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*
Experimental Immunology Branch and
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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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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We have previously shown that the thymic epithelium produces steroids
and have identified a role for endogenously produced glucocorticoids in
thymocyte development. Analysis of transgenic mice that express
antisense transcripts to the 3'-untranslated region of the
glucocorticoid receptor (GR) in thymocytes, and which therefore have
reduced GR levels and are hyporesponsive to glucocorticoids, revealed
that glucocorticoids are critical at least two points during thymocyte
development: progression from the
CD4-CD8- to the
CD4+CD8+ stage of
development and maintenance of viability at the
CD4+CD8+ stage
(3). Moreover, addition of metyrapone, a selective
inhibitor of corticosterone synthesis (4), to thymic organ
culture of TCR 
transgenic mice resulted in the specific
apoptotic death of cells that would otherwise undergo positive
selection (5, 6). These findings indicate that under
normal conditions endogenous glucocorticoids prevent thymocyte
apoptosis when the TCR binds self Ag/MHC with sufficient avidity to
result in positive selection. Importantly, inhibition of glucocorticoid
synthesis did not cause a decrease in cell recovery from thymi
expressing nonselecting MHC-encoded molecules, demonstrating that TCR
occupancy is necessary for cell death under these conditions.
In this report we have assessed the role of glucocorticoids in
thymocyte development in nontransgenic mice. Unexpectedly, inhibition
of glucocorticoid biosynthesis caused an increase in thymocyte
apoptosis, a decrease in cell recovery, and an increase in cell surface
markers of activation that was TCR-dependent and directly
proportional to the number of MHC-encoded molecules present. Moreover,
in the absence of TCR ligands, inhibition of corticosteroid production
actually enhanced thymocyte survival. These results demonstrate that
the fraction of thymocytes that recognize self Ag/MHC with biologically
significant avidity is large and form the basis of a model in which
glucocorticoids inhibit activation (and therefore both positive and
negative selection) of thymocytes in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6), C57BL/10 (B10), B10.BR, and B10.D2 mice were
obtained from the Developmental Therapeutics Program, National Cancer
Institute (Frederick, MD), and were used to generate timed pregnant
animals. Males were removed from females after 16 h, and the day
of separation was counted as day 0 of gestation. Mice in which
2m expression has been eliminated by
homologous recombination
(2m-/-) were bred in
our facility and had been backcrossed to C57BL/6 for at least six
generations (7). C57BL/6
TCRtm1Mom mice
(B6.TCR-/-) (8) were obtained
from The Jackson Laboratory (Bar Harbor, ME). Fetal thymic organ
cultures (FTOC) were performed in serum-free Nutridoma-SP medium
(Boehringer Mannheim, Indianapolis, IN) supplemented with 20 mM HEPES,
100 µM nonessential amino acids, 1 mM sodium pyruvate, and 50 µM
2-ME. Metyrapone was purchased from ICN Biochemicals (Costa Mesa, CA).
The Abs Y3P (anti-I-Ab) (9) and
MKD6 (anti-I-Ad) (10) were
purified by affinity chromatography. Abs used for flow cytometry,
anti-CD4, anti-CD8, anti-TCR, anti-MHC, anti-CD5,
and anti-CD69, were purchased from PharMingen (San Diego,
CA).
Fetal thymic organ cultures
FTOC were performed as described (5). Fetal day 17 thymi were separated into lobes and cultured with 200–225 µg/ml of freshly diluted metyrapone or ethanol as a control on a Millipore filter (Bedford, MA) floating on a Gelfoam sponge in complete serum-free Nutridoma-SP medium (Boehringer Mannheim). Metyrapone, a selective inhibitor of the enzyme P450c11, blocks the conversion of biologically inactive deoxycorticosterone to the active form, corticosterone (4). In some experiments 10-9 M corticosterone, diluted in ethanol, was added. Cultures were conducted in either 1.5 ml of medium/well in 12-well plates or 3 ml of medium in six-well plates. Abs, 30 µg of Y3P (anti-I-Ab) or MKD6 (anti-I-Ad), or PBS as a control were added to cultures by dropping directly onto the thymi. Lobes were harvested after either 24 h (for TUNEL assay) or 3 days of culture, and single cell suspensions were prepared for counting and analyzed for CD4, CD8, TCR, CD5, CD69, and MHC expression by flow cytometry.
TUNEL assay
A modified form of the TUNEL assay (11) was used to detect fragmented DNA in apoptotic thymocytes (3). Briefly, thymocytes were incubated with anti-CD4-Red 670- and anti-CD8-PE-labeled Abs before formaldehyde fixation and permeabilization with 0.1% Triton X-100/0.1% sodium citrate, then subjected to a modified in situ nick translation using fluorescein-dUTP (Boehringer Mannheim). Labeled cells were visualized by flow cytometry with a FACScan. To determine the amount of apoptosis in the double-positive (DP) population, thymocytes were gated for expression of both CD4 and CD8 and analyzed for dUTP-FITC incorporation. The percent specific apoptosis was calculated by the formula: Percent specific apoptosis = [(experimental apoptosis - spontaneous apoptosis)/(100 - spontaneous apoptosis)] x 100.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blockade of glucocorticoid synthesis in FTOC of thymi from TCR
transgenic mice has been shown to result in the death of
thymocytes that normally undergo positive selection (6).
To assess the contribution of endogenously produced glucocorticoids to
the survival of thymocytes with an unrestricted range of TCR Ag
specificities, we performed FTOC with B10 fetal day 17 thymi, which
consist largely of TCR +
CD4+CD8+ DP thymocytes,
cultured in medium alone or with metyrapone to inhibit corticosterone
production. After 3 days the thymi were harvested, counted, and
evaluated for expression of CD4 and CD8. Culture in medium alone
resulted in the recovery of 74.7 ± 12 x
104 DP thymocytes/lobe, whereas 38.9 ±
6.0 x 104 DP thymocytes/lobe were recovered
from thymi cultured in the presence of metyrapone (a 52% decrease;
Fig. 1
). The decrease in DP thymocytes
was reflected in decreased numbers of mature CD4+
thymocytes that developed in these cultures (14.9 ± 2.8 x
104 vs 8.5 ± 0.7 x
104). The number of
CD4-CD8- thymocytes was
similar in the two groups (10.6 ± 2.5 x
104 vs 8.5 ± 1.5 x
104). As we have previously noted, replacement of
corticosterone with physiologic levels (10-9 M)
of free corticosterone largely reversed the effect of metyrapone
(63.4 ± 9.7 x 104 DP
thymocytes/lobe).
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If the decrease in cell recovery caused by the inhibition of
endogenous glucocorticoid production was in fact due to TCR occupancy
unopposed by glucocorticoid signaling, one would expect that cell loss
under these conditions would be reduced by decreasing the number of
available ligands (and thus TCR occupancy). It is possible to vary the
number of MHC-encoded molecules available for Ag presentation by using
C57BL H-2 congenic strains of mice. The level of MHC expression
reflects gene copy number, and it has been shown that both MHC class I-
and class II-mediated positive and negative selection are sensitive to
MHC gene dosage (12, 13, 14, 15). MHC-congenic animals differ in
the number of different MHC-encoded molecules they express and,
therefore, in the quantity and array of potential TCR ligands. That is,
as the number of MHC molecules increases, so will the concentration of
a given Ag/MHC TCR ligand. Moreover, as the number of different MHC
molecules increases, so will the number of unique Ag/MHC complexes.
B10.D2 (H-2d) mice express the full complement of
MHC-encoded molecules, with three class I gene products (K, D, and L)
and two MHC class II gene products (I-A and I-E) (16).
H-2k haplotype (B10.BR) mice do not express an L
allele (17) and therefore have four distinct MHC
molecules. B10 (H-2b) mice also do not express an
L allele and in addition have a deletion in the 5' portion of the gene
encoding the -chain of the I-E molecule, so that the only MHC class
II molecule they express is encoded by I-A (18).
Therefore, the number of different MHC-encoded molecules expressed by
these otherwise genetically identical animals varies from three (B10)
to five (B10.D2). FTOC of day 17 thymi from these mice was performed in
the absence or the presence of metyrapone. To compare the results from
multiple independent experiments, the data are expressed as thymocyte
recovery in the presence of metyrapone compared with that observed with
B10 thymi, which were included in each experiment. There was indeed a
hierarchy of DP thymocyte loss when corticosterone biosynthesis was
inhibited; the relative effect was B10.D2 (H-2d;
Ld+, I-E+) > B10.BR
(H-2k; Ld-,
I-E+) > B10 (H-2b;
Ld-, I-E-; Fig. 2). To further restrict the diversity of
TCR ligands, thymi were tested from H-2b mice in
which the 2m locus has been disrupted by
homologous recombination
(2m-/-) and which
therefore do not express MHC class I molecules (7, 19).
For these thymi, which express only a single MHC-encoded molecule
(I-A), the decrease in cell recovery was substantially less than that
observed with B10 thymi. Therefore, cell loss due to inhibition of
glucocorticoid synthesis varies directly with the number of MHC-encoded
molecules expressed.
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To determine whether the decrease in cell recovery caused by
inhibition of glucocorticoid synthesis was due to enhanced cell death,
apoptosis of DP thymocytes in FTOC was determined. After 24 h of
culture in the absence or the presence of metyrapone, thymi were
harvested, and thymocyte apoptosis was determined by flow cytometry
using a modified TUNEL assay to detect nicked or fragmented DNA
(6). Culture in metyrapone reproducibly induced
substantial apoptosis in B10.D2 thymi, while having only a small effect
in 2m-/- thymi (a
representative experiment is shown in Fig. 3A). Specific apoptosis was
determined by subtracting the percentage of
TUNEL+ thymocytes in the medium control from that
observed in cultures with metyrapone. On the average, specific
apoptosis of DP thymocytes induced by metyrapone in the
2m-/- thymi was 2.2%
(±0.6%), whereas in B10 thymi it was 5.4% (±1.2%).
Metyrapone-induced specific apoptosis of DP cells was even greater in
B10.D2 thymi (13.3 ± 2.8%). Therefore, just as for cell
recovery, induction of cell death by inhibition of glucocorticoid
production varied in direct proportion to the number of different
MHC-encoded molecules. To eliminate any possibility of TCR occupancy by
conventional Ag/MHC ligands, day 17 fetal thymi from
H-2b
2m-/- mice
were cultured with or without metyrapone in medium alone or in medium
containing mAbs to I-Ab (expressed by B10 mice)
or I-Ad (an irrelevant Ab control; Fig. 4). Culture for 3 days in metyrapone
resulted in recovery of 76% of the cells compared with culture in
medium alone. Addition of anti-I-Ad to
metyrapone cultures had no effect (81% recovery). In contrast, when
the only classic MHC-encoded molecule, I-Ab, was
blocked with Ab, metyrapone caused no decrease in thymocyte recovery.
In fact, there was a reproducible increase in thymocyte recovery (134%
of medium alone). Therefore, in the absence of TCR ligands, prevention
of glucocorticoid biosynthesis did not decrease and, in fact, enhanced,
thymocyte survival.
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Although the relationship between MHC expression and the effect of
corticosteroid withdrawal on thymocyte survival indicated that
glucocorticoids play an important role in the survival of cells
recognizing self Ag/MHC, the actual number of cells affected by
metyrapone was larger than would be predicted based upon the number of
CD4+CD8+ cells that
normally undergo positive selection (estimated to be 3–4%)
(20). Rather, the observation that TCR engagement by self
Ag/MHC appears to result in substantial apoptotic death and decreased
cell recovery when glucocorticoid production is inhibited suggests that
a large number (
50%) of thymocytes express TCRs with biologically
relevant avidity for self Ag/MHC. An independent means of testing this
is to measure cell surface levels of CD5, a molecule whose expression
is dependent upon TCR-mediated signaling and whose up-regulation on
immature thymocytes is an early and sensitive marker of even low
(nonselecting) avidity TCR/ligand interactions (21, 22).
Two different methods were used to assess the effect of diminishing
glucocorticoid signaling on DP thymocyte activation. First, thymi from
2m-/- (one MHC
molecule) and B10.A mice (five MHC molecules) were compared (Fig. 5A). As previously noted, CD5
levels increase on DP, but not on
CD4+CD8-, thymocytes as a
function of MHC expression, presumably reflecting low avidity TCR
interactions (22). Fetal thymi from
2m-/- and B10.A mice
were cultured with or without metyrapone, and CD5 expression was
determined 18 h later (Fig. 5B). The low level of CD5
expression on 2-/- DP
thymocytes did not appreciably change in the presence of metyrapone,
indicating that inhibiting glucocorticoid production has little effect
on CD5 expression when there is minimal TCR occupancy. In contrast, CD5
levels on B10.A DP thymocytes increased 
40% in the presence of
metyrapone (CD5 mean fluorescence intensities were 1037 ± 118 in
medium (n = 12) and 1448 ± 105 with metyrapone
(n = 6)). In other experiments, up-regulation of CD5 on
DP thymocytes was found as early as 8 h after adding metyrapone, a
time at which there was no detectable apoptosis, demonstrating that the
increase in CD5 expression was not the result of selective survival of
a thymocyte subpopulation (data not shown). To determine whether the
increase in CD5 expression did indeed depend upon TCR occupancy, a
comparison was made between cells from B6 thymi and those from thymi
from B6 mice lacking TCR (B6.TCR-/-).
Thymocytes from these animals express a pre-TCR, which allows them to
progress to the DP stage of development, but do not undergo selection
because they lack an TCR (8). Treatment of
TCR-/- thymi with metyrapone for 24 h
had no effect on DP thymocyte CD5 expression (Fig. 5C). In
contrast, metyrapone reproducibly increased the levels of CD5 on DP
thymocytes from TCR-expressing mice, demonstrating that a TCR
capable of recognizing Ag/MHC must be present for a decrease in
glucocorticoids to cause thymocyte activation. For an independent
approach to this issue, DP thymocytes from transgenic mice expressing
antisense GR transcripts, and thus hyporesponsive to glucocorticoids
(3), were analyzed for CD5 expression (Fig. 6). As with inhibition of glucocorticoid
synthesis, expression of the GR antisense transgene resulted in
up-regulation of CD5 expression on
CD4+CD8+ thymocytes. It is
interesting that the CD5 level on all DP thymocytes increased when
glucocorticoid synthesis or responsiveness was inhibited, suggesting
that TCRs on all thymocytes may have at least some degree of
biologically significant avidity for any MHC-encoded molecule
regardless of the specific peptide Ag it binds. Together, these results
demonstrate that reduction in endogenous glucocorticoid production or
responsiveness to glucocorticoids leads to an increase in TCR-mediated
activation of DP cells by endogenous Ag/MHC.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This issue has recently been revisited by a number of groups using
different experimental approaches, and the consensus is that a sizable
fraction of the preselection TCR repertoire is, in fact, capable of
recognizing Ag/MHC. For example, addition of a single peptide Ag to
cultured thymi from TAP1-/- mice (which cannot
themselves generate self peptides that bind to MHC class I molecules)
caused the generation of a small, but measurable, population of
CD4-CD8+ cells
(26), as did the addition of 2m
and a single peptide to cultures of
2m-/- thymi
(27). In both cases, mixtures of peptides were more
efficient than single peptides. Another approach that analyzed the
anti-MHC class II repertoire was to generate transgenic mice that
expressed only a single MHC class II molecule,
I-Ab, covalently bound to an antigenic peptide
(28). This resulted in positive selection of a relatively
large number of CD4+ thymocytes. The peripheral
CD4+ T cells in these animals had a diverse
repertoire, as assessed by V expression, and a very high percentage
of T cell hybridomas generated from these cells responded to
I-Ab plus unknown self peptides or allogeneic
MHC-encoded molecules. The authors concluded that the TCR repertoire is
inherently biased toward MHC molecules, and that a relatively large
number of thymocytes do, in fact, recognize self peptides/MHC with
biologically significant avidity. They suggested that these cells are
not apparent in normal animals after positive selection on a low to
moderate avidity peptide/MHC combination because they are subsequently
deleted on a cross-reactive, but higher avidity, ligand. T cell
reactivity has also been studied in mice that lack the I-A -chain
and therefore express only an abnormal MHC class II molecule consisting
of an I-A homodimer (29). The finding that T cells from
these mice, which developed in the absence of MHC class II
heterodimers, nonetheless had a high frequency of cells that responded
to normal allogeneic class II molecules was taken to mean that the
germline TCR repertoire has been selected for MHC reactivity.
Several recent studies that attempted to directly analyze the preselection TCR repertoire. In one case, CD4+ T cell hybridomas were made from anti-TCR-stimulated thymi from MHC class I/II-negative mice (30). The frequency of MHC-reactive hybridomas was high, with 4.4% of the cells responding to a given MHC class II molecule, similar to the frequency of control hybridomas responding to allogeneic MHC. More than 30% of the cells responded to at least one of the eight MHC haplotypes tested. Based upon these results and the assumption that anti-MHC class I cells should arise with similar frequency, it was estimated that 20–30% of thymocytes in an outbred mouse might be autoreactive. In another study, the frequency of preselection thymocytes capable of responding to MHC was determined using a short term thymic reaggregate culture system (22). It was found that 24 h after exposure to MHC+ stroma, 15% of thymocytes expressed CD69. Using CD5 as a measure of activation, it was reported that 11% of cells responded to I-Ab, 10% responded to H-2Kb and Db, and 19% responded when both were present. Furthermore, while CD5 was not expressed on fresh DP thymocytes from mice lacking MHC molecules, over 20% of DP cells from mice expressing either MHC class I or I-Ab were positive for CD5, and it was mentioned that up to 50% were CD5+ in mice expressing the MHC class II I-E molecule.
The data in the present study indicate that glucocorticoids interfere
with the activation of thymocytes with low, but biologically relevant,
avidity for self Ag/MHC, as reflected in lowered levels of CD5. The
up-regulation of CD5 by metyrapone did not occur in the absence of a
mature TCR, indicating that signaling via CD4 or CD8 alone cannot
account for this effect. However, the data do not rule out a
supplementary role for signaling via these molecules, either
independent of the TCR signal or, more likely, in their capacity as TCR
coreceptors. Glucocorticoids are well known to potently antagonize
activation of mature T cells and inhibit transcriptional activation of,
among other gene products, cytokines such as IL-1, IL-2, IL-4, and
IFN-
(31). There are a variety of distinct mechanisms
by which glucocorticoids may mediate these effects (reviewed in Ref.
32). The occupied GR may bind to a response element in the
regulatory region of a target gene and repress transcription.
Alternatively, the GR may interfere, by direct or indirect physical
interactions, with the activity of other transcription factors such as
AP-1. It has also been found that glucocorticoids up-regulate the
expression of I
B, sequestering NF-B in the cytosol and decreasing
its transcriptional activity (33, 34), although direct
interactions between the GR and NF-B p65 may also contribute to this
inhibition (35, 36). Yet another mechanism for inhibitory
cross-talk between the GR and a host of other transcription factors is
competition for coactivators of gene transcription such as p300/CBP
(37). Finally, it has been reported that glucocorticoids
may inhibit some proximal events in TCR signaling, such as
phosphatidylinositol turnover and Ca2+ flux
(38).
The conventional model of thymocyte selection holds that the large majority of thymocytes die in the thymus because their TCRs fail to bind self Ags/MHC with biologically significant avidity (2). Only a small fraction of thymocytes bind self ligands with sufficient avidity to either be rescued from this default "neglect" death pathway or be induced to undergo activation-induced apoptosis. As detailed above, it is becoming clear that a substantial fraction of thymocytes do, in fact, recognize self Ag/MHC with sufficient avidity to receive activation signals, although only a small number actually traverse the entire process to become mature SP thymocytes. To accommodate this and our results with glucocorticoids, we suggest the following relationship between TCR avidity for self Ag/MHC and cell fate. In this model, as with the conventional model, thymocytes bearing TCRs with high avidity are negatively selected, those with intermediate avidity are positively selected. There is a large additional population of cells, however, with TCRs that recognize self Ag/MHC with low, but biologically significant, avidity (sufficient to cause up-regulation of CD5, for example). The activation of all thymocytes in all TCR avidity groups is inhibited by glucocorticoids. In the case of cells with intermediate avidity, this would prevent them from expressing whatever gene products would otherwise be induced to cause apoptosis (negative selection) and allow differentiation (positive selection) to proceed. For low avidity thymocytes, corticosteroids would prevent expression of gene products necessary for differentiation (positive selection). As glucocorticoid levels decrease, the biological consequences of receptor occupancy are enhanced, as reflected by increased expression of CD5 and CD69, so that thymocytes signaled via lower avidity interactions in the absence of glucocorticoids respond like thymocytes signaled via higher avidity interactions in the presence of glucocorticoids. As a result, thymocytes that would be positively selected in the presence of glucocorticoids become negatively selected in their absence, and cells with low avidity that would normally be inadequately activated, and thus be lost, would progress to the SP stage of development. In vivo, the ultimate consequence of this would be the selection of T cells whose receptors would, on the average, have lower avidity for self Ag/MHC than the normally selected repertoire.
This model is consistent with a variety of observations. Inhibition of
glucocorticoid production in FTOC makes DP thymocytes exquisitely
sensitive to anti-TCR-mediated deletion (5). In a more
physiological setting, lack of thymus-derived corticosteroids results
in the TCR-mediated deletion of cells that are otherwise positively
selected because they recognize self Ag/MHC with intermediate avidity
(6). Finally, reduction in thymocyte GR levels, which
renders them hyporesponsive to glucocorticoids, results in loss of
MHC-dependent positive selection of T cells bearing particular Vs
and markedly reduces the autoimmunity and lymphoproliferative disease
of MRL-lpr/lpr mice (39). Thus, the effect of
glucocorticoids on thymocyte development can be viewed as analogous to
their effect on peripheral T cells. They act as immunosuppressants by
preventing expression of activation-induced genes. In the case of
peripheral T cells, this activity results in inhibition of effector
function. In the case of thymocytes, this activity determines what
range of TCR avidities for self Ag/MHC will fall in the positive
selection window (i.e., affects development). It is an interesting
speculation that thymic production of corticosteroids may have evolved
to ensure that T cells surviving selection have sufficient avidity for
self MHC to respond to Ags even in the face of stress-induced
glucocorticoid levels, such as occur during acute illness.
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Acknowledgments |
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2m-/- mice, Jeff Bluestone for helpful
discussions, and Allan Weissman, Ronald Schwartz, Ronald Germain, and
Richard Hodes for critical review of the manuscript. |
Footnotes |
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2 Abbreviations used in this paper: Ag/MHC, Ag in association with self-MHC-encoded molecules; GR, glucocorticoid receptor; FTOC, fetal thymic organ culture; DP, double positive.
Received for publication February 9, 1999. Accepted for publication May 24, 1999.
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J. A. Brewer, B. P. Sleckman, W. Swat, and L. J. Muglia Green Fluorescent Protein-Glucocorticoid Receptor Knockin Mice Reveal Dynamic Receptor Modulation During Thymocyte Development J. Immunol., August 1, 2002; 169(3): 1309 - 1318. [Abstract] [Full Text] [PDF]
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T. Berki, L. Palinkas, F. Boldizsar, and P. Nemeth Glucocorticoid (GC) sensitivity and GC receptor expression differ in thymocyte subpopulations Int. Immunol., May 1, 2002; 14(5): 463 - 469. [Abstract] [Full Text] [PDF]
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O. Lechner, H. Dietrich, G. J. Wiegers, M. Vacchio, and G. Wick Glucocorticoid production in the chicken bursa and thymus Int. Immunol., June 1, 2001; 13(6): 769 - 776. [Abstract] [Full Text] [PDF]
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F. Van Laethem, E. Baus, L. A. Smyth, F. Andris, F. Bex, J. Urbain, D. Kioussis, and O. Leo Glucocorticoids Attenuate T Cell Receptor Signaling J. Exp. Med., April 2, 2001; 193(7): 803 - 814. [Abstract] [Full Text] [PDF]
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J. F. Torres-Roca, J. W. Tung, D. R. Greenwald, J. M. Brown, L. A. Herzenberg, L. A. Herzenberg, and P. D. Katsikis An Early Oxygen-Dependent Step Is Required for Dexamethasone-Induced Apoptosis of Immature Mouse Thymocytes J. Immunol., November 1, 2000; 165(9): 4822 - 4830. [Abstract] [Full Text] [PDF]
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F. Livak, D. B. Burtrum, L. Rowen, D. G. Schatz, and H. T. Petrie Genetic Modulation of T Cell Receptor Gene Segment Usage during Somatic Recombination J. Exp. Med., October 16, 2000; 192(8): 1191 - 1196. [Abstract] [Full Text] [PDF]
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J. Zhang, K. Mikecz, A. Finnegan, and T. T. Glant Spontaneous Thymocyte Apoptosis Is Regulated by a Mitochondrion-Mediated Signaling Pathway J. Immunol., September 15, 2000; 165(6): 2970 - 2974. [Abstract] [Full Text] [PDF]
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 W. Savino and M. Dardenne Neuroendocrine Control of Thymus Physiology Endocr. Rev., August 1, 2000; 21(4): 412 - 443. [Abstract] [Full Text] [PDF]
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U. Bommhardt, Y. Scheuring, C. Bickel, R. Zamoyska, and T. Hunig MEK Activity Regulates Negative Selection of Immature CD4+CD8+ Thymocytes J. Immunol., March 1, 2000; 164(5): 2326 - 2337. [Abstract] [Full Text] [PDF]
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