By
From the * Institut National de la Santé et de la Recherche Médicale (INSERM) U429, Hôpital
Necker-Enfants Malades, F-75743 Paris, France; INSERM U345 and § U373, CHU Necker,
F-75730 Paris, France; and the
Basel Institute for Immunology, CH-4005 Basel, Switzerland
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Abstract |
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Intracellular signals emanating from cytokine and antigen receptors are integrated during the
process of intrathymic development. Still, the relative contributions of cytokine receptor signaling to pre-T cell receptor (TCR) and TCR-mediated differentiation remain undefined. Interleukin (IL)-7 interactions with its cognate receptor complex (IL-7R coupled to the common
cytokine receptor
chain,
c) play a dominant role in early thymopoiesis. However,
/
T
cell development in IL-7-, IL-7R
-, and
c-deficient mice is only partially compromised, suggesting that additional pathways can rescue
/
T lineage cells in these mice. We have investigated the potential interdependence of
c- and pre-TCR-dependent pathways during intrathymic
/
T cell differentiation. We demonstrate that
c-dependent cytokines do not
appear to be required for normal pre-TCR function, and that the rate-limiting step in
/
T
cell development in
c
mice does not involve TCR-
chain rearrangements, but rather results
from poor maintenance of early thymocytes. Moreover, mice double mutant for both
c and
pre-T
show vastly reduced thymic cellularity and a complete arrest of thymocyte differentiation at the CD44+CD25+ cell stage. These observations demonstrate that the pre-TCR provides the
c-independent signal which allows
/
T cell development in
c
mice. Thus, a series of overlapping signals derived from cytokine and T cell receptors guide the process of
/
thymocyte development.
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Introduction |
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The common cytokine receptor chain (
c)1 forms a
critical functional component of the receptors for IL-2,
IL-4, IL-7, IL-9, and IL-15 (for a review, see reference
1). Naturally occurring mutations in
c are responsible
for X-linked severe combined immunodeficiency disease
(SCIDX1) in humans, characterized by a complete absence of T and NK cells, while B cells are present (for reviews,
see references 2 and 3). Targeted deletion of
c in mice also provokes a wide variety of defects in lymphoid development, including a complete absence of NK cells,
/
T
cells, and gut-associated lymphoid tissue (4). Like SCIDX1
patients,
c
mice have some mature peripheral B cells, but
these mice also show a remarkable degree of
/
T cell development (4). These data demonstrate the important
role of
c-dependent signals in lymphopoiesis, but also suggest that fundamental differences exist between the mechanisms that permit
/
T cell development in humans and mice.
Analysis of single cytokine- or cytokine receptor-deficient mice has identified which c-dependent signals are
responsible for some of the observed developmental defects
seen in
c
mice. NK cell differentiation is critically linked
to the expression of the IL-2R
chain (9), thereby implicating IL-2- and/or IL-15-mediated signaling pathways in
the development of these cells. Since IL-2 mutant mice develop NK cells (10), this suggests that IL-15 (or another IL-2R
-binding ligand) is required for the differentiation of
this subset (for a review, see reference 11). In contrast, the
defect in
/
T cell development in
c
mice appears
strictly IL-7 dependent (12). Moreover, since IL-7 was initially identified as an important growth factor for T and B
cell precursors (13, 14), this would explain the severely reduced thymic cellularity and defects in bone marrow B cell
and intrathymic precursors found in IL-7 and IL-7R
mutant mice (15).
The biological consequences of c-dependent receptor
engagement for
/
T cell development include signals
which can potentially promote cell survival, proliferation,
and/or differentiation. Experimentally, however, it has
been difficult to conclusively define which of these processes are adversely affected in the absence of
c. In theory,
the absence of IL-7 signaling in
c
mice could potentially
limit thymocyte development by affecting the survival and/
or expansion of intrathymic precursors, or by reducing the
efficiency of the recombination process. Evidence for the
latter has been suggested by reports that the expression of
functionally rearranged TCR-
/
transgenes in
c- or IL-7R
-deficient mice augmented total thymocyte numbers
(18, 19). However, enforced expression of the antiapoptotic factor Bcl-2 could also rescue
/
T cell development in these mice (20), supporting a major role for IL-7/
c signaling in promoting a survival program. In all of
these cases, thymic reconstitution was not complete, suggesting either that IL-7/
c influences both survival and recombination, or that intrathymic development involves additional mechanisms which are critically dependent on this
receptor complex, such as the efficiency of pre-TCR assembly or function.
In this report, we have analyzed the potential interplay
between c-dependent cytokine pathways and signaling
through the pre-TCR for
/
T cell development.
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Materials and Methods |
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Animals and Cell Preparation.
Antibodies and Immunofluorescence Analysis.
The following mAbs were used as conjugates to fluorescein (FITC), phycoerythrin (PE), Tricolor (TRI), or biotin: CD3 (145-2C11), CD4 (GK1.5), CD8Cell Cycle Analysis.
In vivo labeling of S phase cells with bromo-deoxyuridine (BrdU; Sigma) was performed by a single intraperitoneal BrdU injection at a dose of 50 mg/kg body wt 15 min before killing. Thymocyte subsets were sorted using a FACSVantage®, and cells incorporating BrdU were identified as described previously (27) using an FITC-coupled anti-BrdU mAb (Becton Dickinson) and a FACScan® flow cytometer.Intracellular Staining for Bcl-2, pT, and TCR-
Chains.
TCR- Rearrangements.
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Results |
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We analyzed intrathymic development in c
mice
to better define the nature of any developmental blocks
resulting from the absence of
c. When comparing absolute numbers of CD4
CD8
double negative (DN) cells,
CD4+CD8+ double positive (DP) cells, and CD4+CD8
and CD4
CD8+ single positive (SP) mature T cells, the
DN and CD8 SP populations were more affected by the
absence of
c (Fig. 1 A). While both DP and CD4 SP cells
were reduced by 15-20-fold (similar to the overall decrease
in thymic cellularity), the DN and CD8 SP subsets were
reduced almost 40-fold. The DN compartment contains
both early thymocyte precursors (CD3
) as well as mature
CD3+ TCR-
/
and TCR-
/
cells. While
/
T cells
do not develop in
c
mice (4, 28), DN
/
T cells are
present (32). To specifically evaluate
c
TCR
thymocyte
progenitors, we studied CD44 and CD25 expression on CD3
CD4
CD8
(TN) thymocytes by four-color immunofluorescence analysis. Previous studies have demonstrated
that these cells differentiate through the following stages:
CD44+CD25
CD44+CD25+
CD44
CD25+
CD44
CD25
(33; for a review, see reference 34).
|
Compared with controls, immature thymocytes from c-deficient mice showed altered patterns of CD44 and CD25
expression (Fig. 1 B). The most immature CD44+CD25
TN cells, which can also give rise to B cells, NK cells, and thymic dendritic cells (35; for a review, see reference 36), were found in normal frequency, but were clearly reduced
in absolute numbers. More striking was the relative accumulation of cells at the CD44+CD25+ stage, which were
almost twofold increased in frequency compared with controls (Fig. 1 B). Moreover, absence of
c was associated with a clear defect in the development of cells beyond the
CD44+CD25+ stage. Percentages of CD44
CD25+ and
CD44
CD25
cells were reduced by a factor of 2 and
were markedly reduced (>100-fold) in absolute numbers
(Fig. 1 B).
The
block in thymocyte maturation seen in c
thymi could result from abnormal differentiation, reduced cell survival,
and/or proliferative defects. The ability of
c
thymocyte
precursors to incorporate the analogue BrdU was used as a
measure of intrathymic proliferation. The number of cells in S phase of the cell cycle was analyzed after a single injection of BrdU (Fig. 2 A). Only a fraction of the immature
thymocytes are labeled under these conditions, and it is clear
that T cell precursors in
c
mice show defects in proliferation, as both CD44+CD25
and CD44+CD25+ cells have
markedly reduced BrdU incorporation relative to their
c+
counterparts (the CD44
CD25+ and CD44
CD25
subsets
were not analyzed in
c
thymi due to their extremely
small absolute numbers; these subsets were normally labeled in
c+ controls [data not shown]). DP cells from
c
mice were similarly affected.
|
Decreased BrdU incorporation in c
thymocyte precursors could result from decreased survival of these cells.
c-dependent cytokines have been shown to promote lymphocyte survival by maintaining levels of antiapoptotic
factors such as Bcl-2 and Bcl-XL (37, 38). Therefore, we
examined intracellular levels of Bcl-2 in immature thymocytes from
c
mice and their control
c+ littermates.
c
precursors had markedly reduced levels of Bcl-2 compared with their
c+ counterparts (Fig. 2 B). Moreover,
c
cells showed elevated cell surface staining with Annexin V
(Fig. 2 C), indicating commitment to the apoptotic process
(39). Taken together, these results are consistent with a
critical role for
c cytokines in the survival and expansion
of thymocyte precursors, the absence of which could account in part for their reduction in absolute cell numbers.
Having demonstrated a major role for c in the most immature T cell precursors, we next addressed the impact of the
c mutation on pre-TCR signaling. The activity of the pre-TCR is
presumed to begin at the CD44
CD25+ cell stage when
functional TCR-
chain rearrangements are achieved (24,
40). The role of
c-dependent cytokines in pre-TCR function has not been previously examined, although it has
been suggested that cytokines (like IL-7) may play a role in
the expansion of pre-T cells as they differentiate towards
the DP stage. This hypothesis gains support from the fact
that CD25+ intrathymic precursors express IL-7R
(41).
Moreover, the defect in intrathymic maturation in
c
mice and the marked depletion in CD44
CD25+ and
CD44
CD25
cells could be the consequence of abnormal
pre-TCR assembly or function.
Although the pre-TCR has its main role in the transit of
early /
T cell precursors to the DP stage (for a review,
see reference 42), additional mechanisms independent of
the pre-TCR have been described which can permit the
generation of DP cells in vivo (43, 44). These include effects mediated by
/
TCRs and via
/
TCRs due to
early rearrangements at the TCR-
locus. To focus on the
pre-TCR-mediated pathway and to exclude these alternative pathways of DP cell generation, we crossed
c
mice
(which lack
/
T cells) with TCR-
/
mice (23; to
eliminate TCR-
expression). Thymocyte differentiation was examined in these double mutants. Introduction of the
TCR-
mutation did not further alter the pattern of differentiation of thymocytes to the DP stage compared with
c
mice or further diminish their total thymic cellularity (Fig. 3 A). These results demonstrate that early TCR-
rearrangements do not play a major role in the differentiation
of DP cells in
c
mice.
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Pre-TCR signaling results in selection, i.e., the preferential expansion of early thymocytes expressing a single,
functionally rearranged TCR-
chain (for a review, see
reference 45).
selection was assessed in control,
c
, and
pT
/
thymocytes by intracellular staining of TCR-
expression (Fig. 3 B). As reported previously (44), pT
/
mice show clear defects in
selection as demonstrated by
decreased intracellular levels of TCR-
chains in DP thymocytes compared with control mice. In contrast,
c
DP
thymocytes demonstrated intracellular TCR-
levels comparable to controls (Fig. 3 B, and see below).
We also considered that pre-TCR function might be affected due to reduced synthesis of TCR- chains, thereby
limiting the assembly of a pre-TCR complex. Since TCR-
V(D)J rearrangements are detected at the CD44
CD25+
cell stages (40, 46), and previous studies have suggested that
IL-7/CD127/
c interactions may be important for RAG
expression during the TCR recombination process (for a
review, see reference 47), we tested whether defects in
TCR-
rearrangements were responsible for the developmental block in
c
thymi.
c
mice were bred with mice
bearing a functionally rearranged TCR V
8.2 transgene
(Tg) (48), and thymocyte development was analyzed. As
shown in Fig. 3 C,
c
/TCR-
Tg+ mice demonstrated
no change in the distribution or absolute numbers of thymocytes compared with non-Tg
c
littermates. The lack
of discernible effect of the TCR-
Tg in
c
mice was not
due to an inability to express this TCR, as surface levels of
V
8.2 were equivalent in
c+ and
c
total thymocytes
and CD25+ thymocyte precursors (data not shown). These
results suggest that defects in the TCR-
chain rearrangement process are not rate limiting in the absence of
c, and
are consistent with a role for
c in promoting survival and
proliferation of early thymocytes.
To address the relative
interdependence of c and pre-TCR signals, we intercrossed the
c and pT
null strains to generate mice lacking
both these molecules. Thymocyte development was analyzed in 3-4-wk-old double mutant mice (
c
/pT
/
) as
well as single mutants for
c or pT
and wild-type mice.
Consistent with previous reports (5, 24), the thymi from
either c or pT
mutant mice demonstrated a reduction in
the size (data not shown) and cellularity (20-30-fold; Fig. 4).
In contrast,
c
/pT
/
thymi were severely hypoplastic
and showed a drastic reduction (~4,000-fold) in absolute
cell numbers (Fig. 4). Thymocyte cell surface phenotype
was further characterized in these mice (Fig. 4, A and B).
pT
/
thymi showed an incomplete block in thymocyte
development with an accumulation of cells at the DN stage;
however, pT
-deficient thymocytes are capable of further
maturation to DP and SP mature cells. In marked contrast,
thymi from double mutant
c
/pT
/
mice contained
only immature DN cells (Fig. 4 A). Using CD44 and CD25
markers,
c
thymi demonstrated the characteristic incomplete block at the CD44+CD25+ to CD44
CD25+ transition (Fig. 4 B), whereas the accumulation of cells at the CD44
CD25+ stage in pT
-deficient mice coincides with
pre-TCR-mediated cellular expansion and differentiation
to the DP stage (for a review, see reference 45). Strikingly,
residual thymocytes from
c
/pT
/
mutant mice showed
a developmental block with a complete arrest of differentiation at the CD44+CD25+ stage (Fig. 4 B). To our knowledge, this is the first description of mutant mice harboring
this particular intrathymic defect. In terms of absolute cell
numbers,
c
/pT
/
thymi contained ~4 × 104 TN
precursors, all of which were CD44+, and therefore similar
to the number of CD44+ TN precursors found in
c
thymi
(Fig. 1 B). However, unlike
c
or pT
/
single mutant
mice, the arrest in thymic development in
c
/pT
/
double mutant thymi was complete, as no mature T cells
were found intrathymically or in the peripheral lymphoid
organs (data not shown, and see below). These results (a)
define a critical period of intrathymic development (the
CD44+CD25+ to CD44
CD25+ transition) in which signals delivered by
c and the pre-TCR pathways appear to
overlap, and (b) suggest that pre-TCR signals are responsible for rescue of
/
T cell development in
c
mice.
|
It would follow from these results that a pre-TCR can
form at the CD44+CD25+ stage. Although several studies
have reported the rearrangement status of early thymocyte
subsets (40, 46, 49), no studies to date have examined pre-TCR protein expression in these cells. Using reagents specific for the TCR- (29) and a newly developed antibody
against the pT
chain (30), we characterized intracellular pre-TCR components in early thymocytes from
c+ and
c
mice (Fig. 5). At the CD44+CD25+ stage, thymocytes
demonstrate uniform intracellular staining for pT
chains,
whereas the level of pT
expression increases slightly as the
cells mature to become CD44
CD25+. A small fraction of
CD44+CD25+ cells (3.0 ± 1%; n = 4) also stain intracellularly for TCR-
protein; this fraction increases to ~20% as
these cells downregulate CD44 expression (Fig. 5). TCR-
and pT
protein expression on a per cell basis was not
qualitatively or quantitatively altered in
c
thymocytes
(Fig. 5). These data conclusively demonstrate that a pre-TCR
can form during the CD44+CD25+ to CD44
CD25+ transition, a point at which intrathymic precursors express
IL-7R
/
c (41). These results suggest that
c and pre-TCR signals are independent and overlapping for intrathymic development.
|
Due to the severe reduction in thymocyte cell numbers in
c
/pT
/
mice, a PCR-based strategy (31) was used to
identify any TCR-
rearrangements present in these mutant thymi. DNA from control,
c
, or pT
/
thymi
contained abundant TCR-
V(D)J rearrangements, which
were diverse with respect to junctional sequences present
in the CDR3 region (Fig. 6; and data not shown). In contrast, rearrangements from
c
/pT
/
mutant thymi were
reduced in overall amounts, although samples derived from
independent thymi contained multiple and different bands,
indicating rearrangements to different J
segments (Fig. 6).
Sequence analysis of these PCR products revealed unique
V
CDR3 sequences, suggesting that the observed reduction in rearrangements was related to the paucity of absolute cell numbers and not to a restricted rearrangement potential (data not shown). Finally, TCR-
rearrangements
were absent from the spleens of
c
/pT
/
double mutant mice, demonstrating that the intrathymic block in
/
T cell development was complete and that no mature
/
T cells were produced that could seed the peripheral lymphoid organs (Fig. 6).
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![]() |
Discussion |
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/
T cells are generated intrathymically through a series of developmental steps involving survival, expansion,
and differentiation of immature precursor cells. The
c
chain plays a critical role in this process, primarily by relaying signals from stromal cell-derived IL-7 to developing
thymocytes. The essential role of IL-7 in early thymocyte
differentiation has been difficult to define because this cytokine has been postulated both to act as a trophic factor and to influence the TCR rearrangement process (for a
review, see reference 47). Moreover, deficiencies in IL-7/
IL-7R
/
c abrogate
/
T cell development, whereas
/
T cell development is permissive, suggesting either a differential role for the IL-7 receptor complex in the generation
of these two T cell subsets or the existence of compensatory pathways that rescue
/
T cells in the absence of
IL-7/IL-7R
/
c. In this report, we identify the pre-TCR
as a rescue mechanism for
/
T cell development in
c
mice. This result suggests that a model of intrathymic differentiation involves an overlapping series of signals derived
from growth factors and TCRs that guide the maturation
process (Fig. 7). This model is consistent with the permissive nature of thymocyte development in c-kit-, IL-7R
-,
c-, and pT
-deficient mice (4, 15, 24, 50), and
sheds light on the compensatory signaling pathways that
exist to insure
/
T cell differentiation in these mutant mice.
|
Before the expression of a rearranged TCR chain, immature thymocytes are maintained and proliferate in response to factors provided within the thymic milieu (for a
review, see reference 51). Although several cytokines have
been shown to act on thymic precursors, stem cell factor
(SCF) and IL-7 remain the two dominant factors that can
promote their survival and/or expansion (14, 50, 52). The
receptors for stem cell factor (c-kit) and for IL-7 (the IL-7R/
c complex) are coexpressed on early thymocytes (41, 53, 54), and proliferation of these cells is reduced in
the absence of c-kit or IL-7R
/
c (50, 55; and this report). The permissive nature of thymocyte development in c-kit
or IL-7R
/
c mutants implies redundancy in the pathways
that maintain early precursors. The hypothesis that c-kit
and IL-7R
/
c signals could compensate for each other at
this stage is strongly supported by the complete abrogation
of thymocyte development (before the CD44+CD25
cell
stage) in mice deficient in both c-kit and
c (26). Thus, for
cells up to the CD44+CD25
stage, c-kit and
c act synergistically to maintain cells before TCR rearrangements.
The essential nature of c-kit and
c signals cannot be replaced by other growth factors at this stage of development (26).
At the transition from the CD44+CD25+ stage to the
CD44CD25+ stage, rearrangements of the TCR-
chain
begin (40, 46, 49). Since IL-7- and
c-deficient thymocyte
precursors are most severely affected at this stage (55; Fig.
1 B), the failure to signal through
c could have an adverse
effect on the TCR rearrangement process. Consistent with
this hypothesis, previous studies have demonstrated that
transgenic expression of a functionally rearranged TCR-
/
(against the male-specific [HY] antigen in association with
H-2Db) could partially restore total thymocyte numbers in
c- and IL-7R
-deficient mice (18, 19). However, these
experiments failed to rule out potential effects associated
with TCR signaling under conditions of positive selection,
since increases in thymic cellularity were only observed in
H-2Db female mice. Here we show that the same TCR-
alone has no effect on thymocyte development in
c
mice. This observation strongly suggests that defective
TCR-
rearrangements alone cannot account for the abnormal
/
T cell development in the absence of
c, and
supports the idea that poor survival and reduced proliferation of the CD44+CD25+ and subsequent thymocyte subsets are the major limiting factors for
/
T cell development in these mice.
The results presented here identify the pre-TCR as an
independent and essential signal which acts in concert with
c during
/
thymopoiesis. Although in principle the failure to signal through
c could have an adverse effect on
pre-TCR assembly or function, we find that
selection
and pre-TCR-mediated expansion appear
c independent.
However, the essential role of the pre-TCR in
c
mice
is clearly illustrated by the
c/pT
double mutants. In these mice, thymocyte development proceeds only to the
CD44+CD25+ stage (thereby delimiting the role of the
c-kit pathway), and implies that further development requires either
c or pre-TCR signals. As indicated above,
c
can act via IL-7 to maintain early thymocytes at this stage
(20, 55) and might also serve to drive differentiation to
the CD44
CD25+ stage where TCR rearrangements are
ongoing (40, 46, 49). How, then, could the pre-TCR rescue
c-deficient cells at such an early stage?
To address this issue, we examined expression of TCR-
and pT
proteins in CD44+CD25+ and CD44
CD25+
thymocytes from
c+ and
c
mice. Our results clearly
demonstrate that a pre-TCR complex can potentially form
in a small subset of CD44+CD25+ cells. The expression of
a pre-TCR at this stage could thereby provide a compensatory mechanism in
c
mice to enable
/
T cell development. Moreover, the "window" of pre-TCR expression
was similar in
c+ and
c
mice. In this respect,
c and pre-TCR signals are independent and overlapping at this stage
of intrathymic development (Fig. 7).
The signaling cascades initiated from c and pre-TCRs
appear distinct.
c receptors activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT)
pathway (for a review, see reference 56), whereas the pre-TCR uses immunoreceptor tyrosine-based activation motif
(ITAM)-containing CD3 components which couple to the
src family and ZAP-70/syk family tyrosine kinases (for reviews, see references 42 and 57). How the pre-TCR mediates proliferation of late thymocyte precursors is unknown,
but our results indicate that this process does not require
c-dependent cytokines. Further work will be required to
identify the mechanism by which triggering the pre-TCR
engages the cell cycle.
Our observations provide insights into the difference between /
and
/
T cell development in IL-7/IL-7R
/
c-deficient mice (12, 17, 58). Although the pre-TCR is
capable of rescuing TCR-
/
cells in
c
mice,
/
T
cells lack an equivalent mechanism and therefore must rely
on other signals for their final intrathymic differentiation. We have previously shown that transgenic expression of rearranged TCR-
or TCR-
/
chains failed to rescue
/
T cell development in
c
mice, suggesting that
c-dependent cytokines provide the dominant signals for
/
T cell
survival and/or proliferation both intrathymically and in
the periphery (28). On the other hand, peripheral maintenance of
/
T cells requires continual TCR stimulation
(for reviews, see references 59 and 60) but appears less
c
dependent in their development.
Finally, our model suggests that differences in T cell development between human and murine c deficiency
might be related to species-specific differences in the function of c-kit, IL-7/IL-7R
/
c, or the pre-TCR. Little is
known about the specific patterns of expression of these
molecules with regard to the various stages of intrathymic
development in humans. Moreover, the documented differences between human and mouse pT
cytoplasmic sequences (61) could result in differential signaling properties
of the pre-TCR between species. Support for this model
will require further studies focusing on these pathways in
human thymocyte development.
![]() |
Footnotes |
---|
Address correspondence to James P. Di Santo, INSERM U429, Pavillon Kirmisson, Hôpital Necker- Enfants Malades, 149, rue de Sèvres, F-75743 Paris, France. Phone: 33-1-44-49-50-51; Fax: 33-1-42-73-06-40; E-mail: disanto{at}necker.fr
Received for publication 9 September 1998 and in revised form 17 November 1998.
1 Abbreviations used in this paper: BrdU, bromo-deoxyuridine; DN, double negative; DP, double positive;We thank D. Guy-Grand (Paris), M. Malissen, B. Malissen (Marseille), and H.-R. Rodewald (Basel) for stimulating discussions.
Supported by grants from the Institut National de la Santé et de la Recherche Médicale, the Association pour le Recherche sur le Cancer, and the Ligue Nationale Contre le Cancer. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche.
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