Age-related appearance of a CMV-specific high-avidity CD8+ T cell clonotype which does not occur in young adults
- Angelika Schwanninger†1,
- Birgit Weinberger†1,
- Daniela Weiskopf1,
- Dietmar Herndler-Brandstetter1,
- Stephan Reitinger1,
- Christoph Gassner2,
- Harald Schennach2,
- Walther Parson3,
- Reinhard Würzner4 and
- Beatrix Grubeck-Loebenstein1Email author
© Schwanninger et al; licensee BioMed Central Ltd. 2008
Received: 08 October 2008
Accepted: 12 November 2008
Published: 12 November 2008
Old age is associated with characteristic changes of the immune system contributing to higher incidence and severity of many infectious diseases. Particularly within the T cell compartment latent infection with human Cytomegalovirus (CMV) is contributing to and accelerating immunosenescence. However, latent CMV infection and reactivation usually does not cause overt symptoms in immunocompetent elderly persons indicating immunological control of disease. Little is still known about the clonal composition of CMV-specific T cell responses in donors of different age. We therefore analyzed CD8+ T cells specific for an immunodominant pp65-derived nonamer-peptide (NLVPMVATV; CMVNLV) in different age-groups. Independent of donor age CMVNLV-specific CD8+ T cells preferentially use the V beta family 8. This family has monoclonal expansions in the majority of donors after stimulation of CD8+ T cells with the peptide. By sequencing the CDR3 region of the T cell receptor we demonstrated that CMVNLV-specific, BV8+ CD8+ T cells share the conserved CDR3-sequence motif SANYGYT in donors of all age groups. Interestingly, a second conserved clonotype with the CDR3-sequence motif SVNEAF appears in middle-aged and elderly donors. This clonotype is absent in young individuals. The age-related clonotype SVNEAF binds to the pMHC-complex with higher avidity than the clonotype SANYGYT, which is predominant in young adults. The dominance of this high avidity clonotype may explain the lack of overt CMV-disease in old age.
Ageing is associated with an increase in the incidence and severity of many infectious diseases. The most common infections in the elderly are influenza, infections with Streptococcus pneumoniae, infections of the skin and also of the urogenital tract . In addition, reactivation of latent viruses and bacteria such as Varicella-Zoster-Virus leading to Herpes zoster [2, 3] and Mycobacterium tuberculosis [4, 5] are more frequent in old age. This may be due to decreased immunosurveillance as well as to other factors such as age-associated diseases, poor nutrition, chronic renal failure and institutionalization.
Cytomegalovirus (CMV) is a human beta-herpesvirus with a prevalence of 60–100% in the adult population. The link between CMV-infection, immunosenescence and longevity has recently been a subject of great interest [6, 7]. Despite frequent reactivation of latent CMV in the elderly as suggested by increased anti-CMV antibodies and viral shedding in the urine  there are no reports about overt CMV-disease in immunocompetent elderly persons. T cells are essential for the control of viral replication, spread and disease [9–12]. In CMV-seropositive elderly persons up to 25% of the total CD8+ T cell pool can be specific for CMV with the epitope NLVPMVATV of the pp65 matrix protein (CMVNLV) being immunodominant . These CMV-specific cells show a highly differentiated effector phenotype [14–16] and express markers for cytotoxicity [14, 16]. They are proinflammatory , and to a high degree clonally expanded [13, 17, 18]. This has led to the suggestion that CMV-specific T cell clones take up a lot of space and may therefore be responsible for the loss of T cells of other specificities, such as for instance for Epstein-Barr virus (EBV) . The proinflammatory properties of the steadily increasing number of CMV-specific T cells may represent an additional problem, as age-related subclinical inflammatory processes termed "inflamm-ageing" can be enhanced . Inflammation is known to support the development and progression of age-related diseases such as for instance Alzheimer's disease . In longitudinal studies on octo- and nonagenerians CMV-seropositivity has also been linked to the so-called "immune-risk phenotype" and with increased mortality [22, 23].
Despite the obvious importance of CMV infection in old age little is known about the clonal composition of CMV-specific T cells in apparently healthy elderly persons. We therefore analyzed the clonal composition of CD8+ T cells, which are specific for the HLA-A*0201-restricted, immunodominant pp65-derived epitope NLVPMVATV [24, 25] in persons of different age.
Results and discussion
Stimulation of CD8+ T cells with CMVNLV-peptide leads to expansion of CMVNLV-specific cells with restricted V beta usage
In order to analyze the T cell receptor (TCR) repertoire CMVNLV-specific T cells were further purified using pentamers and microbeads reaching a purity of CMVNLV-specific CD8+ T cells above 95% for all samples. Spectratyping of the CDR3 (complementary determining region 3) region of the TCR beta chain was performed as previously described [26, 27]. CMVNLV-specific CD8+ T cells preferentially used BV 8 and BV 13 after culture (Figure 1B). 64% and 59% of all donors had monoclonal expansions (clonality score 3) in BV8 or BV13, respectively. No differences in the spectratype scores were observed between the different age groups (data not shown). Previous work analyzing the V beta usage of CMVNLV-specific T cells shows that the broad repertoire of CMV-specific T cells, which is stimulated during primary infection rapidly focuses on individual BV families within the first weeks after infection . Restimulation in vitro does not alter the T cell repertoire [29, 30]. In accordance with our results it has been shown that CMVNLV-specific T cells preferentially use BV 8, 13 and 6 in healthy adults as well as in immunosuppressed patients [28–33].
The sequence of the CDR3 region of BV8+ T cell receptors of CMVNLV-specific CD8+ T cells changes with age
CMV-specific BV8+ CD8+ T cells with the TCR-sequence SVNEAF have a higher antigen avidity than corresponding cells with the sequence SANYGYT
High avidity CD8+ T cells are essential for clearance of viral infections [34–37] and for the elimination of tumour cells [38–40]. Therefore, anti-tumour vaccination aims to induce high avidity tumour-specific T cells. In concordance, immunotherapy for viral diseases such as EBV- or CMV-reactivation and infection in immunosuppressed patients after haematopoietic stem cell transplantation benefits from selection of virus-specific T cells with high avidity . Regarding our data, the question arises, why the high avidity clonotype SVNEAF is absent in young individuals while it is dominant in a subset of the middle-aged and elderly persons. In view of the well known decline of immune function with age  it seems likely that a subgroup of elderly persons suffers from high CMV-activity and pronounced viral reactivation , which necessitated the expansion of the high avidity BV8+ CMVNLV-specific clonotype for viral control. Due to its high avidity this clonotype expands and presumably exerts increased effector functions in vivo leading to protection from CMV-disease. However, accumulation of CMV-specific T cells of this specific clonotype may be particularly prone to inhibit T cells of other specificities . CMV-seropositivity has also been associated with non-responsiveness to anti-influenza vaccination  and with frailty . The price for good protection against CMV -as provided by CMV-specific cytotoxic T lyphocytes with high avidity- might thus be accelerated immunosenescence and potentially lower responses to other pathogens.
Gender and age of blood donors
median age (years)
age range (years)
young (≤ 39 y)
middle-aged (40–64 y)
elderly (≥ 65 y)
Cultivation of CD8+ T lymphocytes and enrichment of CMVNLV-specific T cells
CD8+ T cells were isolated using anti-CD8-conjugated microbeads and the magnetic-activated cell sorting (MACS) system (Milteny Biotech) according to the specifications given by the manufacturer. CD8+ T cells were cultivated in RPMI 1640 (Cambrex) supplemented with 10% FCS (Sigma-Aldrich) and 1% penicillin-streptamycin (Cambrex) at 37°C and 5% CO2. T cells were stimulated for 14 days with 0.1 μg/ml of the immunodominant peptide NLVPMVATV (Bachem) derived from the CMV-encoded protein pp65 in the presence of IL-2 (20 ng/ml) and irradiated (30 Gy) autologous PBMC in a CD8+ : PBMC ratio of 1:1. IL-2 (20 ng/ml) was added every three days and cells were restimulated with peptide and irradiated autologous PBMC after 7 days. Percentages of CMVNLV-specific CD8+ T cells were determined prior to culture and after 14 days of stimulation by immunofluorescence surface staining with APC-coupled pentamers containing the CMVNLV peptide (Pro5® MHC, Proimmune). After 14 days of cultivation CMVNLV-specific CD8+ T cells were purified using APC-conjugated CMV-pentamer, anti-APC-antibodies coupled with magnetic beads and MACS-technology. Purity of CMVNLV-specific T cells was >95% in all cases.
Isolation of RNA and cDNA synthesis
RNA was isolated from CMVNLV-specific T cells using the RNeasy Plus Mini Kit (QIAGEN) and cDNA-synthesis was performed using a Reverse Transcription system with Oligo(dT)-primers (Promega).
CDR3 spectratyping of V beta families
PCR fragments were amplified from cDNA for 24 V beta families (BV) and complementarity determining region (CDR3) spectratyping was performed as previously described [26, 27]. Analysis of the raw data was performed with the GeneScan 3.7 analysis software package (PE Applied Biosystems) using the Local Southern method for fragment size estimation . The occurrence of dominant clonal expansions was quantified for each V beta family by assigning scores for clonality (1 = Gaussian distribution; 2 = several peaks; 3 = one peak; compare with ) and intensity as measured in relative fluorescence units (RFU) (0 = < 500 RFU; 1 = 500–3000 RFU; 2 = 3000–8000; 3 = >8000). If necessary, PCR-products were diluted prior to spectratyping and the dilution factor was taken into account for the calculation of the intensity score. Diversity and intensity scores were added and BV families with a total score of ≥ 5 were considered as predominant. This score equally weights monoclonal BV families with intermediate intensity (3+2) as well as oligoclonal BV families with high intensity (2+3). Both categories as well as monoclonal BV families with high intensity (3+3) were considered as predominant.
Bacterial cloning of TCR-sequences and sequence analysis
T cell receptor sequences of the BV8 family were amplified using a forward primer specific for the BV8 family (5' CGTTCCGATAGATGATTCAGG 3') and a reverse primer (5' CTGGGTCCACTCGTCATTCT 3') located in the constant region of the TCR beta chain. PCR fragments were cloned into the pCR®-II-TOPO® vector (Invitrogen) via TA-cloning and the vector was transformed into chemically competent E. coli (One Shot TOP10, Invitrogen). For each donor several positive clones were picked and plasmid DNA was extracted using standard procedures (QIAprep Spin Miniprep Kit, QIAGEN). TCR-sequences were determined by standard sequencing procedures (QIAGEN) and sequence data were analyzed using the Bioedit Sequence Alignment Editor 22.214.171.124.
Measurement of TCR binding kinetics
CMVNLV-specific CD8+ T cells were harvested after 14 days of culture and used for pentamer binding and dissociation assays as previously described [29, 30] with minor modifications. Briefly, T cells were stained with increasing amounts (range 0.1 to 5 μg/ml) of CMVNLV-pentamers. Mean fluorescence intensity (MFI) of pentamer-binding CD8+ T cells was measured by a FACSCalibur flow cytometer (BD Pharmingen). For the analysis of pentamer dissociation T cells were stained with saturated amounts of CMVNLV-pentamers (1.25 μg/ml). 25 μg/ml unlabelled anti-HLA-A2*0201 antibodies (clone BB7.2) were added to prevent re-binding of dissociated pentamers. Dissociation of pentamers was assessed by FACS analysis at different time points (range 0–180 min). The MFI of pentamer-positive T cells at time point 0 (maximum pentamer binding) was considered as 100%.
This work has been supported by the Austrian Science Fund (project S9308-B05) and part of this project was supported by, and carried out within the EU-funded Network of Excellence LifeSpan (FP6 036894). We thank Michael Keller and Brigitte Jenewein for outstanding technical support. DHB is supported by a FLARE (Future Leaders of Ageing Research in Europe) post-doctoral fellowship funded by the Austrian Federal Ministry of Science and Research.
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