(Journal of Leukocyte Biology. 2002;72:65-71.)
© 2002
by Society for Leukocyte Biology
Numerical and functional alterations of circulating 
T lymphocytes in aged people and centenarians
Katy Argentati*,
Francesca Re*,
Alessia Donnini*,
Maria G. Tucci*,
Claudio Franceschi
,
Beatrice Bartozzi*,
Giovanni Bernardini* and
Mauro Provinciali*
* Laboratory of Tumor Immunology, Immunology Center, INRCA Gerontol. Res. Dept., Ancona, Italy; and
Department of Experimental Pathology, University of Bologna, Italy
Correspondence: Mauro Provinciali, M.D., Laboratory of Tumor Immunology, Immunology Center, INRCA Gerontol. Res. Dept., Via Birarelli 8, 60121 Ancona, Italy. E-mail: m.provinciali{at}inrca.it
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ABSTRACT
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The aim of this study was to evaluate the peripheral representation, in vitro expansion, cytokine production, and cytotoxicity of 
T lymphocytes from 104 healthy subjects ranging in age from 19 to 103 years. We demonstrated that the absolute number of circulating + T cells was reduced significantly in old people and centenarians in comparison with young subjects as a consequence of the age-related decreased lymphocyte number. The decrease was a result of an age-dependent reduction of V2 T cells, whereas the absolute number of V1 T cells was unaffected by age. As a consequence, the V2/V1 ratio was inverted in old subjects and centenarians. A higher percentage of + T cells producing tumor necrosis factor 
was found in old donors and centenarians, whereas no age-related difference was observed in interferon - production. After a 10-day in vitro expansion, a twofold lower expansion index of T cells, and particularly of a V2, but not of a V1 subset, was found in old people and centenarians in comparison with young subjects. The cytotoxicity of sorted T cells was preserved in old people and centenarians. The alteration of T cells could contribute to the age-related derangement of T cell-mediated, adoptive responses and may represent a new characteristic of immunosenescence.
Key Words: aging • human • cellular activation • cytotoxicity
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INTRODUCTION
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T lymphocytes bearing the T cell receptor (TCR) represent a minor population of human peripheral lymphocytes (1–10%), the majority of them expressing the V9/V2 TCR and the CD3+CD4-CD8- phenotype [1
2
3
4
]. The second most frequent subset of peripheral blood T cells expresses V1 in association with various V elements. The ability of T cells to respond to nonprocessed and nonpeptidic phosphoantigens in a major histocompatibility complex (MHC)-unrestricted manner is an important feature distinguishing them from ß T cells [5
6
7
8
9
]. Several mycobacterial antigens responsible for the expansion of human T cells were identified recently, as isopentenylpyrophosphate (IPP) and related phenyl pyrophosphate derivatives and a variety of other phosphorylated metabolites [7
]. Although little is known about the physiologic significance of T cells, their marked reactivity toward mycobacterial and parasitic antigens as well as tumor cells suggests that T cells play a role in the anti-infectious and anti-tumoral immune surveillance [4
]. T cells regulate the initiation, progression, and resolution of the immune response to infectious antigens, and T cell-mediated immune responses have been demonstrated in many viral infections, suggesting that antiviral immunosurveillance may be one of the primary T cell functions. Moreover, T cells react strongly against certain lymphoma cells, such as Daudi cells, suggesting a cross-reactivity between microbial and tumor-associated antigens [10
]. T cells stimulated with nonpeptidic phosphoantigens produce high levels of cytokines and mainly interferon- (IFN-) and tumor necrosis factor (TNF-) [11
]. Because of their cytokine production, T cells have been proposed to be involved in coordinating the interplay between innate and adoptive immunity and, in particular, to guide the establishment of acquired immunity contributing to the definition of ß T cell responses toward T helper cell type 1 (Th1) or Th2 phenotype [12
, 13
]. Clinical and experimental data have clearly demonstrated the existence of immunological alterations in aging [14
15
16
17
18
]. In fact, T and B cell number and function are impaired in elderly people, and the alterations of T cell-dependent functions have been shown to be implicated in the dysregulation of Th1 and Th2 responses present in aging, with a shift to the Th2 responses [19
20
21
]. Conversely, nonspecific functions such as natural killer (NK) and lymphokine-activated killer (LAK) cell activity are well preserved throughout life. Furthermore, NK and NK-derived LAK cell populations are more expanded in aging than in young age, suggesting a change of the immune system with increasing age with an increase of non-MHC-restricted cells, which perhaps compensates for the decline in T and B cell number in the elderly [22
23
24
]. Centenarians, a selected group of people with successful aging, have an immune remodeling similar to that found in elderly subjects, suggesting that their immune system did not escape the aging process [25
, 26
]. Apart from data on the shrinkage of T cell repertoire in aged people [27
], we know of no available data regarding the number and function of T cells and of V1 and V2 subsets in aging. On the basis of the pivotal role that T cells may have in protecting elderly people from infectious and tumor diseases by itself and, secondarily, by modulating the phenotype of T cell responses, here we evaluated the peripheral representation and the in vitro expansion, cytokine production, and cytotoxicity of T cells from young, old, and centenarian subjects. Our study demonstrates an age-dependent alteration of T lymphocytes, with a lower frequency of circulating T cells as a consequence of the lower lymphocyte count, an altered pattern of cytokine production, and an impaired in vitro expansion of these cells. The deterioration of the cell system could account for the age-related alterations of T cell-mediated adoptive responses and may represent a new characteristic of immunosenescence.
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MATERIALS AND METHODS
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Cell preparation and stimulation
Human peripheral blood was obtained from 40 young (mean age±SD, 33.5±6.0 years, 19–50), 33 old (80.0±6.3, 60–90), and 31 centenarian (100.1±0.75, 100–103) subjects. Young subjects were healthy volunteers from the laboratory staff. Old subjects and centenarians were in good and stable clinical condition and had laboratory parameters in the physiological range. We excluded subjects in poor health with neoplastic or degenerative diseases or in therapy with drugs interfering with the immune system. The groups did not differ in major clinical problems, mental impairment, or drug therapy.
Peripheral blood mononuclear cells (PBMC) were fractionated on Ficoll-Paque (Pharmacia, Upsala, Sweden) and separated by density gradient centrifugation (400 g, 30 min). Cells from the interface of the gradients were washed twice with Ca2+- and Mg2+-free phosphate-buffered saline (PBS) Gibco/Life Technologies, Grand Island, NY) and were resuspended in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum, penicillin (100 U/ml), and streptomycin (100 µg/ml) (all from Life Technologies, complete medium) at a concentration of 1 x 106/ml. The viability was always greater than 98%, as determined by trypan blue exclusion. To obtain the absolute number of T cells, we first determined the total number of lymphocytes per µL peripheral blood. Mononuclear cells were cultured in the complete medium supplemented with 100 U/ml recombinant interleukin (IL)-2 (Chiron Italia, Milan, Italy). Phosphoantigen-specific stimulation of T cells was performed using the nonpeptidic antigen IPP (30 µg/ml; Sigma Chemical Co., St. Louis, MO). After 1 week of culture, the volume corresponding to half the culture medium was replaced by fresh medium. On day 10 of culture, viable cells were counted and used for fluorescein-activated cell sorter (FACS) analysis and cytotoxicity. The expansion of T cells was followed by cytometric analysis through double-staining of stimulated cells with anti-CD3 [phycoerythrin (PE)] and anti-pan , anti-V1, or anti-V2 T cells [fluorescein isothiocyanate (FITC)] monoclonal antibodies (mAb). The absolute number of T cells in each culture was calculated as follows: (percentage of T cells among total cells) x (total cell count)/100. The T cell expansion index was then calculated by dividing the absolute number of T cells in stimulated cultures by the absolute number of T cells before culture [11
].
mAb and FACS analysis
The PE-conjugated mAb anti-CD3 was purchased from EuroClone (Devon, UK). The FITC-conjugated anti-pan TCR , anti-TCR V1, and anti-TCR V2 were purchased from Endogen (Woburn, MA). Immunoglobulin G1 (Becton Dickinson, San Jose, CA) was used as isotype control.
PBMC (1x106) were labeled with 10 µl anti-CD3 or anti-TCR V1 mAb or 5 µl anti-pan TCR or anti-TCR V2 mAb in a final volume of 150 µl RPMI 1640 with 10% fetal calf serum for 30 min in ice. At the end of the incubation, cells were washed in PBS, resuspended in Isoton II (Coulter, Hialeah, FL), and analyzed immediately with a Coulter XL flow cytometer.
Intracellular detection of IFN- and TNF-
Mononuclear cells were stimulated with IPP and IL-2 for 18 h, and GolgiPlug (a protein transport inhibitor containing brefeldin A; PharMingen, Milton Keynos, UK) was added during the last 17 h of culture to block intracellular transport processes and allow cytokine accumulation. Stimulated cells (1x106) were stained with the anti-pan TCR mAb for 30 min at 4°C. Fixation-permeabilization of cells was performed in PBS/2% paraformaldehyde for 15 min at 4°C, followed by incubation for 30 min at room temperature in the dark with PE-conjugated, anti-human IFN- mAb or anti-human TNF- mAb diluted in PBS, 1% bovine serum albumin (BSA), and 0.05% saponin. Cells were finally washed twice in PBS, 1% BSA, and 0.01% saponin and were analyzed on a XL flow cytometer (Coulter). The controls for unspecific staining included incubation with isotype-matched mAb. Anticytokine mAb and isotype controls were all from PharMingen.
Isolation of T lymphocytes and cytotoxic assay
T lymphocytes, in vitro expanded with IPP and IL-2 for 10 days, were isolated through cytofluorimetric cell sorting (Vantage, Becton Dickinson). The purity of T cells, assessed by cytofluorimetric analysis, was greater than 95%.
Cytotoxic assay was performed by a fluorimetric method as recently reported [28
]. The NK-resistant cell line Daudi and the NK-sensitive K562 cell line were used as target cells. Daudi is a human lymphoblastoid B cell line derived from a Burkitt lymphoma, which constitutively expresses antigens recognized by V9V2 T cells. The fluorescence was read with a 1420 VICTOR2 multilabel counter (Wallac, Turku, Finland). The percentage of specific lysis was calculated as follows:
where F represents the fluorescence of the solubilized cells after the supernatant has been removed, med = F from target incubated in medium alone, and exp = F from target incubated with effector cells.
Lytic units (LU20/107 cells) were calculated by using a computational method [29
]. One LU corresponded to the number of effector cells required to produce 20% of specific lysis.
Statistical analysis
Data were analyzed for statistical significance by using parametric or nonparametric tests according to the distribution of the data. Comparisons of variables among groups were made by one-way analysis of variance (ANOVA) or Kruskal-Wallis one-way ANOVA on ranks. When significant differences were found, the differences among groups were made by the Student-Newman-Keuls method or Dunn’s method. Significance was set at the 5% level (P<0.05). The statistical analysis was performed with SigmaStat software version 1.03 (Jandel Scientific, Germany).
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RESULTS
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Ex vivo analysis of T lymphocytes
To compare the absolute number and the proportion of T cell subsets in the peripheral blood of young (n=40), old (n=33), and centenarian (n=31) subjects, double-staining was performed with anti-CD3 and anti- mAb. As shown in Table 1
, the absolute number of T cells was reduced in old people (77.9±26.3) and centenarians (77.2±43.2) in comparison with young subjects (128.0±60.5; P<.002). The T cell reduction was related to the lower number of peripheral lymphocytes found in old people (P<.01) and centenarians (P<.004) in comparison with young subjects. Once we plotted the absolute number of T cells and the different donor age, we found a significant inverse relationship with an age-related progressive decrease of T cell number (R=-0.32; P<.005; Fig. 1
). As shown in Figure 2A
, the percentage of CD3+ T cells in peripheral blood was heterogeneous in the different age groups with mean values not significantly different among young donors (mean±SD, 6.2±2.5), old subjects (5.3±2.8), and centenarians (5.4±3.3). No significant relationship was found plotting T-cell percentage and donor age (R=-0.14; P=.19; Fig. 2B
). As shown in Table 1
, the absolute number of V1 T cells did not show significant age-related differences (40.6±14.3, 34.1±12.5, and 38.3±5.9 in young, old, and centenarian subjects, respectively). The absolute number of V2 T cells was reduced significantly in old donors (31.4±25.6) and centenarians (22.7±3.1) in comparison with young subjects (76.6±29.9; P<.02 and P<.001 for old donors and centenarians, respectively). The V2/V1 ratio was reduced progressively during aging (Table 1) . The analysis of the proportions of V1 and V2 subsets within total T cells revealed that the proportions of V1 cells were increased in old and centenarians (44% and 49% vs. 31%), whereas the proportions of V2 cells were decreased (40% and 29% vs. 59%; Table 1
).
Cytokine production by T lymphocytes
As it has been demonstrated that T cells stimulated with nonpeptidic antigens produce IFN- and TNF-, we studied the intracellular production of these cytokines in stimulated T cells from different age groups. Preliminary experiments were performed to establish the stimulation time required for optimal cytokine production. We found that the percentage of T cells producing cytokines was higher at 18 h than at 6 h of stimulation (13.8±4.53 vs. 3.4±1.29 for IFN- and 12.8±4.34 vs. 4.2±1.87 for TNF-), and then we chose to use 18 h of in vitro incubation for all of the following experiments. As shown in Figure 3
and Figure 4
, the percentage of T cells producing IFN- was similar in young (mean±SD, 16.5±10.3) and old (15.5±9.4) subjects and centenarians (19.4±14.1). The percentage of T cells producing TNF- was higher in old donors and centenarians in comparison with young subjects (21.1±11.3 and 23.0±15.7 for old people and centenarians vs. 13.3±10.0 for young subjects, respectively; P<.05).
Expansion of T lymphocytes
The expansion of T cells from young and old people and centenarians was evaluated after 10 days of culture in the presence of the nonpeptidic antigen IPP and low dose IL-2. The proportion of T cells through double-staining FACS analysis and their relative increase in comparison with the percentage found on day 0 (expansion index) were evaluated. As shown in Figure 5A
(left), T cells were expanded in different age groups with a percentage of T cells on day 10 significantly higher than those found on day 0 in each age group considered. The proportion of T cells reached on day 10 was lower in old subjects and centenarians compared with young donors (mean±SD, 23.4±20.0, 24.8±22.9, and 45.0±20.3 for old subjects, centenarians, and young subjects, respectively; P<.05; Fig. 5A
, left). Once we plotted the percentage of T cells and the different donor age, we found a significant inverse correlation with a progressive decrease of the proportion of T lymphocytes with increasing age (R=-0.59; P<.0001; Fig. 5B
). The expansion index of T cells on day 10 versus day 0 was 11.0 ± 6.5 in young people, 5.5 ± 4.1 in old people, and 5.7 ± 4.2 in centenarians (Fig. 5A , right). Differences among old subjects and centenarians versus young donors were significant (P<.05). As shown in Figure 5C
(left), the expansion index of the V2 subset was reduced significantly in old donors and centenarians in comparison with young subjects (P<.05). The expansion index of the V1 subset did not show significant age-related difference (Fig. 5C , right).
Cytotoxicity of T lymphocytes
To evaluate the cytotoxic potential of T cell cultures after in vitro expansion, we tested the cell activity of sorted T cells against the Daudi tumor cell line. As shown in Figure 6
, purified cultures of activated T cells, obtained through cytofluorimetric cell sorting, were cytotoxic against Daudi tumor cells. A great heterogeneity of cytotoxic activity was found in the three age groups considered. Mean levels of cytotoxicity were not significantly different among young subjects (231.00±197.85), old people (98.84±110.19), and centenarians (151.95±160.40). The cytotoxic activity of T cells was also tested against the K562 tumor cell line, with levels of cytotoxicity higher than those obtained using Daudi as tumor cell target, but with a similar age-related distribution (data not shown).
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DISCUSSION
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The deterioration of the immune system associated with aging, or immunosenescence, has been correlated with the increased risk for infections and higher incidence of malignancies in elderly people.
T lymphocytes represent a minor population of human peripheral lymphocytes, the majority of them expressing the V2 or the V1 TCR and the CD3+CD4-CD8- phenotype [1
2
3
4
]. Because of their potent MHC-unrestricted cytotoxic activity against virus-infected targets and tumor cells, T lymphocytes have been included in innate immunity and have been suggested to be involved in the anti-infectious and anti-tumoral immune surveillance [4
, 24
]. It has been proposed that the characteristic alterations of the immunosenescence are consequent to the profound reshaping of the immune system, which occurs during aging to ensure its optimal functioning [30
]. To evaluate the role of T cells in the immune reshaping, we studied the peripheral representation, in vitro expansion, cytokine production, and cytotoxicity of T lymphocytes from healthy young and old people and centenarians. We demonstrate that some alterations of T lymphocytes occur with advancing age. In particular, our results show that the absolute number of T cells in peripheral blood and their in vitro expansion are reduced in old people and centenarians in comparison with young subjects. Moreover, T cells from elderly subjects have an altered pattern of cytokine production with an increased proportion of TNF--producing cells. Instead, the cytotoxic activity of T cells seems to be well preserved in aged people. Although age-related changes of T cells have been expected to affect adaptive immunity in elderly subjects, there are very little data on this topic. It has been demonstrated that the TCR1 ( TCR) repertoire may change with age, so that the polyclonal V1 and V2 populations present in children shift to oligoclonality in the elderly as a consequence of the expansion of a few T cell clones [27
]. Nowadays, there is no evidence about the peripheral representation and the in vitro expansion of T lymphocytes in aging. Our data demonstrate an age-related, reduced representation of circulating T cells. The reduction of the absolute number of T cells clearly reflects the age-related decrease of the total number of lymphocytes. The fact that the percentage of circulating T cells is not changed in older subjects indicates that the T cell reduction does not rely on a selective decrease of this population, but rather to a more general age-related impairment of the peripheral lymphocyte count. In fact, a lower peripheral blood lymphocyte count is present in elderly people [31
], which may account for the lower frequency of other lymphocyte cell populations [32
, 33
]. In any case, the consequence is that old people and centenarians have a reduced number of T cells in their peripheral blood in comparison with young subjects, thus having a reduced T cell potential. Certainly, the possibility that some T cells in the elderly may be redistributed to the tissue, thus explaining the lower absolute number in the peripheral blood, may not be excluded completely.
The analysis of V1 and V2 subsets shows that the decreased number of T cells in aged subjects is a result of a reduction of the V2 subset. It is interesting that when the proportions of V1 and V2 subsets within total T cells are calculated, it appears that the proportions of V1 cells are increased in old and centenarian, whereas the proportions of V2 cells are decreased (Table 1)
. The age-related alteration of circulating T cells that we have found stresses the relevant role that this lymphocyte population may have in the alteration of T cell-mediated specific responses in the elderly. A dysregulation in the Th1/Th2 system, resulting in a predominant production of Th2 cytokines, has been shown in aging [19
20
21
]. T cells have been suggested to play a relevant role in the shift of T cell responses toward the Th1 or Th2 phenotype [12
, 13
]. Taking into account these two observations, our data strongly suggest that the derangement of T cells may be responsible, at least in part, for the unbalance of Th1/Th2 responses present in the elderly. T cells from old people and centenarians were less able to expand after in vitro stimulation with nonpeptidic antigen and low dose IL-2. The reduced expansion was also evident at the level of the V2 subset. These data clearly demonstrate the existence of a proliferative defect in T lymphocytes from aged subjects. This defect is similar to the reduced proliferative capacity of ß T cells previously reported in aging [14
15
16
]. The expansion of the V1 subset did not show a significant age-related difference. As we did not stimulate T cells with a specific ligand for the V1 subset, the expansion of V1 cells observed in our cultures, conducted on bulk PBMC and not on isolated T cell subsets, may be partly due to a stimulation of V1 cells by cytokines (like IL-2), which we put in the culture and which are able to induce selective activation of resting human T cells [34
] or to cytokines or growth factors like IL-12 [35
] or TNF- [36
, 37
] produced by other leukocyte populations activated by IPP or IL-2.
T cells from elderly subjects have an altered pattern of cytokine production, particularly evident at the level of TNF- production. In fact, the percentage of T cells producing TNF- was increased after in vitro stimulation in old people and centenarians.
Although anti-infectious immunosurveillance may be one of the primary T cell functions, functionally mature T cells display a potent cytotoxic activity against tumor cells or virus-infected targets [4
, 10
]. We have investigated the cytotoxic activity of sorted T cells from young and old people and centenarians against Daudi and K562 tumor cell lines. Although obtained from a limited number of subjects, our results show that the mean levels of cytotoxicity of T cells from old people and centenarians are well preserved, thus suggesting that, as previously observed for ß T cells, the lytic function of T cells is not impaired during aging [38
].
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CONCLUSION
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In conclusion, our data demonstrate that T cells show some alterations during aging, with a reduced representation and expansion and an altered cytokine production. Based on these results, it can be assumed that T cell deterioration may represent a new characteristic of immunosenescence, and it can be predicted that, because of T cell derangement, old and very old subjects such as centenarians have low protection against infections and tumor diseases.
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ACKNOWLEDGEMENTS
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This work was supported in part by Ministero della Sanità Ricerca Finalizzata 1998 and 2000 (M. P.). The authors thank R. Stecconi for excellent technical assistance and R. M. Lisa and R. Moresi for screening subjects.
Received November 27, 2001;
revised January 24, 2002;
accepted February 20, 2002.
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