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*
Laboratory of Molecular Immunoregulation and
Science Applications International Corporation, Division of Basic Sciences, National Cancer Institute, Frederick, MD 21702
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(2, 3), IL-7 itself (4, 5),
mice treated with Abs against IL-7 (6, 7), and deficiencies of the
c component of the IL-7R in humans (8) and
mice (9, 10).
Some ßT cell development occurs in about 40% of
IL-7R-/- mice, suggesting that alternative pathways can
also support T cell development; however, the peripheral T cells that
eventually accumulate in these leaky mice do not proliferate in
response to stimuli (11). The 
T cell lineage is completely
undetectable in all IL-7R-/- mice (3, 12) based on a
failure to rearrange the TCR locus (13, 14) or a failure to express
these genes (15). The development of B lymphocytes is also severely
impaired in IL-7R-/- mice and c-/-
mice, but not in c-deficient humans reflecting the IL-7
independence of human B cells (16). NK development is normal in
IL-7R-/- mice (12).
The earliest stages in murine T cell development (before expression of CD4, CD8, and CD3) have been distinguished based on CD44 and CD25 expression (reviewed in 17 : pro-T1 (CD44+CD25-), pro-T2 (CD44+CD25+), pro-T3 (CD44-CD25+), and pro-T4 (CD44-CD25-). Expression of c-Kit, the receptor for stem cell factor, corresponds with expression of CD44 at these pro-T cell stages. The CD25+ stages are deficient in IL-7R-/- mice and in mice treated with anti-IL-7. This suggests that one requirement for IL-7R signals occurs before or during the pro-T2 stage. IL-7 has been reported to induce proliferation of early T cells (18) and could therefore play a role in the expansion as well as differentiation or survival of these cells. To clarify the nature of the IL-7R signal requirement, pro-T cells at different stages were isolated from the thymus and examined for the effects of IL-7 on survival and cell cycle, and the cell death process that occurred in the absence of IL-7 was characterized.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 and MRL-lpr/lpr mice were housed in a specific pathogen-free environment. Mice were mated overnight and checked for plugs the following day, which was designated day 1 of gestation. On the indicated day of gestation, mothers were killed by CO2 asphyxiation, and embryos were killed by chilling on ice. Thymi were removed from embryos using a dissecting microscope. Rag-2-/- (19) and p53-/- (20) mice were bred in our facility from breeders purchased from The Jackson Laboratory (Bar Harbor, ME).
Preparation and culture of fetal thymocytes
Fetal thymus lobes were obtained from embryos on day 14, 15, 16, 17, or 18 of gestation. Cell suspensions were prepared by gentle disruption with a micropipette after treatment with 0.2% collagenase (Sigma, St. Louis, MO) dissolved in PBS containing 20% heat-inactivated FCS (HyClone, Logan, UT) for 1 h at 37°C. The cells were cultured in RPMI 1640 supplemented with 2 mM glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, 50 µM 2-ME, and 10% heat-inactivated FCS. Fetal thymocytes (4 x 105/200 µl/well) were cultured in 96-well U-bottom plates in the presence or the absence of IL-7 (50 ng/ml; PeproTech, Rocky Hill, NJ) for the indicated length of time. Hamster anti-Fas (Jo2; 10 µg/ml; PharMingen, San Diego, CA) was added to some cultures. Caspase inhibitors, z-VAD-FMK and z-DEVD-FMK (20 µM; Enzyme Systems Products, Dublin, CA), were preloaded into thymocytes at 0°C for 30 min before placing cells in culture together with inhibitors at 37°C.
Anti-Fas control treatment
Renca cells were stimulated with IFN- (100 U/ml for 18
h) to increase their susceptibility to fas-mediated killing.
Renca cells were then labeled with 51Cr and incubated with
d11S cells that express FasL2
and hamster anti-Fas (10 µg/ml) for 16 h, and the release of
51Cr was determined.
Flow cytometric analysis and cell sorting with Abs
For Ab staining, cells were harvested, washed in a staining
solution of PBS containing 5% FCS and 0.1% NaN3, and
resuspended in 50 µl of staining solution containing 0.5 µg of rat
mAb 2.4G2 (anti-mouse FcRII, PharMingen) and 10% normal mouse
serum to reduce nonspecific binding of Abs to Fc receptors. Cell
suspensions were stained with mAbs (1/200 dilution) for 20 min at
4°C. Abs were purchased from PharMingen, including
R-phycoerythrin-conjugated anti-CD44 (clone IM7),
FITC-conjugated anti-CD25 (clone 7D4), FITC-anti-CD4 (RM4-5),
and R-phycoerythrin-conjugated anti-mouse CD8 (clone
53-6.7). Cells were washed and fixed in 1% paraformaldehyde in PBS,
and analyzed on a FACStar Plus (Becton Dickinson Immunocytometry
System, Mountain View, CA), gating out dead cells by forward low angle
scatter and low right angle scatter. For sorting cells, the same
staining method was used without fixation, and cells were sorted on a
FACStar Plus or a modified FACSII (Becton Dickinson). Pro-T1
(CD44+CD25-) cells were sorted from day 14
thymocytes. Pro-T2 (CD44+CD25+) cells were
sorted from day 14 or 15 thymocytes. Pro-T3
(CD44-CD25-) cells were sorted from day 16
thymocytes or from Rag2-/- adult thymocytes. Pro-T4
(CD4-CD8-CD44-CD25-)
cells were sorted from day 17 thymocytes. From p53-/-
mice a mixture of pro-T2 and pro-T3 cells
(CD4-CD8-CD25+) was sorted from
thymocytes from adult mice. The purity of sorted populations was
generally >98%. Sorted cells were then cultured overnight with or
without IL-7.
Intracellular staining of Bcl-2, Bcl-XL, Bax, and Bad
Single-cell suspensions were permeabilized with saponin buffer (PBS containing 1% BSA (Sigma) and 0.04% saponin) for 20 min, then incubated with monoclonal anti-mouse Bcl-2 (clone 3F11, PharMingen), anti-mouse Bcl-XL (clone 4, Transduction Laboratory, Lexington, KY), anti-mouse Bad (clone 2G11, PharMingen), or a polyclonal anti-mouse Bax (Santa Cruz Biotechnology, Santa Cruz, CA) for 30 min on ice. Isotype-matched control Abs were purified mouse IgG2b (clone 49.2 PharMingen), purified polyclonal hamster IgG (PharMingen), or purified rabbit IgG. Cells were washed twice with saponin buffer, incubated with FITC anti-hamster IgG (clone G94-56, PharMingen), FITC anti-mouse IgG2b (clone R12-3 PharMingen), or FITC-anti-rabbit IgG (Santa Cruz Biotechnology) for 30 min at 4°C, and washed once with saponin buffer and once with PBS containing 1% BSA.
Annexin V staining and viability
Annexin V binding was performed with a commercial kit (Clontech, Palo Alto, CA). Cells were collected, then resuspended in annexin V binding buffer containing annexin V-FITC (1 µg/ml) and propidium iodide (2 µg/ml) for 10 min at room temperature in the dark, washed, and analyzed by microfluorometry. To analyze for viability, cells were incubated with propidium iodide, then the percentage of cells excluding the dye was determined by flow microfluorometry.
Cell cycle analysis
Cells were placed in a detergent buffer (21) and an equal volume of staining buffer (propidium iodide, 50 µg/ml). Cells were mixed by inversion, incubated at room temperature in the dark for 1 h, and analyzed by flow microfluorometry.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, these freshly explanted
thymocytes began to die by apoptosis within 2 h, and by 20 h,
90% had undergone apoptotic death. IL-7 protected about half the cells
from apoptotic death at 20 h, and its survival effects could be
seen as early as 6 h. In >20 experiments, IL-7 protected 50 to
80% of the cells from death at the 20 h point. Further culture in
IL-7 beyond 20 h (not shown) showed that with each additional day,
about half of the cells died. We noted that culture density had an
effect on viability, with IL-7 being less effective as culture density
was lowered.
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both pro-T1 and pro-T2 populations were protected from apoptotic death
by IL-7. We also visualized DNA fragmentation by gel electrophoresis
and observed a comparable IL-7 effect (not shown). It is clear from
this analysis that IL-7 did not promote cycling of pro-T cells, as
shown by the decline in the proportion of cells in S and
G2-M during culture in IL-7 compared with that at the
start of the culture (see also Fig. 6). The percentages of pro-T2 cells
in G1, S, and G2-M phases when initially
isolated were 56.5, 37.5, and 6.1%, respectively. After IL-7 culture,
they were 81.5, 16.5, and 1.9%, respectively. Thus, cell division
declined during culture in IL-7, and its activity is best described as
"trophic" rather than "growth" for pro-T cells.
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, pro-T3 cells were protected by
IL-7 from cell death during culture. Of the first three stages (pro-T1,
-T2, and -T3), the most dramatic IL-7 trophic effects were consistently
observed at pro-T2.
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, these cells survived
independently of IL-7 in culture, and addition of IL-7 produced only a
slight increase in survival that was not observed consistently. Pro-T4
cells also rapidly differentiated in culture (not shown), expressing
CD4 and CD8 after overnight culture, and this, too, was unaffected by
IL-7. Pro-T4 cells were also cycling much more rapidly than pro-T1,
-T2, and -T3 cells (not shown), and this cycling was unaffected by
IL-7. After the pro-T4 stage, thymocytes express CD4 and CD8. We examined CD4+CD8+ cells for IL-7 trophic effects (not shown) and observed that, like pro-T4 cells, these cells survived independently of IL-7 for several days in vitro. We conclude that the trophic effects of IL-7 end with the pro-T3 stage.
The role of p53 in the apoptotic response to IL-7 deprivation was
tested for two reasons. First, p53 mediates one type of thymocyte
apoptosis, that induced by dsDNA breaks (20, 22, 23). Second,
p53-/- mice develop thymic lymphomas at a very high
frequency (24, 25), suggesting that they evade the normal death
mechanisms. Although the phenotype of such p53-/-
thymomas is primarily CD4+CD8+, an
IL-7-independent stage, we nevertheless considered it possible that the
actually transformed cell was a pro-T cell because such thymic
lymphomas also arise in rag-/-
p53-/- mice (24) (S. Candèias and S. Durum,
unpublished observation) that do not develop beyond the IL-7-dependent
pro-T3 stage. However, a role for p53 was ruled out by using pro-T
cells from p53-/- mice, as shown in Figure 4. Thus, a similar dependency on IL-7 was
observed comparing p53-/- thymocytes to their
heterozygous littermates. Note that cell death (in the absence of IL-7)
was not as extensive in this experiment as that shown in Figure 3; this
is because adult pro-T cells die more slowly in culture than their
fetal counterparts. We also tested fetal pro-T cells from
p53-/- mice (not shown) and similarly showed that they
are IL-7 dependent. It can be noted (Fig. 4) that p53-/-
thymocytes survive better in culture than do their heterozygous
counterparts. This improved survival of cultured p53-/-
cells was not observed in studies using unfractionated thymocytes or
pre-B cells (20, 22, 23); however, we consistently observed it in pro-T
cells and activated mature T cells (S. Candèias and S. Durum,
unpublished observations), and it has been noted in embryonic
fibroblasts (26).
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(left panel),
neither caspase inhibitor prolonged life, as assessed by propidium
iodide exclusion. However, both caspase inhibitors notably reduced DNA
fragmentation (right panel). Thus, IL-7
deprivation activates caspases (recognized by these inhibitors),
leading to DNA fragmentation; however, an additional mechanism must
also be involved in cell killing when IL-7 is withdrawn; this mechanism
could involve caspases not blocked by these inhibitors or may be
caspase independent.
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(left), anti-Fas did not block the death
of pro-T cells, nor did the MRL-lpr/lpr thymocytes fail to
die in the absence of IL-7. As a positive control for anti-Fas
blocking, the same Ab was shown to inhibit the FasL-Fas killing pathway
of FasL, expressing d11S killers on the Fas-expressing Renca target
cells (Fig. 6, right). Although this Ab can have
agonist activity and kill Fas targets, we do not observe this unless it
is secondarily cross-linked (T. Sayers unpublished observation).
Further evidence against a Fas mechanism is our failure to detect Fas
expression by flow microfluorometry before or after culture of pro-T
cells (not shown). Thus, Fas is not involved in the death of
pro-thymocytes deprived of IL-7.
The relative concentrations of antiapoptotic (e.g., Bcl-2) and
proapoptotic members (e.g., Bax) of the Bcl-2 family determine whether
a cell will live or die. Intracellular staining was performed for the
antiapoptotic factors Bcl-2 and Bcl-XL and for the
proapoptotic factors Bax and Bad. As shown in Figure 7 (left),
freshly isolated cells expressed high levels of Bcl-2 and Bax, whereas
no Bcl-XL or Bad was detected. During culture (Fig. 7, right panels), Bcl-2 levels declined sharply, and
IL-7 reduced this decline. Bax levels increased during culture, and
IL-7 prevented this increase. Thus, IL-7 preserved the ratio of
Bcl-2 to Bax at a level intermediate between that at initiation and
that of cultures deprived of IL-7. Therefore, the trophic action of
IL-7 on day 14 thymocytes correlated with its maintaining a favorable
Bcl-2/Bax ratio.
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Discussion |
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These findings complement the recent reports that a bcl-2
transgene restores ßT cell development in IL-7R-/-
mice (28, 29) and in c-/- mice (30),
demonstrating that Bcl-2 can substitute for some IL-7 activities. It
has also recently been reported that IL-7 regulates Bcl-2 levels in
pro-T cells, and that this regulation is deficient in
IL-7-/- mice (31). Taken together with our observation
that IL-7 influences the Bcl-2/Bax ratio in vitro, it suggests that
these regulators of apoptosis could mediate the IL-7 response. It has
previously been shown that IL-7 enhanced the Bcl-2 levels in cell lines
(32, 33), and our study extends this to pro-T cells, which have a
physiologic requirement for IL-7R signals. However, Bcl-2 induction
may not completely explain the trophic effects of IL-7 on pro-T cells
in embryonic life. Mice lacking Bcl-2 have relatively normal numbers of
thymocytes at birth; however, these numbers rapidly decline by 1 mo
(34). The decline in thymocytes after birth in these mice has been
attributed to differences in stem cells that seed the thymus before and
after birth (35). Thus, it was proposed that Bcl-2 was not required for
embryonic thymopoiesis generated by stem cells derived from fetal
liver. At birth, thymopoiesis is subsumed by a stem cell arriving from
bone marrow, and it or its progeny are dependent on Bcl-2. Perhaps
another Bcl-2 family member is also induced by IL-7 in fetal cells. We
sought two other Bcl-2 family members; Bcl-XL protein was
not detected in pro-T cells (Fig. 7), nor was bcl-w (36)
mRNA detectable by Northern blotting (not shown). Remaining family
members that have not been evaluated are Mcl-1 (37) and A1 (38). The
trophic activity of IL-3 on a cell line was attributable to
phosphorylation of Bad (39); this mechanism would be resistant to
cycloheximide, as the IL-7 trophic effect is in part; however, we did
not detect Bad in pro-T cells (Fig. 7).
Blocking caspase activity is reported to inhibit apoptosis in many cell
types (reviewed in 40 . It is therefore surprising that caspase
inhibitors, although inhibiting DNA fragmentation, did not preserve the
viability of these pro-T cells. Several lines of evidence suggest that
these cells die by apoptosis, including the phenotype of the cells
(Figs. 1 and 2) and the observation that Bcl-2 protects them (28, 29, 30).
One possibility is that death is mediated by caspases that are
insensitive to the effects of these inhibitors. Another possibility is
that the death pathway does not involve caspases at all. This is
reminiscent of cytotoxic T cell killing, which is primarily mediated by
perforin; caspase inhibitors block DNA fragmentation, but not cell
death, which in that case is caused by pores in the plasma
membrane (41).
It was observed that wortmannin inhibited the trophic action of IL-7 on
a pre-B cell line, suggesting that phosphatidylinositol 3-kinase is
required (42). The same study noted that a tyrosine site on IL-7R
that mediated activation of phosphatidylinositol 3-kinase was required
for the trophic activity in pre-B cells. However, we did not observe
that wortmannin inhibited the trophic activity of IL-7 on pro-T cells
(data not shown). Hence, the seemingly similar activities of IL-7 on
survival of early T and B cells may involve different signaling
pathways and, by extension, different survival and death pathways.
The Fas pathway did not appear to mediate death from IL-7 deprivation. It has been reported that Fas expression does not begin until the CD4+CD8+ stage. We have confirmed this and also observed that its expression is not induced during IL-7 deprivation (not shown). A recent report implicates the Fas system in the death of cells that fail to productively rearrange their TCRß genes (27). This death presumably occurs in cells at stage pro-T3, which, according to our findings, also die when deprived of IL-7. The signal for a successful ß gene rearrangement is thought to emanate from the pre-TCR, which incorporates the successfully produced ß-chain. Thus, the trophic signals from pre-TCR may be different from those of IL-7R, and this is substantiated by the failure of a bcl-2 transgene to rescue T cells in rag-/- mice (which cannot generate ß gene rearrangements), whereas it protects IL-7R-/- thymocytes (28). Consistent with this interpretation, it has been reported that Bcl-2 cannot protect cells from Fas-mediated killing (43, 44). We also found no evidence for IL-7 serving as a cofactor together with the pre-TCR signal, since pro-T4 cells survived independently of IL-7; pro-T4 cells also rapidly proliferated and differentiated into CD4+CD8+ cells within 18 h in the absence of IL-7 (not shown).
We recently observed that the IL-7R activates the
4ß1 integrin, increasing its affinity for
the extracellular matrix protein fibronectin (45). Integrins, in turn,
are known to provide viability signals to some types of cells. However,
we tested whether fibronectin could augment the trophic effect of IL-7
on pro-T cells and could not detect such an effect (data not shown).
IL-7 produced by thymic epithelial cells appears to be bound to
extracellular matrix in the thymus (45), which raises questions about
the molecular form, solubility, and concentration of the IL-7 actually
encountered by pro-T cells. Thus, we do not know whether the
concentrations of IL-7 used in our experiments fall into the
physiologic or the pharmacologic range.
We did not observe an induction of cell cycle progression by IL-7, but, rather, found a completion of the cycle and accumulation of cells in G1. There are reports that IL-7 induced the growth of pro-T cells (for example, 46 , but these effects may be attributable to the presence of other stimuli that in some studies were intentionally added or in other cases may have been produced endogenously; it is also possible that in long term cultures, a subpopulation of cells that grows in response to IL-7 eventually dominates; however, it can be seen from our results (and inferred from the bcl-2 transgenic mice noted above (28, 29, 30)) that this is not the prevailing response. Stem cell factor has been identified as a potent cofactor that, together with IL-7, induces rapid growth (47). Other cytokines may be produced by the thymocytes during culture in our studies. The evidence for such autocrine factors is that culturing the cells at high density in U-bottom wells promoted the trophic effects of IL-7, and conditioned medium from high cell density cultures promoted the survival of low cell density cultures (not shown).
Differentiation of thymocytes has also been reported to be induced by
IL-7. VDJ recombination is promoted by the IL-7R in thymocytes (3, 14, 48, 49) and pro-B cells (reviewed in Ref. 1; 42). This effect is partly
attributable to inducing rag1 and rag2 expression
(48, 50, 51) and perhaps also to enhancing locus accessibility,
especially of the TCR locus. We examined whether IL-7 induced
expression of CD25 on pro-T1 cells, since CD25+ cells are
absent in IL-7R-/- mice, but this was not detectable (not
shown). However, we did observe significant induction of CD8 and
-ß surface expression on pro-T cells after overnight culture with
IL-7 (K. Kim, manuscript in preparation).
In conclusion, IL-7 has a trophic effect on several early stages of pro-T cells, promoting survival without growth. Bcl-2 and Bax levels are associated with these effects, but there may be other mechanisms that remain to be identified for this type of biologic activity.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: FasL, Fas ligand.
Received for publication August 28, 1997. Accepted for publication February 9, 1998.
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C. J. Van De Wiele, J. H. Marino, B. W. Murray, S. S. Vo, M. E. Whetsell, and T. K. Teague Thymocytes between the {beta}-Selection and Positive Selection Checkpoints Are Nonresponsive to IL-7 as Assessed by STAT-5 Phosphorylation J. Immunol., April 1, 2004; 172(7): 4235 - 4244. [Abstract] [Full Text] [PDF]
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J. T. Barata, V. A. Boussiotis, J. A. Yunes, A. A. Ferrando, L. A. Moreau, J. P. Veiga, S. E. Sallan, A. T. Look, L. M. Nadler, and A. A. Cardoso IL-7-dependent human leukemia T-cell line as a valuable tool for drug discovery in T-ALL Blood, March 1, 2004; 103(5): 1891 - 1900. [Abstract] [Full Text] [PDF]
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A. Muthukumar, A. Wozniakowski, M.-C. Gauduin, M. Paiardini, H. M. McClure, R. P. Johnson, G. Silvestri, and D. L. Sodora Elevated interleukin-7 levels not sufficient to maintain T-cell homeostasis during simian immunodeficiency virus-induced disease progression Blood, February 1, 2004; 103(3): 973 - 979. [Abstract] [Full Text] [PDF]
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K. C. Jung, W. S. Park, H. J. Kim, E. Y. Choi, M.-C. Kook, H.-W. Lee, and Y. Bae TCR-Independent and Caspase-Independent Apoptosis of Murine Thymocytes by CD24 Cross-Linking J. Immunol., January 15, 2004; 172(2): 795 - 802. [Abstract] [Full Text] [PDF]
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A. Bhandoola, A. Sambandam, D. Allman, A. Meraz, and B. Schwarz Early T Lineage Progenitors: New Insights, but Old Questions Remain J. Immunol., December 1, 2003; 171(11): 5653 - 5658. [Full Text] [PDF]
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V. Mateo, E. J. Brown, G. Biron, M. Rubio, A. Fischer, F. L. Deist, and M. Sarfati Mechanisms of CD47-induced caspase-independent cell death in normal and leukemic cells: link between phosphatidylserine exposure and cytoskeleton organization Blood, September 26, 2002; 100(8): 2882 - 2890. [Abstract] [Full Text] [PDF]
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T. J. Fry and C. L. Mackall Interleukin-7: from bench to clinic Blood, May 13, 2002; 99(11): 3892 - 3904. [Full Text] [PDF]
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 A. R. Khaled, A. N. Moor, A. Li, K. Kim, D. K. Ferris, K. Muegge, R. J. Fisher, L. Fliegel, and S. K. Durum Trophic Factor Withdrawal: p38 Mitogen-Activated Protein Kinase Activates NHE1, Which Induces Intracellular Alkalinization Mol. Cell. Biol., November 15, 2001; 21(22): 7545 - 7557. [Abstract] [Full Text] [PDF]
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E. Guillemard, M.-T. Nugeyre, L. Chene, N. Schmitt, C. Jacquemot, F. Barre-Sinoussi, and N. Israel Interleukin-7 and infection itself by human immunodeficiency virus 1 favor virus persistence in mature CD4+CD8{-}CD3+ thymocytes through sustained induction of Bcl-2 Blood, October 1, 2001; 98(7): 2166 - 2174. [Abstract] [Full Text] [PDF]
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J. T. Barata, A. A. Cardoso, L. M. Nadler, and V. A. Boussiotis Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27kip1 Blood, September 1, 2001; 98(5): 1524 - 1531. [Abstract] [Full Text] [PDF]
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C.-K. Lee, J. K. Kim, Y. Kim, M.-K. Lee, K. Kim, J.-K. Kang, R. Hofmeister, S. K. Durum, and S. S. Han Generation of Macrophages from Early T Progenitors In Vitro J. Immunol., May 15, 2001; 166(10): 5964 - 5969. [Abstract] [Full Text] [PDF]
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S. Trop, P. De Sepulveda, J. C. Zuniga-Pflucker, and R. Rottapel Overexpression of suppressor of cytokine signaling-1 impairs pre-T-cell receptor-induced proliferation but not differentiation of immature thymocytes Blood, April 15, 2001; 97(8): 2269 - 2277. [Abstract] [Full Text] [PDF]
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L. A. Welniak, A. R. Khaled, M. R. Anver, K. L. Komschlies, R. H. Wiltrout, S. Durum, F. R. Ruscetti, B. R. Blazar, and W. J. Murphy Gastrointestinal Cells of IL-7 Receptor Null Mice Exhibit Increased Sensitivity to Irradiation J. Immunol., March 1, 2001; 166(5): 2923 - 2928. [Abstract] [Full Text] [PDF]
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D. Andrew and R. Aspinall IL-7 and Not Stem Cell Factor Reverses Both the Increase in Apoptosis and the Decline in Thymopoiesis Seen in Aged Mice J. Immunol., February 1, 2001; 166(3): 1524 - 1530. [Abstract] [Full Text] [PDF]
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J. G. Baseta and O. Stutman TNF Regulates Thymocyte Production by Apoptosis and Proliferation of the Triple Negative (CD3-CD4-CD8-) Subset J. Immunol., November 15, 2000; 165(10): 5621 - 5630. [Abstract] [Full Text] [PDF]
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A. M. Baird, J. A. Lucas, and L. J. Berg A Profound Deficiency in Thymic Progenitor Cells in Mice Lacking Jak3 J. Immunol., October 1, 2000; 165(7): 3680 - 3688. [Abstract] [Full Text] [PDF]
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 S. Ghatan, S. Larner, Y. Kinoshita, M. Hetman, L. Patel, Z. Xia, R. J. Youle, and R. S. Morrison p38 MAP Kinase Mediates Bax Translocation in Nitric Oxide-induced Apoptosis in Neurons J. Cell Biol., July 24, 2000; 150(2): 335 - 348. [Abstract] [Full Text] [PDF]
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P. S. Costello, S. C. Cleverley, R. Galandrini, S. W. Henning, and D. A. Cantrell The GTPase Rho Controls a p53-dependent Survival Checkpoint during Thymopoiesis J. Exp. Med., July 3, 2000; 192(1): 77 - 86. [Abstract] [Full Text] [PDF]
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L. Karawajew, V. Ruppert, C. Wuchter, A. Kosser, M. Schrappe, B. Dorken, and W.-D. Ludwig Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia Blood, July 1, 2000; 96(1): 297 - 306. [Abstract] [Full Text] [PDF]
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L. Zhang and T. J. Rogers {kappa}-Opioid Regulation of Thymocyte IL-7 Receptor and C-C Chemokine Receptor 2 Expression J. Immunol., May 15, 2000; 164(10): 5088 - 5093. [Abstract] [Full Text] [PDF]
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M. S. Schlissel, S. D. Durum, and K. Muegge The Interleukin 7 Receptor Is Required for T Cell Receptor {gamma} Locus Accessibility to the V(D)J Recombinase J. Exp. Med., March 20, 2000; 191(6): 1045 - 1050. [Abstract] [Full Text] [PDF]
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N. Benbernou, K. Muegge, and S. K. Durum Interleukin (IL)-7 Induces Rapid Activation of Pyk2, Which Is Bound to Janus Kinase 1 and IL-7Ralpha J. Biol. Chem., March 15, 2000; 275(10): 7060 - 7065. [Abstract] [Full Text] [PDF]
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A. R. Khaled, K. Kim, R. Hofmeister, K. Muegge, and S. K. Durum From the Cover: Withdrawal of IL-7 induces Bax translocation from cytosol to mitochondria through a rise in intracellular pH PNAS, December 7, 1999; 96(25): 14476 - 14481. [Abstract] [Full Text] [PDF]
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 M. D. Johnson, Y. Kinoshita, H. Xiang, S. Ghatan, and R. S. Morrison Contribution of p53-Dependent Caspase Activation to Neuronal Cell Death Declines with Neuronal Maturation J. Neurosci., April 15, 1999; 19(8): 2996 - 3006. [Abstract] [Full Text] [PDF]
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S. K. Durum, S. Candeias, H. Nakajima, W. J. Leonard, A. M. Baird, L. J. Berg, and K. Muegge Interleukin 7 Receptor Control of T Cell Receptor gamma Gene Rearrangement: Role of Receptor-associated Chains and Locus Accessibility J. Exp. Med., December 21, 1998; 188(12): 2233 - 2241. [Abstract] [Full Text] [PDF]
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