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Journal of Virology, July 2007, p. 7269-7273, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00356-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Predictable {alpha}ß T-Cell Receptor Selection toward an HLA-B*3501-Restricted Human Cytomegalovirus Epitope{triangledown}

Rebekah M. Brennan,1,{dagger} John J. Miles,1,2,{dagger} Sharon L. Silins,1 Melissa J. Bell,1 Jacqueline M. Burrows,1 and Scott R. Burrows1*

Cellular Immunology Laboratory and Australian Centre for Vaccine Development, Queensland Institute of Medical Research, Brisbane, Australia,1 School of Population Health, University of Queensland, Brisbane, Australia2

Received 19 February 2007/ Accepted 17 April 2007


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ABSTRACT
 
Human cytomegalovirus (HCMV) elicits a very large burden on the immune system, with approximately one in ten T cells being reserved solely to manage this infection. However, information on the clonotypic composition of these vast T-cell populations is limited. In this study, we sequenced 116 T-cell receptor (TcR) {alpha}/ß-chains specific for the highly immunogenic HLA-B*3501-resticted epitope IPSINVHHY from the pp65 antigen. Interestingly, T cells recovered from all donors bore an identical or near-identical TRBV28/TRBJ1-4/TRAV17/TRAJ33 TcR. The ability to predict the responding {alpha}ß TcR repertoire before viral infection should prove a powerful tool for basic and clinical immunology.


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TEXT
 
Human cytomegalovirus (HCMV) is a betaherpesvirus (human herpesvirus 5) that infects 30 to 70% of individuals in developed countries and upwards of 90% of individuals in developing countries (18, 25). After primary contact, typically through bodily fluid transmission, HCMV quickly infects various cells of myeloid lineage and ultimately establishes a lifelong persistence in the host (24). Normally, a healthy immune system offers lifelong suppression against both primary and latent HCMV-associated pathologies, and large numbers of HCMV-specific CD8+ and CD4+ T cells are observed in the peripheral blood of healthy virus carriers (27). However, if the immune system is weakened, through neonatal immaturity, human immunodeficiency virus infection, or drug-induced immunosuppression, the virus can escape suppression, proliferate, and initiate pathogenesis. The immune mediators primarily responsible for suppressing HCMV are thought to be CD8+ and CD4+ T cells. This idea is supported by the results of early-phase trials showing that the adoptive transfer of HCMV-specific T cells into immunocompromised patients can successfully prevent HCMV viremia and associated diseases (4, 10, 19, 22, 34).

In recent times, numerous large-scale mapping projects have been carried out to identify the precise targets of HCMV-specific T cells and, thus far, approximately 100 CD8+ and CD4+ T-cell epitopes have been mapped across 15 HCMV proteins (reviewed in reference 4). Accordingly, data are now being quickly amassed regarding the immunogenicity and immunodominance of these peptides, along with the magnitudes, fluctuations, and phenotypes of the responding T-cell populations. Information on the clonotypic composition of these vast T-cell populations is, however, limited. Of the >100 mapped HCMV epitopes, only four (HLA-A*0201- and B*0702-restricted epitopes) have been characterized with regard to the responding T-cell receptor (TcR) repertoire. The present study was aimed toward expanding this knowledge through the detailed characterization of the TcR repertoire used by ex vivo-isolated T cells specific for the highly immunogenic, HLA-B*3501-binding epitope 123IPSINVHHY131 (herein referred to as IPS) from the pp65 protein of HCMV (2, 5).

Five healthy, HCMV-seropositive, HLA-B*3501-positive individuals were enrolled in the study. Initially, peripheral blood mononuclear cells (PBMCs) were freshly isolated from each donor; stained with CD3 monoclonal antibody (MAb), CD8 MAb, CD19 MAb (BD Biosciences, NJ), and a multimer of the IPS/HLA-B*3501 complex (ProImmune, Oxford, United Kingdom); and analyzed by flow cytometry. The frequency of IPS/HLA-B*3501-specific T cells was found to range from 0.25% to 1.87% (average, 0.81%) of CD8+ cells (data not shown). These frequencies are consistent with results from a previous study that also exploited IPS/HLA-B*3501 multimers (11) and verify the highly immunogenic nature of the IPS peptide. In order to dissect the total IPS-specific response into separate TcR Vß gene families, we costained the PBMCs with one of 22 Vß-specific MAbs (Beckman Coulter, Fullerton, CA). The results of this analysis are shown in Fig. 1. Obvious TcR Vß gene restriction was observed across all individuals, with each donor utilizing only 1 to 6 TRBV genes from an available array of 22. Significantly, four of the five donors exhibited clear gene skewing toward the TRBV28 family. These TRBV28 expansions ranged from 19% to 55% (average, 34%) of the total IPS-specific response. It is of interest that T cells from donors D4 and D3 stained with only the TRBV28 MAb, while donors D2 and D1 also responded with expansions of T cells expressing the TRBV9 and TRBV20 genes. Overall, the IPS-specific T cells found in unrelated, HLA-B*3501-positive individuals expressed a predictable TRBV gene profile, and this observation represents a classic example of the immunological phenomenon of "TcR bias" (29).


Figure 1
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  		FIG. 1. HCMV-exposed, HLA-B*3501-positive individuals deploy CD8+ T cells with biased TRBV gene usage for recognition of the IPS epitope. PBMCs from five HCMV-exposed, HLA-B*3501-positive individuals were stained with an IPS/HLA-B*3501 pentamer and one of 22 TRBV-specific MAbs. Only gated percentages of 0.02% and more were considered significant. The designation TRBV follows the TcR gene nomenclature specified by IMGT.

To further characterize the virus-specific T-cell response, we studied the clonal diversity and TcR junctional rearrangements of IPS-specific T cells directly ex vivo. Using a previously described method (13), IPS-specific T cells were sorted directly from PBMCs to a purity of at least 96% using the peptide-HLA multimer. The TcR transcripts were then extracted from the pool, cloned, and sequenced. Figure 2a shows the amino acid sequences extrapolated from this junctional, complementarity-determining region 3 (CDR3) DNA sequence analysis. All recovered TRBV28 chains exhibited a strict CDR3 span of 13 residues and an exclusive pairing with TRBJ1-4. A set of residue-identical (so-called public) TRBV28 chains was recovered from D4 and D2. The remaining TRBV28 chains displayed minor variations around these core consensus sequences. A proline (P) residue was favored at position 4 of the CDR3ß region, while glycine (G) at position 5 and threonine (T) at position 6 were also frequently observed. Additionally, substitutions at these positions nearly always involved either synonymous residues or an atomically similar amino acid comprising a small and uncharged side chain.


Figure 2
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  		FIG. 2. TcR junctional rearrangements of IPS-specific CD8+ T cells. (a) One hundred eight translated CDR3 {alpha}ß rearrangements from ex vivo-sorted IPS-specific T cells. (b) The CDR3 {alpha}ß rearrangements from four in vitro-derived IPS-specific T-cell clones show a pairing of the TRBV28/TRBJ1-4 with TRAV17/TRAJ33. (c) The nucleotide redundancy exhibited by public IPS-specific T cells. The dagger ({dagger}) denotes the donor origin and T-cell clone number. The asterisk (*) denotes multiple, codon redundant nucleotide sequences that were found in this donor. The greyed area designates nucleotides of germ line origin. The designations TRBV, TRAV, TRBD, TRBJ, and TRAJ follow the TcR gene nomenclature specified by IMGT. The colored areas designate common characteristics of the amino acid side chain: purple, nonpolar aliphatic; blue, positively charged; pink, polar uncharged; yellow, negatively charged; and green, aromatic.

In light of this fastidious ß-chain selection, we next wondered if the {alpha}-chain that paired with the TRBV28/TRBJ1-4 chain might also be restricted. Four IPS-specific, TRBV28+ T-cell clones were raised from donor D4, and a full panel of 34 TRAV PCR primers was used to identify the {alpha}-chain that paired with TRBV28/TRBJ1-4 (method described previously [13]). Direct sequencing revealed that all clones were likely to have originated from the same progenitor and that the TRBV28/TRBJ1-4 ß-chain paired with a TRAV17/TRAJ33 {alpha}-chain (Fig. 2b). Using a TRAV17 primer, we then proceeded to amplify TRAV17 transcripts from the sorted pool of IPS-specific cells from all five donors. The results of the TRAV17 sequencing, shown in Fig. 2a, revealed a high degree of restriction, very similar to that seen with the TRBV28 chains. All recovered TRAV17 chains exhibited a strict CDR3 span of 13 residues and an exclusive pairing with TRAJ33. Moreover, two further sets of residue-identical (public) TRAV17/TRAJ33 transcripts were recovered from donors D4, D1, and D3 and from donors D2, D5, and D1 (Fig. 2a) and, like the TRBV28 chains, the remaining TRAV17 chains exhibited patterning around these consensus TRAV17/TRAJ33 sequences. It is of interest that several of the recovered TRAV17 transcripts were encoded entirely by germ line nucleotides (Fig. 2c). Such "N-nucleotide-deficient" TcRs are thought to be expressed chiefly by various lineages in the innate immune system ({gamma}{delta} T cells and NKT cells) and to be very rare among {alpha}ß T cells (23). Of further interest is the stringent requirement for a negatively charged aspartic acid (E) at position 3 of the CDR3{alpha}. This residue was frequently encoded by different N nucleotides (Fig. 2c). These data suggest a vital structural role for this CDR3{alpha} residue when engaging the IPS/HLA-B*3501 target. In summary, we have verified the existence of class III TcR gene bias (29) in the IPS-specific HCMV response, with evidence that genetically unrelated HLA-B*3501-positive individuals deploy IPS-specific {alpha}ß T cells with public or near-identical TRBV28/TRBJ1-4/TRAV17/TRAJ33 TcR chains.

In recent years, there have been mounting reports of the use of public {alpha}ß TcRs to engage a variety of human viruses, bacteria, and cancers (reviewed in reference 14). Among these are four public TcR signatures from HCMV, specific for the HLA-A*0201-binding epitopes NLVPMVATV and VLEETSVML (6, 8, 28) and the B*0702-binding epitopes RPHERNGFTV and TPRVTGGGAM (35). Indeed, it is becoming increasingly apparent that public {alpha}ß TcRs may represent a widespread feature not only in HCMV defense but in T-cell immunity in general. This is an intriguing concept when considering that (i) each adult human can draw on a stockpile of 2.5 x 107 different naïve TcR structures to engage a foreign antigen (1) and (ii) deployment of a single oliogoclonal T-cell population can leave a host vulnerable to viral escape (12, 21). Presently, no clear explanation for this level of TcR bias has been suggested. There is, however, evidence suggesting that public TcRs have specific genetic (33), functional (3, 20, 28), and structural (9, 26, 30-32) advantages over their rivals, which may outweigh the immunological risks associated with their dominance.

In conclusion, we have found that five of five HLA-B*3501-positive, HCMV-seropositive donors deployed IPS-specific T cells bearing predictable TRBV28/TRAV17 TcRs. The identification of these and other public {alpha}ß T-cell populations is important for a variety of reasons. First, they will aid in advancing our understanding of antigen-driven T-cell selection (20, 28) and major histocompatibility complex restriction (13), since they provide a fixed variable in an often exceedingly complex biological system. Additionally, public TcRs are valuable models for structural studies, since they appear to represent an evolutionary pinnacle in antigen-driven selection. Indeed, the atomic dissection of public TcR-peptide-major histocompatibility complex engagement can reveal distinct features which constitute superior TcR architecture (9, 26, 31, 32). The identification of public TcRs is also relevant clinically. First, HCMV appears to drive a massive but dysfunctional CD8+ T-cell expansion in the elderly, which can influence factors leading to early death (15, 36). These large T-cell populations, which frequently utilize public TcRs, show a loss in antigen sensitivity and cytokine production (17), exhibit a marker for end-stage differentiation and apoptosis resistance (16), and can often exceed one quarter of the total CD8+ T-cell pool (7). Thus, the identification of novel public T-cell populations in HCMV immunity may allow for the rapid detection of senescent cells. In theory, these cells could then be specifically purged from the immune compartment. Finally, due to their high affinities and traceable alloreactivity profiles, public TcRs should also prove to be excellent candidates for future adoptive therapies and receptor-guided therapeutics (14).


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FOOTNOTES
 
* Corresponding author. Mailing address: Queensland Institute of Medical Research, 300 Herston Road, Brisbane 4029, Australia. Phone: 61-7-3845-3793. Fax: 61-7-3845-3510. E-mail: scott.burrows{at}qimr.edu.au Back

{triangledown} Published ahead of print on 25 April 2007. Back

{dagger} R.M.B. and J.J.M. contributed equally to this work. Back


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Journal of Virology, July 2007, p. 7269-7273, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00356-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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