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*
Children’s Research Centre, Our Lady’s Hospital for Sick Children, Dublin, Ireland; and
Conway Institute for Biomolecular and Biomedical Research, University College, Dublin, Ireland.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain cytokines, in particular
IL-7, they show enhanced potential to survive, entry into cell cycle,
and proliferation. Although common -chain cytokines were also potent
antiapoptotic stimuli for mature adult-derived naive
CD4+CD45RA+ T cells, these cells were
refractory to IL-7-induced expansion in vitro. RTEs cultured with IL-7
could not reinduce recombination-activating gene-2 gene expression in
vitro. These data suggest that postthymic naive T cells in the
periphery during early life are at a unique stage in ontogeny as RTEs,
during which they can undergo homeostatic regulation including
expansion and survival in an Ag-independent manner while maintaining
their preselected TCR repertoire. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The common -chain (c) receptor family of
cytokines is essential for the development, expansion, and survival of
the lymphoid system (8). Among this family, IL-7 is
essential for thymocyte development and is intimately involved with
cell survival (9, 10). In animals that lack IL-7 or
components of its receptor, thymocyte development is severely
compromised, and T cells that mature in these animals have shortened
half-lives and abnormal phenotypes (11, 12). These defects
can be overcome by the introduction of a transgene driving bcl-2
expression (13, 14, 15). Therefore, it is likely that members
of the c cytokine family play a major role in
regulating T cell homeostasis in the periphery throughout
life.
Unlike the murine model at birth, the peripheral T cell system in humans is thymically selected, such that thymectomy, which is often a technical neccessity associated with cardiac surgery, does not result in any clinical consequences or any major T cell deficit later in life (16, 17). At birth, there is an unexplained relative peripheral lymphocytosis (18). Whether this is associated with the significant expansion observed in mature single-positive (SP) thymocytes before they exit the thymus (19) is not known. However, in this study, we show that newborn T cells represent a unique stage in T cell ontogeny as RTEs, with a "carry-over" thymocyte phenotype in the periphery, and we have identified a pathway whereby RTEs continue to expand, ensuring maintenance of the preselected TCR repertoire pool in the periphery.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-2 was purchased from Boehringer Mannheim (Mannheim, Germany) and IL-4 and IL-7 from Genzyme (Kent, U.K.). PMA and propidium iodide (PI) were purchased from Sigma (Poole, U.K.). CFSE was obtained from Molecular Probes (Leiden, The Netherlands). Abs to bcl-2 and bax were bought from Santa Cruz Biotechnology (Heidelberg, Germany). FITC-conjugated annexin V was obtained from R&D Systems (Oxford, U.K.). Anti-CD2 Abs AICD2 M1 and AICD2 M2 were a gift from Dr. S. Meuer (Deutsches Krebsforschungszentrum, Heidelberg, Germany) and are known to be mitogenic (20). Anti-CD28 mAb (9.3) was a gift from Bristol-Myers Squibb Pharmaceutical Research Institute (Seattle, WA).
PCR detection of TCR excision circles (TRECs)
Genomic DNA was extracted using Qiagen DNA spin columns (Qiagen,
Crawley, U.K.). To detect 
1 circles, a molecular beacon was used in
combination with real-time PCR according to the protocol described by
Zhang et al. (21). The primers (sense, 5'-GGA TGG AAA ACA
CAG TGT GAC ATG G-3', and antisense, 5'-CTG TCA ACA AAG GTG ATG CCA CAT
CC-3') and beacon, which recognized the target sequence 5'-GAG AAC GGT
GAA TGA AGA GCA GAC AG-3' were synthesized by Oswel DNA Services
(Southampton, U.K.) containing a fluorophore (6-carboxfluorescein) and
quencher (methyl red (4-dimethylaminoazo benzene 2'- carboxylic acid)).
PCR was conducted in a Bio-Rad (Hercules, CA) Icycler machine for 45
cycles of amplification (94°C for 30 s, 55°C for 60 s,
and 72°C for 30 s). As a control to normalize for cell
equivalents in the input DNA, a TaqMan assay to quantify CCR5 (Applied
Biosystems, Warrington, U.K.) was used, because it is known that
this gene is present at two copies per cell and contains no pseudogenes
(21).
Cell purification
Cord blood was collected in 0.1 M EDTA from the umbilical vein immediately after delivery in uncomplicated pregnancies at term. Venous peripheral blood was obtained from healthy adult volunteers. CD4+CD45RA+ T cells were purified by negative selection using magnetic beads as previously described (9). Mononuclear cells were isolated by Ficoll-Hypaque (Lymphoprep; Nycomed, Oslo, Norway) density gradient centrifugation and resuspended in Lymphokwik Th (VHBio, Newcastle-upon-Tyre, U.K.) for 45 min at 37°C to deplete CD8+ cells, B cells, and monocytes. Two rounds of centrifugation using Ab-coated magnetic beads (Dynal Biotech, Oslo, Norway) were performed to deplete the remaining CD8+, CD45RA+, CD16+, CD19+, CD14+, and HLA-DR+ cells. The resulting populations were >99% viable, >98% CD3+, >97% CD4+, and >98% CD45RA+; they contained <1% CD8+, CD16+, CD45RO+, CD19+, CD14+, and HLA-DR+ cells. Purity was confirmed by nonresponsiveness to PHA at a final concentration of 2.5 µg/ml.
Cell culture
Cells were cultured in RPMI 1640 (Life Technologies, Paisley, U.K.) supplemented with HEPES (10 µM), glutamine, gentamicin, sodium pyruvate, nonessential amino acids, and 10% FCS. Cultures were set up in 1-ml volumes in 24-well plates at a concentration of 1 x 106/ml at 37°C in a humidified incubator containing 5% CO2. In some cultures, IL-2 at 100 U/ml, IL-4 at 40 ng/ml, and IL-7 at 10 ng/ml was added.
Measurement of apoptosis
Cells undergoing apoptosis were detected by flow cytometry using FITC-conjugated annexin V and PI double labeling as previously described (9).
Analysis of cell cycling
Freshly isolated CD4+CD45RA+ T cells (107 cells/ml) were labeled with CFSE (5 µM) by incubation for 10 min at room temperature in PBS. Cells were washed three times before culture. Cell cycling was also analyzed following staining with PI (5 µg/ml). The percentages of cells in G0/G1 and S/G2M were identified by flow cytometry. Cells (2 x 105/well) were cultured with or without cytokine in 96-well flat-bottom plates. Lymphocyte proliferation was measured by adding 0.3 µCi [3H]thymidine (Amersham, Berkshire, U.K.) for the last 18 h of culture before harvesting and counting in a 1450 MicroBeta PLUS liquid scintillation counter (Wallac, Gaithersburg, MD).
Measurement of bcl-2 and bax
Naive T cell lysates were prepared, electrophoresed, and probed for bcl-2 and bax with specific Abs according to the manufacturer’s protocols (Santa Cruz Biotechnology). The enhanced chemiluminescent detection system was used to visualize bcl-2 and bax protein expression.
Statistical analysis
Statistical analyses were performed using the Wilcoxon rank test for nonparametric data.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To postthymically define the stage in T cell development of cord
blood naive T cells, we used the measurement of TRECs as a molecular
marker of tracking T cell division and distinguishing between newly
emigrated lymphocytes and "old" lymphocytes. Naive
CD4+ T cells isolated from four separate cord
bloods showed significantly higher expression of TRECs compared with
adult naive T cells (Fig. 1
). The high
levels of TRECs in cord blood T cells are evidence of "new" T cells
in the periphery that have recently emigrated from the thymus and
indicate that cord naive T cells represent RTEs. The reduction in TREC
frequency in adult-derived T cells suggests that these naive T cells
have undergone several rounds of division postthymically in the
periphery and, hence, dilution of TREC levels is observed.
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Having established that cord blood T cells were RTEs, it was of
interest to determine whether, as RTEs, they retained responsiveness to
thymic cytokines such as the c cytokines. As
shown in Table I, cord naive T cells
proliferated in response to IL-2, IL-4, and IL-7 in the absence of any
other stimulus, with IL-7 showing the most vigorous response. To
examine the possibility that IL-7 might be inducing IL-2 and IL-4
production in these cells and mediating its proliferative response via
these cytokines, cultures were performed in the presence of specific
anti-IL-2 or anti-IL-4 neutralizing Abs. No alteration of the
IL-7 response was observed. Furthermore, no IL-2 or IL-4 could be
detected in the supernatant of these cultures by ELISA. Similarly, the
proliferative response to IL-4 was not due to the presence of IL-2.
Combining IL-2 with IL-4 or IL-7 had an additive effect on the
proliferative response of cord blood T cells to these cytokines. Naive
CD4+ T cells isolated from both adult and cord
blood proliferated vigorously in the presence of mitogenic anti-CD2
Abs and anti-CD28 and phorbol ester (Table I). However, long-lived
mature naive T cells from adults showed no proliferation in response to
any of the c cytokines. Increasing the dose of
IL-7 10-fold to 100 ng/ml did not alter the unresponsiveness of adult T
cells (data not shown). This difference in proliferative responses of
RTEs and mature naive T cells suggests that responsiveness to
c cytokines is lost as T cells develop in the
periphery. Evidence for this is shown in Fig. 2A, where high rates of cell
division were observed during the early culture period, but in late
cultures of up to 4 wk, a waning of the IL-7-induced proliferative
response was observed. A reduction in mean fluorescence intensity of
IL-7R expression was also seen (Fig. 2B). Long-lived
naive T cells represent the classical nondividing naive population
previously described in the periphery, whereas RTEs show unique
expansion characteristics principally in the presence of IL-7.
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DNA content of naive T cells as a measure of cell cycling status
was evaluated using PI staining of freshly isolated cells and after 7
days of culture with IL-2, IL-4, IL-7, or alone. Freshly isolated adult
and cord naive T cells were all in the
G0/G1 resting stage,
correlating with the low proliferative counts observed in these cells
(see Table I
). Cord naive T cells cultured with IL-4 or IL-7 showed
that 10 and 31% of cells, respectively, were in
S/G2M phase (Fig. 3A). All of the adult cells
remained in the G0/G1
resting stage of the cell cycle (Fig. 3B). These data
paralleled those observed with [3H]thymidine
incorporation, although the disadvantage with PI staining is that cells
that have divided and returned to the
G0/G1 phase appear as
resting cells with 2N amounts of DNA. To determine what proportion of
the cells had undergone cell division, the cells were tracked using
CFSE labeling (Fig. 3, C and D). Small numbers of
cord blood naive T cells underwent cell division in IL-2- and
IL-4-supplemented cultures. Cells cultured with IL-7 underwent up to
four rounds of division; 43% of cells underwent one cycle, 23%
underwent two cycles, 7.5% underwent three cycles, and 1.5% underwent
four cycles of cell division after 7 days. Twenty-five percent of cells
did not appear to divide. Long-lived naive T cells showed no evidence
of cell division in response to any of the cytokines (Fig. 3D). TREC levels were measured in RTEs before and after
culture with IL-7. RTEs showed a dramatic reduction in TREC levels by
up to 3 log orders, confirming the expansion data, whereas long-lived
naive T cells showed no change. This homeostasis-driven proliferation
by c cytokines, which we have previously shown
preserves the naive phenotype (9), provides a novel
extrathymic mechanism for RTE expansion.
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It is not known whether RTEs, at their particular stage of
development, have acquired the survival characteristics of mature T
cells in the periphery. The survival profile of cultured naive T cells
in the presence of c cytokines was examined
using annexin V/PI staining over an 11-day period. Cord blood T cell
apoptosis was more rapid when compared with adult T cells (i.e., 30 vs
12% at day 3 and 60 vs 44% at day 7). In the presence of IL-2, cord T
cell apoptosis was reduced to 20% at day 3 and 33% at day 7 (Fig. 4A). Addition of 10-fold
excess IL-2 did not further reduce the rate of apoptosis. Apoptosis was
not observed in cultures containing IL-4 or IL-7. Any contribution of
endogenous T cell-derived IL-2 or IL-4 to the IL-7-mediated naive T
cell survival was ruled out by the use of the corresponding
neutralizing Abs (Fig. 4, A and B). A similar
survival profile was obtained in adult cells, except the rate of death
in IL-2-supplemented cultures was slower (i.e., 10% at day 3 and 22%
at day 7; Fig. 4B). Apoptosis is regulated by the balance of
expression of pro- and antiapoptotic genes such as bcl-2 and bax.
Because, c cytokines are known to up-regulate
bcl-2 expression, levels of protein were measured in resting cord and
adult peripheral naive T cells and following culture with IL-2, IL-4,
IL-7, or alone (Fig. 4, E and F). Expression of
bcl-2 was lowest in cells cultured alone and highest in the presence of
IL-4 and IL-7, suggesting that c cytokines
play a pivotal role in the homeostasis of the naive peripheral T cell
pool through the maintenance of antiapoptotic pathways. The expression
of bax was relatively unchanged in the presence or absence of
cytokines.
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Apart from its role in promoting survival and proliferation of
intrathymic precursors, several studies using in vitro cultures of
fetal liver cells or fetal thymocytes suggested that IL-7 signaling
could specifically induce the recombinase genes
recombination-activating gene (RAG)-1 and RAG-2 and thus
have an effect on TCR- or TCR-
gene rearrangements (22, 23). To investigate the possibility that RTEs, while undergoing
expansion in the presence of c cytokines,
might activate recombinase activity, we examined IL-7-treated RTEs and
long-lived naive T cells for the presence of RAG-2 mRNA using RT-PCR
(Fig. 5). No RAG-2 mRNA was detected in
freshly isolated RTEs or mature naive T cells or in cells cultured
with IL-7.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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c cytokines. The presence of IL-7 had a
striking effect in sustaining cell survival with concomitant entry to
cell cycle and proliferation. These results clearly distinguish RTEs
from adult naive T cells, representing a mature long-lived naive T cell
population showing none of these thymocyte-like characteristics. Recent studies using mice and addressing the question of whether thymic selection involves cell division have shown that division of resting SP cells in the perinatal thymic microenvironment is driven by stimulatory cytokines released by thymic epithelial cells such as IL-7 (5, 19). This proliferation was proposed to be a device to expand the T cell pool before export to the periphery (19). In this study, we provide evidence that, in the presence of IL-7, the proliferation of postselected SP CD4+ T cells continues after these cells have been exported to the periphery. RTEs cultured in the presence of IL-7 showed an increase in size (data not shown) associated with the presence of 30% of cells in cell cycle and four rounds of cell division undergone in 7 days of culture. These findings show that human RTE naive, SP CD4+ T cells are at a transitional stage of development when compared with mature, resident adult-derived naive CD4+ T cells. Their propensity to respond to IL-7 akin to thymocytes is intact at birth and is lost later in life, as observed in the mature adult-derived naive T cell population.
Homeostatic regulation of lymphocyte numbers in humans in early life is
such that a relative leukocytosis exists during the first week of life
with T cell numbers subsequently assuming lower adult levels during the
first month of life (18). Notwithstanding the ethical
difficulties of studying the nature of human T cell development in the
early days of life, it is tempting to speculate that the early naive T
cell expansionary phase, seen in vivo, is driven in an Ag-independent
manner. The initial response to the c
cytokines, which is later switched off, would be an ideal mechanism for
regulating this expansion phase of T cell development in the periphery.
For this to be an important regulatory mechanism, it might be argued
that circulating T cells in the blood of newborns should be in cell
cycle. However, we have shown that this is not the case (Fig. 3). Any
postthymic expansion of T cells that may be occurring is likely to be
restricted to sites of IL-7 production in tissues, and the expanded T
cells in circulating blood may be in a resting, noncycling phase. This
has recently been demonstrated in a mouse model in which pre-emigrant
mature thymocytes undergo active cell cycling and expansion (19, 24). However, upon migration from the thymus, RTEs are in a
postcycling phase in which DNA synthesis has been terminated
(24). Our observation on noncycling RTEs in newborns is
consistent with these findings. Interestingly, IL-7R levels, which
are initially high in cord blood-derived T cells, returned to lower
levels following exposure to IL-7 and became similar to those expressed
on adult-derived T cells. Loss of proliferative or expansionary
capacity in the presence of c cytokines (Fig. 2) while maintaining the potent antiapoptotic effect of these cytokines
would ensure the long-term survival of resting naive T cells in the
periphery.
It has been established that IL-7 mediates T cell survival by
up-regulating bcl-2 expression (13, 14, 15). During T cell
development, bcl-2 is expressed at high levels in double-negative
cells, declines in double-positive cells, and is then re-expressed in
the SP populations (25). This biphasic expression of bcl-2
in early precursors and then later in mature thymocytes coincides with
IL-7R expression. In the present study, IL-7 induced higher bcl-2
expression in RTEs than mature naive T cells (Fig. 4C), and
this correlated with higher IL-7R expression observed on RTEs.
However, bcl-2 may not be the sole pathway of IL-7-mediated survival.
It should be noted that IL-7 can also promote the survival of
bcl-2-deficient peripheral T cells, implying that the antiapoptotic
effect of IL-7 can be bcl-2 independent (26). Other
proteins studied but found not to be likely agents for the
antiapoptotic activity of IL-7 include bcl-xL
(27) and Bad (28). Bcl-2 has been shown to
interfere with the Bax-induced release of cytochrome c
(29), suggesting that IL-7 may function at various levels
regulating the balance of anti- and proapoptotic factors.
Although the trophic action of IL-7 is probably not unique, its VDJ
effects may be unique (8). The influence of IL-7 on
recombination may be partially explained by the regulation of RAG
expression (22). Addition of rIL-7 to fetal liver or
thymic cell cultures promotes RAG expression (22, 23),
whereas reduced expression of RAG-1 and -2 genes were observed in
thymocytes from IL-7R-/- mice compared with
wild-type controls (30). In the present study, we
addressed the question of whether RTEs retain the potential to express
RAGs given the observation that a subset of T cells in the human
perinatal period (RTEs) may recirculate through the thymus
(31). Using sensitive PCR methods, RAG-2 expression could
not be reinduced in the presence of IL-7, suggesting that preselected
TCR repertoires in the thymus are not further rearranged in response to
homeostatic regulation by c cytokines. Whether
the subset of T cells that can re-enter the thymus undergoes Ag
receptor editing, as has recently been shown in developing T cells,
remains to be addressed (32).
It is an interesting biological issue that IL-7 delivers a more potent
signal to RTEs compared with IL-2 or IL-4 even though they all signal
through the c receptor. Clearly, the
requirement for IL-7 is unique because the thymus is the site of
highest IL-7 production (33, 34), and studies on knockout
mice have indicated the essential role of IL-7 in T cell development
(28). That RTEs have retained this vestige of their
development is shown by their unique responsiveness to IL-7.
A recent study in monkeys by Sodora et al. (35) using
TRECs to track the movement of RTEs showed that they home initially to
lymph nodes, as TREC levels in lymph node T cells were higher than in
corresponding peripheral T cells. It is possible that homing of RTEs to
sites of IL-7 production such as the gut (36), skin
(37, 38), and liver (39), especially in the
newborn animal, may be vital for the initial non-TCR-restricted
expansion of naive immune cells. This increase in cell number may be
the first means of mounting an effective primary challenge to Ags. The
c cytokines tested in this study, IL-2, IL-4,
and IL-7, serve a dual function: As well as inducing cell expansion of
resting naive T cells, they are also known to be potent costimulators
of activated T cells (40, 41). Such a means of amplifying
the immune response in an Ag-inexperienced host in a TCR-independent
and TCR-dependent fashion is unique. Later in life, in an
Ag-experienced host, only the TCR-dependent costimulatory capacities of
these cytokines remain. The responsiveness of the mature, naive resting
T cell becomes practically obsolete as the memory response
predominates. Although there are some studies showing responsiveness of
human adult T cells to IL-7 alone, these have involved separation of T
cells using sheep RBCs (42, 43), a method known to
activate the T cells, and, therefore, the response observed is probably
that of IL-7 acting as a costimulus.
In summary, this study demonstrates that after export from the thymus, the human RTE population is clearly distinct from resident, long-lived peripheral T cells. The role of secondary lymphoid organs in providing suitable T cell niches for postthymic cell development and peripheral T cell maintenance needs to be addressed. Importantly, manipulation of the unique expansion potential of RTEs could have a significant impact on the neonatal response during infection and possibly in the context of vaccination.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: RTE, recent thymic emigrant; c, common -chain; SP, single positive; PI, propidium iodide; TREC, TCR excision circle; RAG, recombination-activating gene.
Received for publication December 15, 2000. Accepted for publication May 23, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells in secondary lymphoid organs. J. Exp. Med. 177:891. chain-deficient mice. Immunity 7:155.[Medline]
gene. Science 261:93. variable region genes in murine fetal liver cultures. J. Exp. Med. 178:2201. chain-deficient mice. Eur. J. Immunol. 27:100.[Medline]
-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not proapoptotic (bax, bcl-xS) gene expression. Eur. J. Immunol. 26:294.[Medline]
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S. Cookson and D. Reen IL-15 drives neonatal T cells to acquire CD56 and become activated effector cells Blood, September 15, 2003; 102(6): 2195 - 2197. [Abstract] [Full Text] [PDF]
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S. Hue, R. C. Monteiro, S. Berrih-Aknin, and S. Caillat-Zucman Potential Role of NKG2D/MHC Class I-Related Chain A Interaction in Intrathymic Maturation of Single-Positive CD8 T Cells J. Immunol., August 15, 2003; 171(4): 1909 - 1917. [Abstract] [Full Text] [PDF]
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S. O. Schonland, J. K. Zimmer, C. M. Lopez-Benitez, T. Widmann, K. D. Ramin, J. J. Goronzy, and C. M. Weyand Homeostatic control of T-cell generation in neonates Blood, August 15, 2003; 102(4): 1428 - 1434. [Abstract] [Full Text] [PDF]
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S. Jaleco, L. Swainson, V. Dardalhon, M. Burjanadze, S. Kinet, and N. Taylor Homeostasis of Naive and Memory CD4+ T Cells: IL-2 and IL-7 Differentially Regulate the Balance Between Proliferation and Fas-Mediated Apoptosis J. Immunol., July 1, 2003; 171(1): 61 - 68. [Abstract] [Full Text] [PDF]
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R. M. O'Neill, J. Hassan, and D. J. Reen IL-7-Regulated Homeostatic Maintenance of Recent Thymic Emigrants in Association with Caspase-Mediated Cell Proliferation and Apoptotic Cell Death J. Immunol., May 1, 2003; 170(9): 4524 - 4531. [Abstract] [Full Text] [PDF]
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B. Adkins, T. Williamson, P. Guevara, and Y. Bu Murine Neonatal Lymphocytes Show Rapid Early Cell Cycle Entry and Cell Division J. Immunol., May 1, 2003; 170(9): 4548 - 4556. [Abstract] [Full Text] [PDF]
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E. Verhoeyen, V. Dardalhon, O. Ducrey-Rundquist, D. Trono, N. Taylor, and F.-L. Cosset IL-7 surface-engineered lentiviral vectors promote survival and efficient gene transfer in resting primary T lymphocytes Blood, March 15, 2003; 101(6): 2167 - 2174. [Abstract] [Full Text] [PDF]
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N. Manel, S. Kinet, J.-L. Battini, F. J. Kim, N. Taylor, and M. Sitbon The HTLV receptor is an early T-cell activation marker whose expression requires de novo protein synthesis Blood, March 1, 2003; 101(5): 1913 - 1918. [Abstract] [Full Text] [PDF]
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S. Jaleco, S. Kinet, J. Hassan, V. Dardalhon, L. Swainson, D. Reen, N. Taylor, and L. Al-Harthi IL-7 and CD4+ T-cell proliferation Blood, December 15, 2002; 100(13): 4676 - 4677. [Full Text] [PDF]
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S. Kinet, F. Bernard, C. Mongellaz, M. Perreau, F. D. Goldman, and N. Taylor gp120-mediated induction of the MAPK cascade is dependent on the activation state of CD4+ lymphocytes Blood, September 18, 2002; 100(7): 2546 - 2553. [Abstract] [Full Text] [PDF]
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P. Ye and D. E. Kirschner Reevaluation of T Cell Receptor Excision Circles as a Measure of Human Recent Thymic Emigrants J. Immunol., May 15, 2002; 168(10): 4968 - 4979. [Abstract] [Full Text] [PDF]
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S. Kimmig, G. K. Przybylski, C. A. Schmidt, K. Laurisch, B. Mowes, A. Radbruch, and A. Thiel Two Subsets of Naive T Helper Cells with Distinct T Cell Receptor Excision Circle Content in Human Adult Peripheral Blood J. Exp. Med., March 18, 2002; 195(6): 789 - 794. [Abstract] [Full Text] [PDF]
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,
n = 3) showed a reduction in the proliferative
response over the time interval tested. Adult-derived T cells (•,
n = 3) remained nonresponsive throughout the
culture period. Similarly, a reduction in the mean fluorescence
intensity of IL-7R
