a TCRB CDR3 codon-degenerate motif (17), and a high presursor frequency of such TCRs generated through convergent recombination could fuel primary responses to this antigen. Indeed, the SL8-specific response is markedly less dominant after infection in the presence of vaccine-induced CD8+ T cell populations specific for other epitopes (Fig. 1) (18), further supporting the notion that TCR repertoire skewing underlies this pattern of immunodominance. Second, the associations between public clonotype usage and virologic outcome were only apparent at the initial point of antigen contact (the PV time point in the vaccination study and week 5 after infection in the unmanipulated acute SIV cohort); although the publicity of individual responses was maintained to some extent throughout the period of study (Fig. 3), these correlations were lost at later time points (the PI time point and week 12 after infection, respectively). Thus, consistent with an effect mediated by the predominance of cognate public clonotypes within the naive T cell pool, it seems that the nature of the primary interactions is determinant and that the initially relevant clonal topography is obscured with subsequent adaptation to persistent antigen (51). Third, recruitment of all cognate clonotypes, both public and private, during the vaccination process is likely to mask any advantage conferred by high precursor frequencies in the naive T cell pool; these considerations could explain the lack of association between public clonotype usage and virologic outcome at the PI time point, and the weaker correlation at the PV time point with respect to the acute infection cohort. Overall, these considerations invoke subtle differences in the nature of the primary CD8+ T cell response as profound determinants of outcome (52). However, ongoing recruitment of antigen-specific CD8+ T cells from a munificent naive pool may continue to sustain a more effective response throughout the course of infection (53); in this regard, the correlation between clonotypic diversity and the number of public clonotypes is notable despite the fact that the latter parameter in isolation did not achieve significance with respect to measures of disease progression in the present study.
In summary, these data provide compelling evidence that the fundamental nature of the initial encounter between a constrained viral antigen and the adaptive cellular immune system dictates subsequent biological outcome. The potential for vaccine-based initiatives to alter such interactions with beneficial effect will likely depend on the balance between the extent to which differential public clonotype usage is predetermined by the composition of naive pool (54), or perhaps even the heterologous memory pool (37), versus stochastic elements in the initial antigen-specific selection process. Further studies are necessary to clarify the associations described in this paper, especially with respect to mechanistic determinants at the clonal level and quantitative relationships at the sites of active viral replication. However, the observation that clonotypic parameters can predict virologic outcome provides ample reason to consider such effects in the design and monitoring of vaccine efficacy trials.
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MATERIALS AND METHODS |
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Virus load quantification.
pVL was determined for all SIVmac239 studies using previously published protocols (57, 58) with minor modifications (18).
IFN- ELISPOT assays.
Direct ex vivo production of IFN- in response to stimulation of PBMCs with the concentrations of wild-type CM9 peptide or variants thereof indicated in the figures was assessed in ELISPOT assays, as previously described (59, 60). All conditions were tested in duplicate. Spot imaging and quantification were automated with an ImmunoSpot Series 3B Analyzer (CTL Analyzers LLC). Background counts in the absence of exogenous peptide were subtracted from experimental counts; for comparative analyses, results were calculated as the percentage of spots induced by variant peptide with respect to wild type.
Cytokine bead arrays.
Direct ex vivo production of multiple soluble factors in response to stimulation with wild-type CM9 peptide at a concentration of 2 µg/ml was assayed using the Cytokine Bead Array Flex Set (BD) containing mAbs and detection reagents specific for 25 different cytokines, each of which was shown in preliminary experiments to cross react with rhesus macaque cytokines. Unstimulated samples were used in parallel to determine background levels of cytokine secretion resulting from in vivo activation; these values were subtracted from the data shown in Fig. 5 B.
Flow cytometry and cell sorting.
Soluble fluorochrome-labeled pMamu-A*01 tetramers were produced and used as previously described (17, 61). For functional analyses of CD8+ T cell populations, 2 x 106 PBMCs were stimulated with cognate peptide at a final concentration of 2 µg/ml in R10 medium (RPMI 1640 supplemented with 10% heat-inactivated fetal calf serum, 100 U/ml penicillin, 100 µg/ml streptomycin, and 2 mM L-glutamine) for 6 h in the presence of 5 µg/ml anti-CD28–Alexa Fluor 680 mAb, 10 µg/ml anti-CD49d mAb, and 10 µg/ml brefeldin A; for each experimental condition, parallel negative controls without cognate peptide were included. Subsequent staining procedures to exclude aberrant binding events, identify surface markers, and detect intracellular cytokine production or granzyme B content were conducted as previously described with minor modifications (62). For phenotypic analyses of pMamu-A*01–allophycocyanin (APC) tetramer–labeled cells, the following directly conjugated mAbs were used: anti-CD3–Cy7APC, anti-CD8–Pacific blue, anti-CD28–FITC, anti-CD45RA–Texas red–PE, and anti-CD95–Cy5PE. At least 106 events were acquired on an LSR II flow cytometer (BD) equipped for the detection of 17 fluorescent parameters, and data were analyzed with FlowJo software (Tree Star, Inc.). In all cases, electronic compensation was performed with antibody-capture beads (BD) stained separately with individual mAbs present in the experimental samples. Flow cytometric cell sorting was conducted with a modified FACSAria (BD) at 70 PSI; postsort purity was consistently >98%.
Clonotype analysis.
Tetramer-labeled CD8+ T cells were sorted viably into 1.5-ml microtubes containing 100 µl RNAlater (Applied Biosystems); for the CM9-specific populations in this study, the median number of sorted cells was 5,000 (range = 740–10,000). All expressed TCRB gene products were amplified without bias using an anchored template-switch RT-PCR (17, 41); amplicons were subcloned, sampled, sequenced, and analyzed as previously described (17, 63). For consistency with previous studies, Arden's nomenclature is retained throughout (64); macaque TCRBV and TCRBJ sequences were assigned according to the closest human equivalent (17).
Statistics.
The presented analysis comprised hypothesis generation and confirmation as two distinct steps. First, the relationship between several candidate measures of SIV antigen-specific CD8+ T cell repertoires at week 5 after infection and mean postprimary pVL from week 6 to 16 was explored using simple linear regressions in an analysis restricted to data derived from a previous study of SIVmac251 infection (17). Due to heteroskedasticity, a logarithmic scale was used for pVL data. Variables considered included the total number of unique clonotypes (diversity), the total number of public clonotypes, and the percentage of captured clonotypes that were public; these parameters were assessed both as absolute values and in relation to response magnitude. The number of public clonotypes at week 5 after infection emerged as the strongest predictor of mean pVL during the later interval. Further multivariate linear regression models were considered to examine the independence of this predictive variable, to assess whether predictions could be significantly improved with combinations of variables, and to determine the impact of additional variables on the observed relationships. Second, an independent dataset was collected from the cohort of eight macaques as described in this study; this information was used to test the hypothesis generated in the first step. Simple linear regressions were used as the primary models to relate the number of public clonotypes, identified both within this cohort and in relation to the first cohort, at both week 2 after vaccination and week 4 after infection to mean log10 pVL from week 6 to 16 after infection. As the time points at which pVL was measured were not quite evenly spaced, we also computed the area under the curve from week 6 to 16 and repeated the linear regressions with this variable. For thoroughness, the alternative measures described previously were also examined in the second cohort. In a final step, we returned to the first cohort of macaques with the expanded compilation of public clonotypes based on the incorporation of data from the second cohort to confirm that the observed relationships were maintained.
Online supplemental material.
Fig. S1 shows the clonotypic architecture of SL8-specific CD8+ T cell populations at week 2 after vaccination with Ad5 and at week 4 after infection with SIVmac239; the corresponding nucleotide sequences are displayed in Table S1. Fig. S2 presents a functional analysis of CM9-specific CD8+ T cell populations from six macaques in the acute phase after infection; based on the simultaneous and independent measurement of five separate effector functions directly ex vivo in a flow cytometric panel comprising 13 distinct parameters, no significant differences were observed in the functional profile of CM9-specific CD8+ T cells irrespective of virologic outcome. Fig. S3 shows the antigen sensitivity and cross-reactivity profiles of CM9-specific CD8+ T cell populations from four macaques at week 2 after vaccination with Ad5; consistent with the data shown in Fig. 6, CM9-specific CD8+ T cell populations that were enriched for public clonotypes exhibited greater levels of cross-reactivity in response to both natural and selected monosubstituted peptide epitope variants. Table S2 displays the 3' sequences of expressed TCRBV13 family genes. Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20081127/DC1.
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Acknowledgments |
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The authors have no conflicting financial interests.
Submitted: 23 May 2008
Accepted: 16 March 2009
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