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* Institute for Biomedical Aging Research of the Austrian Academy of Sciences, and
Institute of Legal Medicine,
Institute of Pathophysiology,
Central Institute for Blood Transfusion, University Clinics Innsbruck, Innsbruck, Austria; and
¶ Aventis-Pasteur, Marcy l’Etoile, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(but no IL-5) upon
stimulation with anti-CD3 or autoantigen. These autoreactive
CD8+ type 1 effector cells seem to trigger a Th1
polarization, as CD4+ T cells from elderly persons without
in vivo Ab production produce Th1, but only low amounts of Th2
cytokines upon in vitro stimulation with PHA. Therefore, the increased
occurrence of CD8+CD28- clonal expansions may
be decisive for the development of immune deficiency in the
elderly. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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has been reported to be high
(7, 8) or low (9, 10, 11) during aging and
multiple similar examples could be given (12).
Controversial observations may result from variations among species,
strains, organs, or culture systems, but may also be due to
interindividual differences in the course of the biological aging
process. To circumvent the problems of heterogenous cohorts and large
deviations, we have made use of the fact that influenza vaccination
induces protective Abs in only 40 to maximally 70% of the elderly
(13, 14) and selected a very homogenous "model" cohort
of elderly persons, none of whom produced specific Abs 1 mo after
influenza vaccination. Other vaccination types might have been equally
suitable to define elderly persons with a lack of Ab production
following immunization, but influenza vaccination is most frequently
performed and easy to monitor.
Using this special cohort, we demonstrate that lack of Ab production
following immunization is associated with the increased occurrence of
expanded autoreactive
CD8+CD28- T cell clones.
These clones, which are frequently CD45RA+,
produce large amounts of IFN- which might be the basis for a change
in the polarization of the immune system in elderly persons and the
development of age-related immune deficiency.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 27 elderly (>60 years), apparently well, mentally
alert persons who live in the community were included in the study.
These persons had been selected from a cohort of 78 elderly persons on
the basis of their Ab response to influenza vaccination with a
commercially available trivalent split vaccine (Vaxigrip;
Aventis-Pasteur, Paris, France) that contained influenza virus
of the A/Sydney/184/93, the A/Beijing/262/95, and the B/Beijing/184/93
strain (similar to B Harbin). A total of 13 persons (6 females, 7
males, mean age 68 ± 9; range 61–89 years) were chosen who had
failed to raise a humoral immune response to all three influenza
strains present in the vaccine and had Ab titers below the protective
level of 1:40 1 mo after vaccination. These elderly persons are in the
whole manuscript referred to as "old nonresponders"
(ONR)3. Aged persons
(5 females, 9 males, mean age 67 ± 7; range 61–85 years) who did
not have influenza-specific Abs before vaccination, but titers of
1:40 to all three influenza strains 4 wk after vaccination were
chosen as a humoral responder group and are in the manuscript referred
to as "old responders" (OR). Six people from the ONR and seven from
the OR group had previously been immunized against influenza. Six young
healthy adults (Y; 3 females, 3 males, mean age 31 ± 3; range
28–35 years), who did also not have influenza-specific Abs before, but
Ab titers of 1:40 1 mo after vaccination were chosen as a young
control group. Four of the six young people had previously been
immunized against influenza. All participants had given their informed
written consent and the study was approved of by the local ethical
committee.
Blood samples
Peripheral blood was taken by venipuncture at three different time points, before as well as 1 and 12 mo after influenza vaccination. Serum samples (5 ml) were obtained before as well as 1 mo after vaccination. Before bleeding, a health check was performed in each participant. Preparation of PBMC was performed by Ficoll-Paque gradient centrifugation as previously described (15). Purified cells were stored in liquid nitrogen until pre- and postvaccination Ab titers had been assessed and the final selection of participants had been made. PBMC samples obtained before vaccination were used to perform the full set of experiments in all donors. In two to four people from each group, complementarity-determining region (CDR)3 spectratyping and phenotypic analysis were repeated using cells obtained 1 and 12 mo after vaccination.
Ab titers
Ab responses to the vaccine hemagglutinin components were determined by standard hemagglutination inhibition assay as described previously (15).
Cell culture reagents
The following reagents were used for in vitro cultures: FCS (SEBAK, Stuben, Austria), RPMI 1640 (Life Technologies, Grand Island, NY), PHA (20 ng/ml; Sigma-Aldrich, St. Louis, MO), live influenza virus (kindly provided by Berna, Swiss Serum and Vaccine Institute, Berne, Switzerland), live CMV (kindly provided by Dr. H. P. Huemer, University of Innsbruck, Innsbruck, Austria), live EBV (diluted supernatant; kindly provided by D. Kraft, University of Vienna, Vienna, Austria), and OKT-3 (20 ng/ml; American Type Culture Collection, Manassas, VA).
Flow cytometry
Cells were preincubated with an Fc block (mAb to CD16-CD32,
2.4G2; BD PharMingen, San Diego, CA) and washed in FACS buffer (PBS,
0.5% BSA, 0.01% sodium azide). Next, they were incubated with
specific Ab directly conjugated as described below, washed, and
analyzed using FACScan, FACSort, and FACSCalibur cytometers; and data
were analyzed with CellQuest software (BD Biosciences, San Jose,
CA). The mAbs used were purchased from BD PharMingen: CD4
(CyChrome-, PerCP-, or allophycocyanin-labeled), CD8 (CyChrome-,
PerCP-, or allophycocyanin-labeled), CD3 (PE-labeled), CD11a
(PE-labeled), CD28 (FITC- or CyChrome-labeled), CD45RO (FITC- or
PE-conjugated), CD45RA (FITC- or CyChrome-labeled), CD95
(FITC-conjugated), CD16 (PE-labeled), V
1 (PE-labeled), V5
(PE-labeled), V9 (FITC-labeled), and V17 (PE-labeled).
Purification of T cells
CD4+ and CD8+ T
cells were purified as follows. PBMC were passed through a nylon
mesh. CD4+ and CD8+
T cells were then purified by a positive selection procedure using
anti-CD4+/CD8+-labeled
microbeads and the MACS system (Miltenyi Biotec, Bergisch Gladbach,
Germany) (purity: 97 ± 3%
CD4+/CD8+/CD3+
cells, range 92–100%). For the isolation and characterization of
expanded T cell clones, CD4- cells were stained
with anti-CD8 and V-specific anti-TCR Abs and
double-positive T cells were sorted with a FACS sorter. Only clones
that dominated one V family in a way that no other clones were
visible (diversity score 3, see CDR3 spectratyping)
were selected for purification. The selected T cells were then washed,
phenotyped, and placed into culture. The clonal nature of the selected
cells was confirmed by immunoscope technology and sequencing.
RNA and cDNA preparation
Total RNA was extracted from T cells using Tri Reagent
(Sigma-Aldrich). A total of 1 µg of total RNA was used for
first-strand cDNA synthesis using a Reverse Transcription system
(Promega, Madison, WI). TCR V transcripts were amplified by PCR
using primers (Life Technologies, Vienna, Austria) specific for each of
the human V families and a specific primer for the constant region
of the -chain (labeled with the fluorescent dye marker 6-FAM).
CDR3 spectratyping
An aliquot of the PCR product was diluted in 16 µl deionized
formamide and 1.2 fmol internal lane standard GeneScan-350 Tamra
(PerkinElmer, Norwalk, CT). The samples were denatured at 90°C for 2
min and snap cooled on ice before loading on a CE 310 Genetic Analyzer
(PerkinElmer). Each sample was injected for 5 s at 15 kV
and electrophoresed for 24 min at 10 kV using a 36-cm capillary and
POP4 (PerkinElmer). Analysis of the raw data was performed applying the
GeneScan 2.1 analysis software package (PE Applied Biosystems, Foster
City, CA) using the Local Southern method for fragment size
estimation. In the case of a normal distribution of individual clones
within the V family, a Gaussian profile was depicted. Deviations
from the Gaussian profile indicated the presence of large expanded
clones. The occurrence of dominant clonal expansions within the
different V families was quantified by using a diversity score
between 1 and 3; 1 was assigned to a Gaussian distribution, 2
corresponded to a pattern with one to three peaks above the Gaussian
background, and 3 corresponded to one predominant peak above the
Gaussian distribution (Fig. 1
). The mean
of all scores assigned to the clonal distributions within the different
V families was then calculated for each individual blood donor for
CD4+, as well as CD8+
cells. These individual scores were then used for further analysis,
when the clonal diversity of CD4+ and
CD8+ cells in the different groups (Y, OR, ONR)
was assessed. The classification of CDR3 spectratypes as Gaussian,
oligoclonal, or monoclonal was done "blind" by three different
persons. The ratings were then compared. In the rare case of
discrepancies, the assessment made by two of the three investigators
was used for further calculations. Three different opinions never
occurred.
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Individual V families that were seemingly dominated by one
expanded clone were selected and amplified by PCR. The clonal nature of
the observed expansions was confirmed by DNA sequencing. Purified PCR
products were ligated with pCRScriptAmp SK vector (Cloning kit;
Stratagene, La Jolla, CA) for 60 min at room temperature. One Shot
competent cells (Invitrogen, San Diego, CA) were used for the
transformation. After PCR screening, positive colonies were selected
and expanded. Plasmids were purified, digested with restriction
enzymes, and the inserts were sequenced using an ABI Prism Genetic
Analyzer CE 310 (PE Applied Biosystems) DNA sequencer. The
sequence data were analyzed using GeneScan Analysis Version 2.1
software.
Cell culture
FACS sorted and isolated T cell clones were cultured together with equal numbers of autologous irradiated (35 Gy) PBMC as APC at a density of 5 x 104 cells/well in 96-well plates in the presence or absence of different stimuli as previously described (16). Cells and conditioned supernatants were harvested after 6 days.
Purified CD4+ T cells were seeded at a density of 106 cells/well in 24-well plates (Falcon; BD Biosciences) together with 106 autologous irradiated (35 Gy) PBMC and stimulated with PHA. Cells and conditioned supernatants were collected after 6 days for cytokine analysis.
Cytokine determinations
Cytokine concentrations in conditioned supernatants were
assessed by commercially available ELISA kits (CYTELISA;
Cytimmunesciences, Vienna, Austria). IFN- was analyzed as a
characteristic type 1, and IL-5 as a characteristic type 2
cytokine.
Statistical analysis
All statistical analyses were based on Student’s t tests for paired and unpaired data. Differences in Ab titers between the groups were assessed by Fisher’s exact test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Elderly persons were selected who did not produce protective Abs 1
mo after influenza vaccination. This group is in the following referred
to as ONR. Two groups were chosen as controls: elderly persons who did
produce protective Abs to influenza following vaccination (OR), and a
cohort of young persons (Y) who had a satisfactory humoral immune
response to influenza vaccination. None of the persons studied had Abs
specific to the three influenza strains present in the vaccine before
vaccination. Postvaccination Ab titers in the respective groups are
listed in Table I.
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The clonal composition of the different CD8+
and CD4+ TCR families was studied in the three
donor groups. Immunoscope technology was applied. A representative
example of results obtained with this technique is depicted in Fig. 1
a. In the CD4+ population, V
subfamilies had a Gaussian or close to Gaussian CDR3-size distribution
pattern in all three groups. Clear deviations from the Gaussian profile
were only noted in the V families in the CD8+
population. Pronounced differences among the groups were observed.
Although the Gaussian profile was most frequently observed in young
persons, deviations from the Gaussian profile were often present in
both elderly groups, but were more pronounced in the ONR group (Fig. 1, a and b). All V families were equally
affected. Single large expanded clones dominating a V family
(diversity score 3) were detected in 2 of 6 (33%) of the young control
persons, and in each person in both elderly groups. However, their
frequency was higher in the ONR group, in which the shift affected a
large majority of V families in all but one person. In this person,
50% of the V families were affected. Fifty percent of the V
families were also dominated by single peaks in one member of the OR
group, while the frequency of expanded clones was lower in all other
members of this group. One of the two young people who had dominant
peaks in their CD8+ repertoire showed a pattern
similar to elderly responders, while dominant peaks were very rare in
the other one. In two donors from each group, CDR3 spectratyping was
repeated 1 mo and 1 year after vaccination. However, no alterations
from the original pattern were observed in any of the samples
studied.
Clonal expansions which dominate the CD8+ repertoire
have a
CD28-CD11a++(bright)CD95++(bright)
phenotype and produce IFN-, but no IL-5 in response to stimulation
with autologous cells
To learn more about the phenotypic and functional characteristics
of expanded T cell clones, clones which dominated a V family and
were also stably detected over a year (Fig. 2a) were isolated by cell
sorting (Fig. 2b). Seven clones from five donors (one Y, two
OR, and two ONR) were obtained. Characterization of the sorted cells by
immunoscope technology always demonstrated one large peak identical in
size to the one observed before sorting (Fig. 2c). The
identity of the clones at different time points as well as before and
after sorting was additionally confirmed by cloning and sequencing. All
sorted clones expressed CD11a and CD95 at high density (Fig. 3a). However, they did not
express CD28. Five of the seven clones (71%) were
CD45RA+, and two (29%; one from a donor from the
Y, the other one from a donor from the OR group) contained
CD45RA+ as well as CD45RO+
cells. The sorted clones retained their phenotype in cell culture in
the absence of stimuli over an observation period of 2 wk. During this
time the cells stayed viable, but failed to increase in number.
Cytokine secretion analysis demonstrated that the clones produced
IFN-, but failed to secrete the type 2 cytokine IL-5 in response to
stimulation with irradiated autologous PBMC (Fig. 3b). Thus,
they were autoreactive, although due to the low numbers of sorted cells
available, the exact nature of the autoantigen could not be defined.
IFN-, but no IL-5, was also secreted when the cells were stimulated
with OKT-3; but no cytokines were produced when irradiated allogeneic
PBMC were used as stimulus. No increase in the production of IFN- by
the clones took place when the autologous PBMC which were used as APC
were pulsed with a panel of different Ags including influenza virus,
CMV, or EBV. IFN- production was not accompanied by proliferation.
There was no difference in the cytokine secretion pattern between
clones from the Y, the OR, and the ONR donor groups, or between
CD45RA+ clones and clones that also contained
CD45RO+ cells (data not shown). These data
indicated that the phenotypic and functional characteristics of the
expanded clones were more or less the same, but that their frequency
was different in the three donor groups.
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To define whether the predominance of expanded clones observed in
the ONR group was reflected in the phenotype of PBMC, we analyzed the
expression of CD28 and of CD45RA and CD45RO on peripheral
CD4+ and CD8+ lymphocytes.
Although the percentage of
CD4+CD28- cells was low in
all three groups, CD8+ cells were frequently
CD28-, and there was a clear cut difference in
the number of CD8+CD28-
cells among the groups (Fig. 4a). Within the
CD8+CD45RO+ population,
CD28- cells were more frequent in both the OR
and the ONR group than in the young group. In contrast, the percentage
of CD28- cells within the
CD8+CD45RA+ population was
markedly higher in the ONR than in the OR group.
CD8+CD45RA+CD28-
cells coexpressed CD11a at high intensity (Fig. 4b). They
did not express CD16. Thus, they were most likely effector T cells with
a CD45RA phenotype, and corresponded to the predominant clonotypes
described above. Phenotypic analysis was repeated 1 mo and 1 year after
vaccination in two to four donors from each group. No significant
changes from the original prevaccination samples were observed in these
donors.
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As the predominance of IFN- producing autoreactive
CD8+ T cell clones may lead to a polarization of
immune responses in the direction of Th1 responses,
CD4+ T cells were studied for their cytokine
production. CD4+ cells were purified from PBMC
and stimulated with PHA. Conditioned supernatants were tested for the
presence of IFN- and IL-5. Following PHA stimulation, the secretion
of IL-5 was similar in the Y and in the OR group, but significantly
lower in the ONR group (Fig. 5). In
contrast, IFN- production did not differ among the groups,
suggesting an imbalance in the production of Th1 and Th2 cytokine in
elderly persons, who fail to produce Abs following influenza
vaccination.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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upon autoantigenic
stimulation. However, they do not produce IL-5. Frequent and ubiquitous
restimulation by autoantigen could be a reason for the persistence of
these clones in vivo (Fig. 3), and represent a possible basis for a
relative overproduction of IFN- in old age. Many studies which
consistently report that neopterin (a macrophage product the production
of which is exclusively triggered by IFN-) is elevated in the
elderly support this possibility (17, 18, 19, 20). Measuring the
production of Abs of the IgG2a istoype could be another way to assess
the functional consequences of IFN- production in the elderly. A
high type 1 cytokine production could change the cytokine
microenvironment in lymphatic tissues, and thus be responsible for a
decreased production of type 2 cytokines by CD4+
T cells (Fig. 5). Type 2 cytokines act on B cells to induce activation
and differentiation, whereas low type 2 cytokine production is likely
to hamper B cell propagation, and thus may be responsible for a
decreased production of Abs following immunization in the elderly. A
recent study in aged mice, which fail to raise a Th2 response following
in vivo challenge, is also in favor of this concept (21).
It would also be of interest to test whether
CD28- clones might have a direct effect on the
differentiation and polarization of CD4+ cells.
Experiments presently underway in our laboratory, in which the cytokine
production pattern of cocultured CD4+ and
CD8+ T cells is tested, will help to elucidate
this possibility.
Th1 polarization may not only be a problem in the context of decreased
Ab production in old age, but may also be detrimental for other
reasons. Proinflammatory cytokines are now believed to exacerbate the
functional pathology and disease course of age-related disorders, such
as Alzheimer’s disease (22, 23) and atherosclerosis
(24). IFN- triggers the production of the Alzheimer
amyloid (A) in combination with TNF-
by human neural and
extraneural cells (25), and increases the production of
oxygen radicals by microglial cells (26). TNF- can also
increase the toxicity of A (27) as well as stimulate
smooth muscle cell proliferation (24), a key event in the
development of atherosclerosis.
Although the etiology of CD28- T cells is not
fully understood in healthy individuals, there is strong evidence that
these cells have arisen in response to continued antigenic stimulation
(28, 29). CD28 expression is characteristically lost after
many rounds of cell division (30), and the strong
expression of CD11a on CD28- cells (Figs. 3 and 4b) is also consistent with their prior activation by Ag.
Telomere shortening has also been described in
CD28- T cells and is more pronounced than in
CD28+ cells from the same donor (31, 32). This also indicates that the former have undergone more
rounds of cell division than the latter.
It is striking that CD28- memory/effector cells mostly have a CD45RA phenotype in people who fail to produce specific Abs following influenza vaccination. CD28-CD45RA+ memory/effector T cells have previously been described to occur at increased frequency in old age, but their origin and significance were unclear (7, 33). It seems now likely that the CD28-CD45RA+ phenotype is consistent with a state of terminal effector cell differentiation (34), although its role as a reservoir of long-lived memory cells has also been discussed. Characteristics such as a loss of growth potential (7) and an increased resistance to apoptosis-inducing stimuli (35, 36), which are reminiscent of the well-defined phenotype of senescent fibroblasts or keratinocytes (37, 38), do in any case suggest that CD28-CD45RA+ T cells can be considered as truly "old."
The accumulation of expanded CD28- clones of old effector/memory T cells in elderly persons could lead to a restriction of the space still available for functioning T cells. This could be another cause for the development of age-related immune deficiency (39). In this context, it seems of interest that predictions of longevity have been made based on the ratio of naive vs memory T cells. Thus, mice characterized by relatively low levels of CD4 and CD8 memory cells and high levels of CD4 naive cells lived longer than conventional controls (40). No information is presently available on the presence or absence of clonal expansions in the CD8+ T cell pool of these long-lived mice, but age-related clonal T cell expansions have also been demonstrated in rodents (41). These animal studies in combination with our present data support the concept that the number of memory cells, or more precisely the number of CD28-CD45RA+CD8+ T cells could be used as a biomarker of immune senescence in middle-aged and elderly humans. Work presently underway in our laboratory will demonstrate whether aged persons with a high proportion of CD28-CD45RA+CD8+ T cells in their peripheral blood are also likely to have a low humoral immune response to vaccines such as tetanus, diphtheria, or rabies.
In conclusion, our data illustrate the accumulation of
CD8+CD28- IFN-
producing T cells in the aging immune system. Due to their special
properties, these cells may drive a Th1 polarization. Of course, we
realize that our data make only an indirect case for cause and effect
at this time and that we still have to prove that poor in vivo Ab
responses are due to effects of the CD28- cells on CD4
cell differentiation. The possibility that CD8+
clones and low Ab production may both be due to the same underlying
alteration that contributes to differences in several signs of immune
aging cannot yet be ruled out. It is still tempting to speculate that
an imbalance in the production of pro- and anti-inflammatory
cytokines could diminish the chances of elderly persons to be protected
from infectious diseases, and increase their likelihood to develop
age-related disorders, such as Alzheimer’s disease and
atherosclerosis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Beatrix Grubeck-Loebenstein, Immunology Division, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria. E-mail address: Beatrix.Grubeck{at}oeaw.ac.at
3 Abbreviations used in this paper: ONR, old nonresponder; OR, old responder; Y, young healthy adult; CDR, complementarity-determining region.
Received for publication November 21, 2001. Accepted for publication March 19, 2002.
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 M. Leslie All Pain, No Gain Sci. Aging Knowl. Environ., July 7, 2004; 2004(27): ns4 - ns4. [Abstract] [Full Text] [PDF]
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Y. Deng, Y. Jing, A. E. Campbell, and S. Gravenstein Age-Related Impaired Type 1 T Cell Responses to Influenza: Reduced Activation Ex Vivo, Decreased Expansion in CTL Culture In Vitro, and Blunted Response to Influenza Vaccination In Vivo in the Elderly J. Immunol., March 15, 2004; 172(6): 3437 - 3446. [Abstract] [Full Text] [PDF]
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D. Frasca, E. Van der Put, R. L. Riley, and B. B. Blomberg Reduced Ig Class Switch in Aged Mice Correlates with Decreased E47 and Activation-Induced Cytidine Deaminase J. Immunol., February 15, 2004; 172(4): 2155 - 2162. [Abstract] [Full Text] [PDF]
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 M. S. Diamond, E. M. Sitati, L. D. Friend, S. Higgs, B. Shrestha, and M. Engle A Critical Role for Induced IgM in the Protection against West Nile Virus Infection J. Exp. Med., December 15, 2003; 198(12): 1853 - 1862. [Abstract] [Full Text] [PDF]
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R. J. Davenport Immunity Challenge Sci. Aging Knowl. Environ., June 11, 2003; 2003(23): oa1 - 1. [Abstract] [Full Text] [PDF]
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M. S. Diamond, B. Shrestha, A. Marri, D. Mahan, and M. Engle B Cells and Antibody Play Critical Roles in the Immediate Defense of Disseminated Infection by West Nile Encephalitis Virus J. Virol., February 15, 2003; 77(4): 2578 - 2586. [Abstract] [Full Text] [PDF]
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S. Schwaiger, A. M. Wolf, P. Robatscher, B. Jenewein, and B. Grubeck-Loebenstein IL-4-Producing CD8+ T Cells with a CD62L++(bright) Phenotype Accumulate in a Subgroup of Older Adults and Are Associated with the Maintenance of Intact Humoral Immunity in Old Age J. Immunol., January 1, 2003; 170(1): 613 - 619. [Abstract] [Full Text] [PDF]
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