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ugich*,ugich2,*,,
*
Laboratory of T Cell Development, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Division of Geriatrics and Gerontology, Department of Medicine, Weill Medical College of Cornell University, and
Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+CD8+ or
CD4+ T cells bearing different TCRVß elements remain
virtually constant in mice up to 12 mo of age. In 22-mo-old mice,
however, there is a dramatic disturbance of this pattern owing to the
emergence of CD8+ TCE. Expanded T cells did not show any
obvious bias in Vß usage and were derived in all cases examined thus
far from a single clone. TCE appeared later in life, compared with B
cell clonal expansions. However, and in contrast to those detected in
humans, TCE were frequently unstable disappearing within 2–4 mo, with
other TCE appearing within the same time frame. Additional studies
carried on thymic T cells, thymectomized mice, and young T transferred
cells into Rag1-/- mice suggest that the clonal
expansions occur in the periphery and that their onset is accelerated
by decreased thymic output and/or function(s). |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunological senescence is characterized by thymic involution and by a subsequent decrease in naive T cell production. Thus, with age, the peripheral T cell compartment progressively ceases to be renewed. Consequently, to continue to function, the peripheral T cell compartment must adapt to immediate immunological priorities. These adaptations involve repeated cycles of clonal selection, expansion and deletion, and residual immune memory. In a nonrenewing T cell population, such changes can be predicted to scar the peripheral repertoire by altering its structural diversity as well as functional responsiveness. In fact, a decrease in the immunological competence of the aged immune system is well established (1). Some of the documented consequences include the decreased capacity of T cells to specifically clear pathogens, the reduced efficiency of vaccination in aged individuals, the reactivation of previously contained pathogens, and the appearance of age-related clonal T cell expansions (TCE)3 (2, 3, 4, 5).
Previously, it was shown that the percentage of
ß+CD8+ T cells bearing
particular Vß elements varies considerably between aged individuals
in humans, as well as between individual aged C3H.SW and B10.BR mice,
although it is remarkably constant among individual young humans and
mice within a given strain (2, 3, 4). In the mouse system,
such TCE can be transferred into young irradiated recipients and even
cultured in vitro. However, they expand slowly and are difficult to
maintain in vitro. It was strongly suggested that expanded T cell
populations are clonal, as they have been reported to be in humans, and
similarly to age-related B cell clonal expansions (2, 3).
Here, we expand these findings to the C57BL/6 mouse strain and
establish that age-related T cell expansions are indeed caused by
clonal expansions of CD8+ T cells. We further
show that expanded T cells appear late in life compared with their B
cell counterparts, and longitudinal studies showed that their frequency
increases rapidly after the age of 18 mo. Unexpectedly, most TCE are
long lasting but nevertheless transient. For this reason, the T cell
repertoire of aged mice seems highly unstable, rather than terminally
altered, although infrequent stable alteration can be seen. Additional
studies carried on thymic T cells, thymectomized mice, and young T
transferred cells in Rag1-/- mice suggest that
the clonal expansions occur in the periphery and that their onset may
be accelerated by decreased thymic output and/or function(s).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 (B6) mice 1.5, 3, 6, 9, 12, and 24 mo old were purchased from the National Aging Institute breeding program (Frederick, MD). Rag1 knockout mice (C57BL6J-Rag1tm1 Mom) were purchased from The Jackson Laboratory (Bar Harbor, ME), and MHC class I knockout mice were purchased from Taconic Farms (Germantown, NY).
Adult thymectomy, partial splenectomy
Adult thymectomy was performed as described (6, 7), except that vacuum suction was applied to remove the organ. Partial splenectomy was performed on 18-mo-old mice as described (8, 9).
Monoclonal Abs and flow cytofluorometric (FCM) analysis
For surface staining, the F23.1 mAb (anti-Vß8.1/8.2/8.3) was purified and conjugated to FITC in our laboratory. FITC-conjugated anti-TCRß; anti-Vß 2, 4, 5, 6, 8.3, 9, 10, 11, 13, 14; PE-conjugated anti-CD49d; and FITC- and APC-conjugated anti-CD62L mAbs were purchased from PharMingen (San Diego, CA). FITC-conjugated anti-Vß 7, 12; anti PE-conjugated anti-CD4; and Tri-Color-conjugated anti-CD8 mAbs were from Caltag (San Francisco, CA). Analysis was performed on a FACScan instrument using CellQuest 3.1 software (Becton Dickinson, Mountain View, CA). At least 104 cells were acquired per sample. Dead cells were excluded by selective scatter gating.
RNA and cDNA samples
Total RNA was extracted using the RNA-Isolator Kit (Genosys Biotechnologies, The Woodlands, TX) and quantitated by OD. For cDNA synthesis, up to 5 µg of total RNA were reverse transcribed using the avian myeloblastosis virus-reverse transcriptase kit (Boehringer Mannheim, Indianapolis, IN) and oligo(dT)15 primers in a 30-µl reaction. After the reaction was completed, 30 µl double-distilled water were added.
Oligonucleotides
Oligonucleotides specific for the murine Vß families (BV
primers) and for the Cß genes (BC primers), as well as the
5-carboxyfluorescein (FAM), 6-carboxy-X-rhodamine, or
6-carboxy-N,N,N',N'-tetramethylrhodamine-labeled
BC_RO primers (BC_RO_X) are listed in Table I
and Ref.
10 .
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PCR and runoff reactions were performed as previously described (11). Briefly, classical PCR were performed on 2–5 µl cDNA in 25 µl with a sense primer specific for a BV family and an antisense primer specific for the constant BC region (BV and BC1 primers). For these PCRs, we used 0.2 µM concentrations of each primer, 1.5 mM MgCl2, and 1 U Taq DNA polymerase (Perkin-Elmer, Roche Molecular Systems, Branchburg, NJ). The PCR products were visualized on a 1% agarose gel by ethidium bromide staining. Two microliters of the BV-BC1 PCR products were then labeled by 10 cycles of runoff elongation using the fluorescent BC_RO_X primers. Runoff elongation products, mixed with the same volume of 95% (v/v) formamide/10 mM EDTA, were run on a 6% acrylamide sequencing gel (FMC Bioproducts, Rockland, ME) loaded on an automated ABI 377 DNA sequencer (Applied Biosystems, Foster City, CA). 6-Carboxy-X-rhodamine-labeled size markers GS350 (Applied Biosystems, Foster City, CA) were also loaded. Size determination of the runoff products and CDR3 size analysis was performed with Immunoscope software (11).
Sequencing
For sequencing, BV-BC1 PCR products were purified using the QIAquick PCR purification kit (Qiagen, Valencia, CA). One-fourth of the purified PCR products were then sequenced using the nested BC3 primer or the appropriate BV primer and the BigDye Terminator sequencing kit (Applied Biosystems). Nucleotides contributed by the BV, BD, or BJ genes were identified by alignment with germline gene sequences (12).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For these studies on the influence of age on T cell subpopulation percentages, we chose to follow 1) TCRVß protein expression using all available TCRVß-specific mAbs and 2) diversity at the level of Tcr-ß gene rearrangement using TCRBV CDR3 length analysis. Thus, the terms Vß and BV will be used for the protein and gene, respectively. Spleen cells of 5 individual mice aged 3, 6, 9, 12, and 24 mo were triple-stained with anti-CD4, anti-CD8, and with each of the available anti-Vß mAbs. As described before, in 3-mo-old animals (1, 3), the proportions of CD4+ or CD8+ T cells expressing a particular Vß element seem to be tightly regulated, because they did not differ from one animal to the other. The same was true of 6-, 9-, and 12-mo-old mice. In addition, no differences in the proportions of CD4+ or CD8+ T cells expressing a particular Vß element were detected when mice of different age groups were compared.
It has been previously reported that in old C3H.SW and B10.BR animals
(3), proportions of T cell subpopulations expressing a
particular Vß element vary considerably between animals. We studied
more than thirty 22-mo-old C57BL/6 mice. Similarly to findings
published for the C3H.SW and B10.BR mouse strains, we observed
expansions of some T cell subpopulations, sometimes to dramatic
proportions. These expansions involved the CD8+
but not the CD4+ T cell subset.
CD8+ TCE did not seem to exhibit any bias in Vß
element utilization, suggesting that they were equally recruited from
among T cells expressing all TCRVß families. Fig. 1 shows representative FCM results
obtained for the CD8+ subset of two mice younger
than 12 mo and three 22-month-old mice.
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Total RNA was extracted from the samples analyzed by FACS as
above, and CDR3 length analysis was performed for every functional BV
gene, to evaluate the diversity of the quantitatively expanded and
nonexpanded T cell populations. We found a strong correlation between
alteration of the percentages of CD8+ T cells
expressing a particular BV gene and alteration of the TCRBV CDR3 length
analysis patterns for this same population. Indeed, in mice up to 12 mo
of age, the CDR3 length analysis patterns were bell-shaped (i.e.,
"polyclonal" in Fig. 2A,
Box 1) and indistinguishable regardless of age. This strongly suggests
that the TCR diversity of T cells remains unaltered between the ages of
3 and 12 mo. This apparent stability of the overall TCR repertoire at
the molecular level correlates tightly with the stability of the
percentages of T cells expressing a particular Vß segment seen in
Fig. 1
.
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A, boxes 2
and 3). Representative results for a 22-mo-old mouse are presented in
Fig. 2B. The alterations in TCRBV CDR3 length patterns were
of two magnitudes: 1) small alterations, with losses of the
characteristic bell shape but clear maintenance of the other parameters
indicating relative CDR3 length diversity (Fig. 2B, BV2 and
BV12); and 2) dramatic alterations, with the detection of only one CDR3
length (Fig. 2B, BV10). Invariably, alterations of the CDR3
length patterns happened in the T cell populations expressing a Vß
protein for which the percentage of CD8+ T cells
was altered by mAb staining (Fig. 2C). T cell populations
bearing Vß families that exhibited only slight
CD8+ T cell expansions were also those for which
only small alterations of the TCRBV CDR3 length patterns were detected
(small TCE). By contrast, large expansions of the percentages of
CD8+ T cells expressing a particular TCRVß
protein corresponded to the most dramatic alterations of the CDR3
length patterns. In cases where only one CDR3 peak was detected per
TCRBV family, CDR3 were sequenced using the BV-BC PCR product as a
template. All such PCR products yielded clear and unambiguous CDR3
sequences, indicating that the great majority of the BV-BC PCR product
was made up of only one sequence (data not shown). This indicates that
the expansions detected by mAb staining were due to the expansion of
clonal T cells. Furthermore, we conclude that there is precise
correlation between the TCE detected by FCM and the appearance of
expanded clones detected by TCRBV CDR3 length analysis at the molecular
level. The frequency of age-related T cell clonal expansions increases between the ages of 18 and 25 mo
To further investigate the kinetics of appearance and the
stability of TCE, we followed a set of eight mice over time using TCRBV
CDR3 length analysis of PBLs at 18, 20, 22, 24, and 25 mo. Analysis was
performed for all functional BV genes at 18 and 25 mo of age and for
BV4, BV5, BV6, BV8S2, and BV10 at 20, 22, and 24 mo of age. At 18 mo of
age, only two mice showed TCE, none of them in BV4, BV5, BV6, BV8S2, or
BV10. For the later time points, however, such clonal expansions could
be detected with increasing frequency (Table II). Consequently, at the age of 25 mo,
60% of the mice had developed at least one TCE (study conducted on a
cohort of 20 mice, data not shown). To more closely study the kinetics
of appearance and the stability of individual TCE, we compared the CDR3
length profiles at all five time points for the five Vß families
selected for study.
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. Many of the
TCE were transient and dominated the CDR3 length patterns of a Vß
family at one or two successive time points only. This is illustrated
in column 1 in which a BV5 clonal expansion is not detected at the age
of 18 mo, dominates the BV5 CDR3 length pattern at 20 mo, "fades"
and loses its dominance of the patterns although still altering them at
22 and 24 mo, and has completely disappeared at 25 mo. Some of the T
cell clones, however, remained stable. This is illustrated in column 2:
at 18 and 20 mo, the CDR3 length patterns for the BV8S2 family are not
altered; at 22 mo, the pattern is altered by the expansion of one peak
which, at 24 and 25 mo dominates the repertoire completely. In columns
3 and 4, the most common situation is shown; no clonal expansion
dominated the CDR3 length patterns completely at any time point.
However, the CDR3 length patterns were often altered. In column 3, for
example, an alteration appears at 22 mo, is still present at 24 mo, and
has faded at 25 mo to be replaced by another. Similarly, in column 4,
the CDR3 length patterns change significantly at each time point
between the ages of 18 and 25 mo. Overall, of 60 mice analyzed, 19
(32%) had at least 1 TCE at 18 mo, and that number increased to 34 of
60 (57%) at 20 mo. When the same group of mice was followed for the
stability of clones in 6 BV families (BV 2, 3, 5.2, 9, 11, and 12
(Table III)), 6 of the initial 14 TCE (in as many mice)
persisted, whereas the others receded to background. These data show
that the repertoire of aged mice is highly unstable, as compared with
the virtually constant repertoire of mice between 3 and 12 mo of age.
They also indicate that T cell clonal expansions, although frequent and
sometimes dramatic, are frequently fluid and unstable, particularly in
early senescence.
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To determine whether the T cell clonal expansions detected in the
periphery originated from the thymus or from peripheral cells, we
compared the CDR3 length profiles of PBLs and of the thymic cells of
20-mo-old animals. Although peripheral TCE were clearly detected among
PBLs, they were never found in the thymus of the same animals (not
shown). This strongly suggested that TCE originate from the periphery.
To further investigate this hypothesis, we transferred peripheral T
cells from old mice with clonal expansions and from young control mice
into Rag1-deficient animals, devoid of lymphocytes. Six months after
transfer, PBLs were collected, CDR3 length analysis was performed, and
the profiles before and after transfer were compared (Fig. 4, Old Donor). Of 20 attempted transfers,
only one T cell clone (5% frequency) could be transferred successfully
(not shown). All other T cell clones had completely disappeared,
indicating that such T cell clonal expansions were of the
"transient" type described above, that such T cell clones grow much
more slowly than other T cells that are not expanded, or that their
growth in the donor mouse was driven/supported by elements not
transferred to the Rag1-deficient recipients. The most interesting
finding, however, came from the fact that 1) although the T cell clones
present in the donor mice had disappeared 6 mo after transfer (Fig. 4, lower panel, BV10 and, to a lesser extent BV20), new clonal
expansions had arisen (Fig. 4, Old Donor, BV9 and BV15), and that 2) T
cell clonal expansions had developed in a similar fashion in the
recipients that had received PBLs from young control mice (Fig. 4, upper panel, BV9 and BV20).
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ugich, unpublished
observations). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CDR3 length analysis enabled us to carry longitudinal studies on the T cell clonal expansions previously identified by mAb staining, and we showed that age-dependent T cell clonal expansions are often transient. Over time, however, stable clonal expansions do develop, sometimes to dramatic proportions. Overall, the T cell compartment seems to become increasingly unstable with age. Parallel CDR3 length analysis carried on the thymic and peripheral T cells suggested that T cell clonal expansions arise from the peripheral pool. This was strengthened by the finding that transfer of T cell clones into "empty" Rag1-deficient recipients was possible, although difficult. More importantly, the originally diverse old or even the diverse young T cell populations would generate clonal expansions rapidly if isolated and deprived of thymic input, either by adult thymectomy or by transfer to Rag1-deficient recipients.
The simplest explanation for the transitory skewing of the CDR3 length
patterns, as well as for the transitory clonal expansions is that they
are the consequences of a single cause and may just represent normal,
although accentuated, responses against foreign Ags. These responses
would go unnoticed in young animals because of the availability of many
relevant T cell clones with overlapping specificities for a given
pathogen. This redundancy would allow numerous T cell clones to expand
moderately and would increase the efficiency and efficacy of an immune
response, speeding the clearance of the pathogen. Such polyclonal
immune responses would not necessarily significantly disturb the Vß
mAb staining profile, nor would they obligatorily skew CDR3 length
patterns, especially against a very diverse background that would
"buffer" the CDR3 length pattern variations (Fig. 5, situation A). The reason
for which these benign immune responses would become TCE in an old
animal is unclear. On the basis of our results, we propose that the T
cell pool of such an animal is no longer diverse enough to select
multiple T cell clones specific for the same pathogen. In such a
"reduced diversity" system, the few T cell clones specific for the
pathogen would need to expand more vigorously than in a young animal,
in which more T cell clones can be recruited. Furthermore, in a reduced
diversity system, T cells highly specific for the Ag might not be as
available as in a diverse system. This would decrease the quality of
the response, delay the clearance of the pathogen, and cause the
selected T cells to multiply even more (Fig. 5, situations B
and C). If this is the case in aged mice, it is not
surprising that their peripheral T cell repertoire seems to be
unstable; greater clonal expansions against a less diverse, less
buffering background would show (transiently) until the pathogen is
cleared. As for the stable TCE, we hypothesize that they arise from
transient TCE by losing responsiveness to homeostatic control
mechanism(s). We do not know whether the TCE we detected were made
up of premalignant or malignant cells. However, preliminary data show
that they do not divide actively, not even to the pace of other,
nonexpanded peripheral T cells (not shown).
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). Ultimately, such a deprived T cell pool is
doomed to encounter a pathogen it cannot fight efficiently enough to
ensure survival. Indeed, recent data from our laboratory confirm that
TCE directly impact on the capacity of the immune system to
efficiently respond to pathogens (J. LeMaoult, I. Messaoudi,
B. M. Metzner, R. Rivi, K. Remus, M. E. Weksler, and J.
Nikolich-ugich, manuscript in preparation).
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Footnotes |
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.), Memorial Sloan-Kettering Cancer Center Core Support Grant CA-08253, the Wright Chair in Geriatric Research (M.E.W.), and the DeWitt Wallace Fund (J.N.-.). 
2 Address correspondence and reprint requests to Dr. Janko Nikolich-ugich, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 98, New York, NY 10021.
3 Abbreviations used in this paper: TCE, T cell clonal expansion; CDR3, complementarity-determining region 3; TCRB, rearranged ß gene of the TCR; FCM, flow cytofluorometric.
Received for publication April 14, 2000. Accepted for publication June 14, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-ugi, J., M. J. Bevan. 1988. Thymocytes expressing CD8 differentiate into CD4+ cells following intrathymic injection. Proc. Natl. Acad. Sci. USA 85:8663.
-ugi, P. Kourilsky, M. E. Weksler. 1997. Clonal expansions of B lymphocytes in old mice. J. Immunol. 159:3866.[Abstract]
-ugi, M. E. Weksler. 1999. Cellular basis of B cell clonal populations in old mice. J. Immunol. 162:6384.This article has been cited by other articles:
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M. Ahmed, K. G. Lanzer, E. J. Yager, P. S. Adams, L. L. Johnson, and M. A. Blackman Clonal Expansions and Loss of Receptor Diversity in the Naive CD8 T Cell Repertoire of Aged Mice J. Immunol., January 15, 2009; 182(2): 784 - 792. [Abstract] [Full Text] [PDF]
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, significantly altered (skewed) CDR3 length
patterns in which several CDR3 length are still present; 
,
dramatically altered CDR3 length patterns in which only one CDR3 length
was detected.
