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Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß and 
T cells,
a significant number (
3 x 104 per day) of
B220+IgM+ mature B cells are exported from the
thymus of C57BL/6 mice. Of these emigrating B cells, we estimate that
at least 2 x 104 per day are cells which developed
intrathymically, whereas a maximum of 0.8 x 104
per day are cells which circulated through the thymus from the
periphery. The thymus possesses a significant number of pro-B and pre-B
cells that express CD19, VpreB, 
5, and pax-5. These B cell
progenitors were found in the thymic cortex, whereas increasingly
mature B cells were found in the corticomedullar and medullary regions.
Other lymphoid cells, including NK cells and lymphoid dendritic cells,
are not exported from the thymus at detectable levels. Thus, the thymus
contributes to the formation of peripheral pools of B cells as well as
of ß and T cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells and TCR T cells. During their tenure in the
thymus, maturing thymocytes interact with the thymic microenvironment,
which provides the appropriate cellular and/or soluble factors to
enable thymocyte proliferation, development, and selection. This
microenvironment includes several types of thymic epithelial cells,
bone marrow-derived dendritic cells, macrophages, bone marrow derived B
cells, and several mesenchymal elements. Thymic epithelial cells
produce a number of cytokines, including steel factor and IL-7, both of
which play important roles in progenitor proliferation, survival, and
commitment to the T cell lineages (1, 2). Both steel
factor and IL-7 are also critical for the maturation of B cells in the
bone marrow (3, 4, 5). In early mouse fetal life, the first seeded thymic progenitors collectively include cells capable of T or B cell maturation (6, 7, 8). In adults, the thymus is continuously seeded at a low rate. These bone marrow-derived precursors have not yet been fully characterized as to their phenotype or function. One candidate is the recently identified common lymphoid progenitor (CLP),4 which has lymphoid-restricted differentiation potential into T, B, and NK cells (9), found in adult bone marrow. The CD4lowCD44highc-Kit+ earliest thymic precursor population (10) has been shown to be capable of differentiating not only into T cells but also into NK cells, B cells, and lymphoid dendritic cells at low frequencies (10, 11, 12). Therefore, one might expect to find some B cells, NK cells, and dendritic cells maturing within and emigrating from the adult thymus.
To test this hypothesis, we analyzed recent thymic emigrants (RTEs) to
peripheral lymphoid organs. FITC was injected intrathymically to label
cells in the thymus, and at various time points after labeling, the
spleen and lymph nodes were analyzed for the presence of RTE. We found
that, in addition to ß and T cells, a significant number
(3 x 104 per day) of non-T cells were
exported from the thymus; these were
B220+IgM+ B cells. We also
demonstrated that the majority of these cells were generated from
precursors in the thymus, whereas a minority could have been derived
from circulating B cells that had entered the thymus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The congenic strains of mice, C57BL6-Ly5.2 or C57BL6-Ly5.1 mice, were used. The C57BL6-Ly5.1/Ly5.2 mice were made by crossing C57BL6-Ly5.2 with C57BL6-Ly5.1 (F1). The strains differed only at the Ly5 allele, and this difference made it possible to detect donor-derived cells. C57BL6-TCRß-deficient mice (13) were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were bred and maintained in the animal care facility at Stanford University School of Medicine and were used at 4–8 wk of age.
Labeling of thymocytes and flow cytometric analysis
The technique for in vivo intrathymic labeling of thymocytes
with FITC has been previously described (14). Briefly, 10
µl of FITC (1 mg/ml; Sigma, St. Louis, MO) was injected into both
thymic lobes of 5- to 8-wk-old C57BL/6 mice. Single-cell suspensions
were made from the spleen and the lymph nodes, including cervical,
axillary, submandibular, inguinal, brachial, and mesenteric lymph
nodes. Cells were stained with PE or allophycocyanin-conjugated
anti-IgM (clone 331; obtained from Dr. L. A. Herzenberg,
Stanford University, Stanford, CA), Mac-1 (M1/70), Gr-1 (8C5),
anti-CD3 (KT31.1), anti-CD4 (GK1.5), anti-CD5 (53-7.8),
and/or anti-CD8 (53-6.7) Abs. Anti-IAb,
anti-CD11c, anti-ßTCR, and anti-TCR Abs were
purchased from PharMingen (San Diego, CA). In analyzing
CD4-CD8- RTEs, cells were
additionally stained with Texas Red-conjugated anti-CD4 and
anti-CD8 Abs. For thymic B cell progenitor analysis, thymocytes
were stained with FITC-conjugated anti-CD43 (S7) and anti-mouse
IgD (clone 11-26; obtained from Dr. L. A. Herzenberg); PE; or
Cy5-PE-conjugated anti-mouse IgM, PE-conjugated anti-CD19,
allophycocyanin-conjugated B220, and Texas Red-conjugated anti-CD4
and anti-CD8 Abs (PharMingen). Cells were analyzed by a highly
modified five-color FACS Vantage (Becton Dickinson, Mountain View, CA)
(9). Dead cells were excluded by positive staining with
propidium iodide and were detected in a Cy5-PE channel.
Estimation of mature T and B cell immigrants into the thymus
Single spleen cell suspension was obtained from
C57BL6-Ly5.1/Ly5.2 mice. Myeloid spleen cells were removed by
incubation with Gr-1, Mac-1, and Ter119 Abs before negative selection
using anti-rat IgG-conjugated immunomagnetic beads (Dynal, Oslo,
Norway). The purified 1 x 108 splenic
lymphocytes from adult (Ly5.1 x Ly5.2)F1
mice were injected into 1.5- to 3-wk-old Ly5.1 mice. The percentages of
donor-derived mature ß T cells and B cells in the secondary
lymphoid organs were analyzed 7, 18, and 24 days postinjection, when
the injected Ly5.1 mice reached the age of 4–5 wks.
Immunohistochemical staining
Sections of the thymus were cut from frozen samples at 4 microns and were fixed with acetone for 10 min (15). Samples were treated with the Vector Avidin/Biotin Blocking Kit (Vector Laboratories, Burlingame, CA) and stained with biotinylated anti-IgM, B220, or MD2 Abs (16). They were incubated with Streptavidin HRP (Caltag, South San Francisco, CA), visualized with 3-amino-9-ethylcarbazole as the chromagen for 20 min, and counterstained with Gill’s hematoxylin (Medical Chemical, Fairfield, NJ). Isotype-matched rat IgG was used as a negative control.
RT-PCR analysis
Total RNA was isolated from 1000 purified thymic pro-B and pre-B
cells. cDNA was analyzed for the presence of pax-5, VpreB, or 5 by
amplification of 36, 32, or 32 cycles, respectively. The following
primers were used: pax-5-forward, CTA CAG GCT CCG TGA CGC AG;
pax-5-reverse, TCT CGG CCT GTG ACA ATA GG
(Tanneal, 65°C; expected length, 439 bp; Ref.
17); VpreB-forward, GTC TGA ATT CCT CCA GAG CCT AAG ATC
CC; VpreB-reverse, CAG GTC TAG AGC CAT GGC CTG GAC GTC TG
(Tanneal, 60°C; expected length, 400 bp; Ref.
18); 5-forward, GGG TCT AGT GGA TGG TGT CC; and
5-reverse, CAA AAC TGG GGC TTA GAT GG
(Tanneal, 60°C; expected length, 205 bp; Ref.
19).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß and
T cells
FITC was injected intrathymically to label cells in the thymus,
and the spleen and lymph nodes were later analyzed for the presence of
RTE. After intrathymic FITC injection, the percentage of labeled cells
in the thymus was followed over time (Fig. 1
A). Six hours postinjection,
95% of the thymocytes were FITC+ (Fig. 1A) in comparison with noninjected controls. From 6 to
48 h postinjection, the percentage of FITC-labeled cells decreased
in a nearly linear fashion. One of the main causes of the loss of FITC
might be cell division, resulting in a 50% decrease in surface
labeling per cell division (20), although it is possible
that the loss of FITC label could be due to normal turnover of membrane
proteins in the absence of division (21). As shown in Fig. 1B, the intensity of FITC signals at 6 h postinjection
was strong enough to detect more than 85% of FITC-labeled cells after
one or two cell divisions and 50% of cells after four cell
divisions. Because the estimated cycling time for thymocytes is
8–12 h (22), the majority of progeny from cycling
FITC-labeled thymocytes might maintain detectable levels of FITC at
least 24 h after injection. At 24 h postinjection, 84% of
thymocytes retained detectable levels of FITC, indicating that the bulk
of thymocytes can be estimated to turn over in 6 days. This estimate
is in accordance with turnover rates of thymocytes in previous reports
(23). Because only 1% of thymocytes emigrate per day
(14), the major loss of labeled cells is likely due to
apoptosis of thymocytes that either failed positive selection or were
deleted by negative selection (22, 24).
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. Approximately 95% of
FITC+ recent thymic emigrants were
CD4+CD8- or
CD4-CD8+ single-positive
ßT cells (Fig. 2A). The remaining 5% of
FITC+ RTEs were
CD4-CD8- double-negative
cells that were composed of
CD3+TCR+ T cells,
B220+IgM+ mature B cells,
and some CD3+TCR- T
cells (Fig. 2C). The majority of
B220+IgM+ mature B cells
expressed IgD, but only a minority were CD5+
(Fig. 2C). The rate of appearance of FITC-labeled RTEs is
almost linear in the periphery up to 24 h postinjection (Fig. 3). The profiles of RTE in the lymph
nodes were similar to those in the spleen (data not shown). Because
most lymphocytes collect in the spleen and lymph nodes, it can be
estimated that the thymus exports at least 1.2 x
106 ß T cells, 3 x
104 T cells, and 3 x
104 B cells per day to the periphery (Fig. 3).
The estimated numbers of ß and T cell emigrants are
compatible with previous reports (14, 25). On the other
hand, Mac-1+Gr-1+
granulocytes/macrophages,
CD3-NK1.1+ NK cells, and
CD8+/-CD11c+MHC-class
II+ dendritic cells were not detectable in the
RTE (FITC+) fractions throughout these
experiments (Fig. 2C). The lack of
FITC+ granulocytes/macrophages indicates that the
FITC label did not leak into the circulation, and therefore,
unincorporated FITC does not persist in a form that would be available
for labeling newly immigrating or circulating cells.
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It is important to know whether the export of B cells from thymus
reflects B cell production in the thymus or results from FITC labeling
of B cells that have migrated into the thymus from the periphery. We
tested whether or not peripheral B cells could reenter the thymus and
contribute to the thymic B cell pool. We injected i.v. 1 x
108 splenic lymphocytes from adult (Ly5.1 x
Ly5.2)F1 mice into Ly5.1 mice and evaluated the
percentages of donor-derived mature ß T cells and B cells in the
secondary lymphoid organs 7, 18, and 24 days postinjection. The peak
chimerism for donor-derived cells was seen at 18 days postinjection.
Approximately 4% of ß T cells in peripheral organs were of donor
origin, whereas only 0.01% of mature ß T cells in the thymus were
of donor origin (Table I). The rare
reentry of these T cells into the thymus is compatible with previous
reports (26, 27). On the other hand, 5–7% of B cells
in peripheral organs were of donor origin, whereas only 0.6% of
thymic mature B cells were of donor origin (Table I and Fig. 4). If 100% of peripheral B cells could
be replaced by donor-derived B cells, then 0.6 x (100/57)
= 1215% of thymic B cells could be replaced by B cells of donor
origin. Therefore, a maximum of (1215%) x (5 x
104) = 0.60.8 x
104 thymic B cells could have migrated from the
periphery. Even if all such B cell immigrants could leave the thymus in
1 day, a maximum of 3 x 104 - 0.8 x
104 = 2 x 104
thymic B cell emigrants that developed intrathymically would be
exported each day.
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It has been reported that B cell progenitors are present in the
thymus and that isolated thymic B cell progenitors can intrathymically
differentiate into mature B cells after reinjection into the thymus
(28). The phenotype of thymic B cell progenitors is
similar to that of bone marrow B cell progenitors
(29). In the C57BL/6 strain, the thymus contains
significant numbers of immature
B220+CD43-IgM-
pre-B cells (1.8 x 104/thymus) and
B220+CD43+IgM-
pro-B cells (1.2 x 104/thymus)
(Fig. 5A and Table II). These thymic
B220+ B cell progenitors coexpressed CD19 but not
NK1.1 (Fig. 5B). The thymic IgM+ B
cells were composed of IgD- and
IgD+ B cells as in bone marrow B cells. Although
thymic B cells are reported to express a broad range of CD5 in the C3H
mouse strain (28, 30, 31), CD5 expression was almost
limited to the pro-B cell fraction in the C57BL/6 strain thymi (Fig. 5B).
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5 as
well as a transcription factor, pax-5. All of these were detectable in
the thymic pro-B cells and were increasingly expressed in pre-B cells
(Fig. 6). The expression pattern of these
molecules was consistent with that in bone marrow pro-B and pre-B cells
(data not shown).
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A) and more than a 10-fold
increase in absolute numbers of both mature B cells and B cell
progenitors in comparison to wild-type thymi (Table II).
In immunohistochemical stainings of normal and TCRß-deficient thymi,
IgM+ B cells reside mainly in the corticomedullar
junction and in the medulla, whereas B220+ cells
were found throughout the thymus, indicating that immature
B220+IgM- B cells mainly
reside in the cortex through the corticomedullar junction (Fig. 7). Accordingly, thymic B lymphopoiesis
might occur concomitantly with B cell progenitor migration from the
cortex to the medulla of the thymus, mirroring T lymphopoiesis
(32).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cell development in the
bone marrow (33, 34) challenge the paradigm of lymphocyte
classification into bone marrow-derived B cells and thymus-derived T
cells. Our study also suggests that the thymus may not actively export
NK cells and dendritic cells into the periphery or that the level of
export may be below the level of detection in this study. The thymus possesses B cell progenitors of each stage that are similar to those in bone marrow. This suggests that the thymic microenvironment can fully support B as well as T cell maturation. Adult thymi have been shown to be capable of generating B cells after intrathymic injection of hematopoietic stem cells or CLPs (9, 35). Although it has not been shown that the CLPs themselves migrate from the bone marrow to the thymus, it is possible that CLPs or one of their immediate offspring could migrate to and seed the thymus. We have previously reported that IL-7, which is presumably secreted from thymic epithelial cells, promotes survival of thymocytes undergoing positive selection through the up-regulation of Bcl-2 (1, 4). IL-7 is essential also for Ig gene rearrangement in developing B cells (5). Because IL-7 is known to exist in the thymic milieu, IL-7 would be available for the intrathymic development of B cells as well as T cells (36). Therefore, the thymic microenvironment should be able to physiologically support B lymphopoiesis as well as T lymphopoiesis.
Recent studies have shown that, in CD3-
transgenic mice
(37) and Notch1-deficient mice (38), the
number of thymic B cells significantly increases in association with
severe impairment of thymic T cell development. It is possible that
alterations of these genes could skew the commitment of immature thymic
progenitors toward the B cell lineage (37, 38). However,
we demonstrate in this study that the disruption of T cell development
simply by a TCRß gene knockout also results in a relative and
absolute increase in thymic B cell compartments. Accordingly, these
data collectively suggest that in normal thymi, rapid expansion of T
cells might take up most of the microenvironmental niches, preventing
efficient thymic B cell maturation.
The presence of B cell development in and export from the thymus has potential implications for the immune system. For example, B cells that develop in the thymus may have a different repertoire of Ig receptors than do bone marrow-derived B cells, resulting from local Ags and stimuli mediating their positive and negative selection. This may allow a more diverse set of Ig receptors in the periphery. It is also possible that the thymic B cells may contribute to the cellular interactions that mediate positive and negative selection of maturing T cells (39), including Ig isotype and idiotype as selecting elements (40). Thus, it is important to clarify the role of these ectopically but physiologically developed thymic B cells in the immune system.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Koichi Akashi at the current address: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Sm 770B, 44 Binney Street, Boston, MA 02115.
3 K.A. and L.I.R. contributed equally to the research described in this paper.
4 Abbreviations used in this paper: CLP, common lymphoid progenitor; RTE, recent thymic emigrants.
Received for publication August 30, 1999. Accepted for publication February 25, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain transmits distinct signals for proliferation and differentiation during B lymphopoiesis. EMBO J. 15:1924.[Medline]
chain-deficient mice. Immunity 7:155.[Medline]
and ß block thymocyte development at different stages. Nature 360:225.[Medline]
+ T cells from the adult murine thymus. Int. Immunol. 5:331.ß T cells from hemopoietic stem cells. J. Immunol. 155:3338.[Abstract]
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, Limit of FITC intensity detectable on FACS. Each
vertical broken line represents a scale for a two-fold difference in
FITC intensity. Therefore, the number on top of each vertical line
indicates the time of cell division that allows the cells on the lines
to remain detectable by FACS.
