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ß T Cells in lpr Mice: The Appendix in Normal Mice1
*
Department of Immunology and
Third Department of Internal Medicine, Niigata University School of Medicine, Niigata, Japan; and
Department of Anatomy, Hokkaido University School of Agriculture, Sapporo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells,
seen in autoimmune mice carrying the lpr gene (abnormal Fas
gene), in any immune organs of normal mice. We herein report, however,
that such ß T cells were abundant at intraepithelial sites of the
appendix in normal mice. They lacked the expression of NK1.1 Ags
(C57BL/6 mice), but had the morphology of granular lymphocytes and
contained forbidden T cell clones in the minor lymphocyte-stimulating
antigen (Mls) system (C3H/He mice with
Mls-1b2a). In other words, many properties of
intraepithelial T cells in the appendix resembled those ascribed to
abnormal ß T cells, which expand in the lymph nodes and spleen of
lpr mice. In the case of lpr mice,
CD4-8-B220+ ß T cells first
expanded in the appendix and then extended to other organs.
CD4-8-B220+ ß T cells seemed
to originate in situ from c-kit+ stem cells in
the appendix. These results suggest that the appendix is one of the
primary sites in which
CD4-8-B220+ ß T cells exist,
and that these cells carry many primordial properties as prototype T
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells
appears in MRL-lpr/lpr (lpr) mice,
and these mice fall victim to autoimmune disease as a function of age
(1, 2, 3, 4, 5). The lpr gene is now estimated to be an abnormal Fas
gene into which an early transposon of a retrovirus is transfected
(6, 7, 8). Due to this lpr gene, a lymphoproliferative disorder
is induced, especially in
CD4-8-B220+ ß T cells. These
T cells were found recently to be generated extrathymically in the
liver and through an alternative intrathymic pathway (9, 10, 11, 12). However,
the proportion of such DN T cells was small even in these organs of
normal mice.
To date, there have been no reports of an abundance of DN
CD4-8-B220+ ß T cells in any
immune organs of normal mice. Although a few cells were found to exist
at some sites of normal mice (13), a large number of or a large
proportion of such DN CD4-8-B220+
ß T cells has not been detected at any sites in normal mice. We
herein report that such ß T cells were abundant at intraepithelial
sites of the appendix in normal mice, irrespective of strains. This
might be because the appendix developed from the intestine in early
phylogeny. The appendix, therefore, still carries primordial T cells in
mice. The present results reveal that abnormal ß T cells seen in
lpr mice might be a normal T cell subset that exists even in
normal mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6), BALB/c, C3H/HeN, and lpr mice at the age of 5 to 15 wk were used. All mice were fed under specific pathogen-free (SPF) conditions in the animal facility of Niigata University (Niigata, Japan). B6 mice fed under conventional conditions and germfree conditions were also used at the age of 15 wk. B6.Ly-5.1 mice were also used. All of these mice were purchased from Clea Japan (Tokyo, Japan).
Cell preparations
Mice anesthetized with ether were killed after complete exsanguination through incised axillary arteries and veins, and the liver, spleen, appendix, small intestine, and colon were removed. The liver was pressed through 200-gauge stainless steel mesh and then suspended in Eagle’s MEM medium supplemented with 5 mM HEPES (Nissui Pharmaceutical Co., Tokyo, Japan) and 2% heat-inactivated newborn calf serum. After washing, the cells were fractionated by centrifugation in 15 ml of 35% Percoll solution (Pharmacia Fine Chemicals, Piscataway, NJ) for 15 min at 2000 rpm (14). The pellet was resuspended in erythrocyte-lysing solution (155 mM NH4Cl, 10 mM KHCO3, 1 mM EDTA-Na, and 170 mM Tris, pH 7.3). The spleen was pressed through 200-gauge stainless steel mesh. The pellet was treated with the erythrocyte-lysing solution. The appendix, small intestine, and colon were removed and flushed with PBS to eliminate luminal contents (15). The mesentery, Peyer’s patches, or appendix lymphoid follicles were then resected. To obtain intraepithelial lymphocytes (IEL), the intestine was cut longitudinally and then into 1- to 2-cm pieces. These fragments were incubated for 15 min in 15 ml Ca2+- and Mg2+-free PBS containing 5 mM EDTA, in a 37°C shaking-water bath. The supernatant was then collected. The cell suspensions were collected and centrifuged in a discontinuous 40%/80% Percoll gradient solution at 2800 rpm for 25 min. Cells from the 40%/80% interface were collected.
Lamina propria lymphocytes (LPL) were prepared after the digestion of intestine with collagenase type II at a concentration of 90 U/ml in the medium. Samples were incubated for 45 to 90 min in a 37°C shaking-water bath. Digested intestine was then pressed through 200-gauge stainless steel mesh and suspended in medium. Cells were fractionated by the Percoll solution.
Immunofluorescence tests
The surface phenotype of cells was analyzed using mAbs in
conjunction with two-color or three-color immunofluorescence tests
(14). The mAbs used in this study included FITC-, phycoerythrin (PE)-,
or biotin-conjugated reagents of anti-CD3 (145-2C11), anti-B220
(RA3-6B2), anti-CD2 (RM2-5), anti-CD5 (53-7.3),
anti-TCR-ß (H57-597), anti-TCR-
(GL-3), anti-CD4
(RM4-5), anti-CD8 (53-6.7), anti-Gr-1 (RA3-8C5), anti-Mac-1
(M1/70), and anti-c-kit (SC1) mAbs (PharMingen Co., San
Diego, CA). Biotin-conjugated mouse anti-Ly-5.1 mAb was kindly
provided by Dr. T. Kina, Chest Disease Research Institute, Kyoto
University (Kyoto, Japan). Biotin-conjugated reagents were developed
with PE or Red 613-conjugated streptavidin (Becton Dickinson, Mountain
View, CA). To prevent nonspecific binding of mAbs, CD32/16 (24G2) was
added before staining with labeled mAbs. The fluorescence-positive
cells were analyzed with FACScan using Lysis II software (Becton
Dickinson).
Cytotoxicity assay
Cytotoxicity was examined by a 51Cr release assay (16). Fresh mononuclear cells (MNC) in various organs and IEL in the appendix and small intestine were prepared from B6 mice. 51Cr-labeled YAC-1 cells (1 x 104/well) or 51Cr-labeled syngeneic thymocytes (2 x 104/well) were incubated with effector cells at the indicated E:T ratios at 37°C for 4 h. After the incubation, radioactivity released into supernatants was counted and percent specific lysis was calculated.
Morphologic study
IEL isolated from the appendix and small intestine for morphologic study were fixed in 2.5% glutaraldehyde and 1% OsO4, as described previously (14). Pellet samples were dehydrated through a graded series of ethanol and embedded in Epon 812. Ultrathin sections stained with uranyl acetate and lead citrate were observed at the same magnification with a Hitachi H-7000 transmission electron microscope. Anti-c-kit (ACK-2) mAb was a gift from Dr. Y. Kanamori (Keio University, Tokyo, Japan). The longitudinally opened appendix was embedded in O.C.T. compound at -80. The tissue segments were sectioned with a cryostat at 6 µm and applied to poly-L-lysin-coated slide glasses (14). The tissue sections that had been air dried and fixed in acetone for 10 min at room temperature were incubated with appropriately diluted rat anti-c-kit mAb for 30 min at 37°C or overnight at 4°C, and rinsed three times with PBS, followed by incubation with biotin-conjugated goat anti-rat IgG (Cedarlane Laboratories, Ontario, Canada). Subsequently, the sections were incubated with avidin-biotin peroxidase complex (Vectastain ABC kit; Vector Laboratories, Burlingame, CA).
Adoptive transfer experiment
Lineage marker-negative (Lin-: Ly-1-, B220-, Gr-1-, Mac-1-) cells were thought to be fluorescence-negative cells after staining with all markers described above. Lin- c-kit+ cells were obtained from IEL of the appendix in BALB/c mice by FACStar IIPlus (Becton Dickinson). These cells (2 x 105/mouse) were injected i.v. into 4-Gy irradiated C.B17-Icr/scid(scid) mice. Similarly, Lin- c-kit+ cells were also obtained from IEL of the appendix in B6.Ly-5.1 mice, and were injected into 4-Gy irradiated B6.Ly-5.2 mice. Four weeks after injection, the surface phenotype of cells was analyzed by using mAbs in conjunction with two-color or three-color immunofluorescence tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T
cells in IEL of the appendix
MNC were isolated from the liver, spleen, appendix, and small
intestine of B6 mice at the age of 8 wk (Fig. 1
A). Two-color staining
for CD3 and B220, that for CD3 and a mixture of CD4 and CD8, and that
for CD3 and CD2 were conducted (14). In the liver and spleen, the
populations of CD3+ T cells and B220+ B cells
were found to be isolated from each other. In contrast, a large
proportion of B220+ cells was found among CD3+
cells in IEL of the appendix. It was estimated that
CD3-B220+ cells were surface Ig+
(sIg), while CD3+B220+ cells were
sIg- in IEL of the appendix (data not shown). Although a
few CD3+B220+ cells were present in IEL of the
small intestine, the majority were CD3+B220- T
cells. In addition to the uniqueness of
CD3+B220+ cells, IEL of the appendix contained
considerable proportions of DN CD4-8- cells
and CD2- cells among CD3+ cells (Fig. 1A, center and lower columns).
In the liver, there were DN CD4-8- cells, but
not CD2- cells. In the case of the intestine, there was an
abundance of CD2- cells, but few DN
CD4-8- cells. In other words, the phenotype
of IEL in the appendix (i.e.,
CD3+CD4-8-B220+CD2-)
is different from those in the liver, spleen, and intestine. Rather, it
resembles the phenotype of abnormally expanding T cells in
lpr mice.
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ß and TCR- were
conducted (Fig. 1
B). It was estimated that only a few
CD3-B220+sIg+ B cells existed in
the appendix (<5%). In the cases of the liver and spleen, both
CD4+ and CD8+ cells, mainly ß T cells,
existed. In contrast, the majority of IEL T cells in the appendix and
intestine were CD8+ and contained a considerable proportion
of T cells. Comparisons of the proportion of CD3+B220+ cells at various sites and in various mice
We obtained IEL from the appendix, cecum, and colon and compared
their phenotypes with each other (Fig. 2). IEL in the cecum and colon were also
found to contain CD3+B220+ cells. However,
the proportion of CD3+B220+ cells was the
highest in the appendix. These experiments were repeated three
times.
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To directly confirm the existence of CD3+CD4-CD8-B220+CD2- cells in the appendix, three-color staining for CD3, B220, and a mixture of CD4 and CD8, and that for CD3, B220, and CD2 were conducted. CD3+B220+ cells in the appendix were found to contain DN CD4-8- cells and CD2- cells.
The appendix of nude mice and lpr mice
Since many T cells in the liver (17, 18, 19) and intestine (15, 20, 21, 22, 23) are known to be generated extrathymically, athymic nude mice at
the age of 8 wk were also examined (Fig. 3A). In general, the
proportion of CD3+ T cells was extremely low in all tested
organs of nude mice. However, the phenotype of IEL T cells in the
appendix of these mice was mainly
CD3+B220+CD8+ (data not shown)
CD2-. Except for the dominance of
CD3-CD8+ cells, the other phenotype resembled
those of IEL T cells in the appendix of normal mice.
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B). lpr mice were used at the age of 5 wk
before the onset of autoimmune disease and at the age of 15 wk after
the onset of disease. Even before the onset of disease and
splenomegaly, a large proportion of
CD3+B220+CD4-8- cells
was seen in the appendix (the absolute number of
CD3+B220+CD4-8- cells
in this organ was more than twice that of control mice at the same
age). The only way in which they differed from those of
B220+CD4-8- cells in the other
organs of lpr mice was CD2+. After the onset of
autoimmune disease and splenomegaly (i.e., 15 wk),
CD3+B220+CD4-8- cells
became dominant in all other tested organs. Some CD2+ cells
were also present in organs other than the appendix. Self-reactive T cell clones in the appendix
In a series of recent studies, we have emphasized that extrathymic
T cells in the liver and intestine contain forbidden clones estimated
in the minor lymphocyte-stimulating antigen (Mls) system and that they
exert self-reactivity against syngeneic thymocytes (as well as NK
targets) (14, 16, 18, 24). In this experiment, such a possibility was
examined in IEL of the appendix in parallel with MNC in the spleen,
liver, and small intestine (Fig. 4).
C3H/HeN mice (Mls-1b2a) at the age of 8 wk were
used. The Vß3+ and Vß11+ cells are
forbidden clones, whereas Vß2, Vß7, and Vß8 (8.1+8.2) are
nonforbidden clones in these mice. Three-color staining for CD3,
IL-2Rß, and each Vß was conducted. By gated analysis, the
proportions of Vß+ cells in each fraction were
determined. As shown previously (14), forbidden clones were abundant in
CD3int cells (i.e., extrathymic T cells) in the liver. This
was true in both Vß3+ and Vß11+ cells. On
the other hand, CD3high cells (i.e., thymus-derived T
cells) contained only a few Vß3+ and Vß11+
cells in the spleen and liver. In the case of IEL in both the small
intestine and appendix, such forbidden clones were abundant. The levels
of nonforbidden clones, Vß2+, Vß7+, and
Vß8+, were almost the same in all tested organs.
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It was then examined whether IEL in the appendix had killer
activity against NK-sensitive YAC-1 targets or syngeneic thymocytes
(Fig. 5A). Liver MNC exerted
cytotoxicity against both targets. In the case of the appendix, the
cytotoxicity against syngeneic thymocytes was extremely high in
comparison with those of other organs. Appendix IEL were also cytotoxic
against YAC-1 targets. Since appendix IEL lacked any NK1.1+
cells (i.e., neither CD3-NK1.1+ NK cells nor
CD3+NK1.1+ T cells), all of these
cytotoxicities were mediated by CD3+ T cells in the
appendix. Interestingly, IEL in the intestine as well as splenocytes
had very low cytotoxic activity against YAC-1 targets, while IEL in the
intestine had some cytotoxic activity against syngeneic thymocytes.
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The morphology of IEL in the appendix and IEL in the intestine was
then compared using electron microscopy (Fig. 6). It was found that all IEL in the
appendix were large granular lymphocytes (Fig. 6A).
CD3+B220+ cells had a larger number of
cytoplasmic granules than did CD3+B220- cells
(data not shown). IEL in the intestine had fewer granules and were
smaller in size than those in the appendix (Fig. 6B).
In the final portion of this experiment, immunohistochemical staining
for c-kit+ cells in the appendix was performed.
The impetus for this study was recent evidence that
c-kit+ cells for their own extrathymic T cells
exist in the liver and intestine (25, 26). We found that many
c-kit+ cells were present in the lamina propria
(Fig. 6C) and at the cryptopatches (Fig. 6D), similar to the case of the intestine. In the
cryptopatches, c-kit+ cells tended to form
clusters.
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Characterization of c-kit+ cells yielded by
the appendix was further performed (Fig. 7). MNC were isolated from the liver,
spleen, small intestine, and appendix. In the intestine and appendix,
MNC were isolated from both intraepithelial sites (i.e., IEL) and the
lamina propria (i.e., LPL). As shown in Figure 7A, it was
found that the appendix was a site with an abundance of
Lin- c-kit+ cells; this was true
for both IEL and LPL. However, the majority of LPL in the appendix were
B220+ B cells, and there were no
CD3+B220+ T cells.
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B). Originally,
scid mice did not carry any TCR-ß+ and
TCR-+ cells and carried only a few CD3, CD4, and CD8
cells (<2%) in all tested organs. On the other hand, 1 mo after an
injection of Lin- c-kit+ cells of
the appendix (2 x 105 cells) into 4-Gy irradiated
scid mice, many CD4+ and CD8+ cells
had been newly generated in all tested organs. One point to be noted
was a failure of the reconstitution of double-positive (DP)
CD4+8+ cells in the thymus. This experiment was
repeated five times. Although the majority of the CD3+
cells that appeared in the intestine and appendix were
B220-, there was a significant proportion of
CD3+B220+ T cells in IEL of both organs. Such
CD3+B220+ cells were very few in all other
organs.
A transfer experiment of Lin-
c-kit+ cells obtained from IEL of the appendix
was also conducted by using B6.Ly-5.1 congenic mice (Fig. 8). Namely, 2 x 105
Lin- c-kit+ cells of the appendix
of B6.Ly-5.1 mice were i.v. injected into 4-Gy irradiated B6.Ly-5.2
mice. One month after such transfer, Ly-5.1+ cells appeared
in various organs of recipient B6 mice. Gated analysis revealed that
the majority of donor cells belonged to T cells and they were mainly
CD3+B220+, especially in the appendix. These
results confirmed the data of cell transfer experiment in
scid mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells in normal mice. Although such DN B220+
ß T cells have been known to be the major T cell population
expanding in lpr mice (1, 2, 3, 4, 5, 6, 7), they have never been detected
in great numbers in normal mice. It is speculated that the property of
CD2- among
CD4-8-B220+ ß T cells in the
appendix (as well as lpr T cells) may be due to the
resemblance to intestinal T cells. Thus, all IEL T cells in the
intestine were CD2-. In a previous study, we reported the
fact that DN T cells in lpr mice are mainly generated
through the extrathymic pathway in the liver or at the other
extrathymic sites (9, 10, 11, 12). This speculation seems to be reasonable,
because the appendix in athymic nude mice also comprises
B220+ T cells.
In the case of lpr mice, the number and proportion of
CD4-8-B220+ ß T cells in the
appendix were extremely high even before the onset of autoimmune
disease. However, after the onset of disease, such DN B220+
ß T cells became prominent in all tested organs of lpr
mice. In a preliminary experiment, we conducted appendectomy in
neonatal (3 days) and young (4 wk) lpr mice. In both cases,
it was not possible to ameliorate the autoimmune disease, although some
lpr mice showed a retarded onset (0–4 wk) of disease. One
speculation is that the other sites also contain
c-kit+ cells and offer microenvironments to
support the differentiation of DN B220+ T cells in
lpr mice. Depending on the microenvironments, DN
B220+ T cells seem to change their phenotype, e.g.,
DN
CD8+, CD2-CD2+,
B220+B220-, etc. This indication is based
on findings of experiments in which c-kit+ cells
were injected into scid mice (this study) and into MRL-+/+
mice (unpublished observation).
The majority of T cells expanding in lpr mice were CD3+B220+DN CD4-CD8-TCRint cells, especially in the spleen and lymph nodes. However, there are some other types of cells, for example, CD3+B220+CD4+TCRint cells. These T cells were dominant in the liver and thymus (thymic medulla) of lpr mice. We think that abnormal T cells expand at several sites, including the appendix, liver, and thymic medulla, of lpr mice, depending on the type of cells.
The proportion of CD3+B220+ cells as well as the absolute number of CD3+B220+ cells were extremely low in nude mice. It is speculated that they were thymus independent, but that thymic humoral factors might be important for their maximal expansion. This speculation may be reasonable because it was reported that the expansion of even extrathymic T cells in the liver and intestine was under the control of thymic influence (27, 28). Indeed, the numbers of T cells in nude mice were very low in all immune organs, even at extrathymic sites (e.g., the liver and intestine).
We have emphasized that forbidden T cell clones estimated in the Mls
system are always confined to CD3int cells generated in the
liver or through an alternative intrathymic pathway (14, 17, 18, 19). This
is true even in intestinal T cells (29, 30). There is no leakage of
forbidden clones into CD3high cells (i.e., thymus-derived T
cells) in the periphery. In this study, we demonstrated that this was
also the case with IEL T cells in the appendix (see Fig. 4). Reflecting
this situation, hepatic CD3int cells and appendix T cells
mediated NK-like cytotoxicity against YAC-1 cells and autologous
cytotoxicity against syngeneic thymocytes. It is interesting that
intestinal T cells had a lower grade of cytotoxicity in comparison with
that of the appendix. In addition to these primordial properties of
self-reactivity, the morphology of appendix T cells as large granular
lymphocytes is noteworthy. Taken together with their phenotype of DN
B220+, all of these properties would appear to indicate
that appendix T cells are prototype T cells (i.e., possibly the most
primordial T cells in phylogeny).
In recent studies, c-kit+ cells were demonstrated even in the liver and intestine (25, 26). Such stem cells localize in the parenchymal space of the liver and in the cryptopatches of the small intestine. In the appendix, c-kit+ cells were also found to localize at both the intraepithelial sites and in the lamina propria (i.e., cryptopatches). Since the liver and appendix originated from the intestine in phylogeny (25), it is concluded that all such organs keep their own c-kit+ stem cells in situ. The major site of c-kit+ stem cells is the bone marrow in land-based organisms on land. However, the lower vertebrates before landing do not have bone marrow (31). This raises the possibility that c-kit+ stem cells in the liver, intestine, and appendix have a longer history than those in the bone marrow in phylogenic development. In a recent study, we demonstrated that c-kit+ cells isolated from the liver were pluripotent and produced erythroid, myeloid, and lymphoid cells (including DP CD4+8+ cells in the thymus) (25). In sharp contrast, c-kit+ cells isolated from the appendix and intestine produce only some lymphocytes and myeloid cells, but not any erythroid cells at all (our unpublished observation). One of the limited functions of c-kit+ cells of the appendix and intestine is also explained by the present result of the failure in the reconstitution of DP CD4+8+ cells in the thymus.
Finally, primordial T cells were found in IEL of the appendix. All
sites in which primordial T cells exist express monomorphic MHC class I
Ags (e.g., CD1 in the thymic medulla, HLA-F in the liver, HLA-E in the
intestine, and HLA-G in the uterus) (32). It is therefore speculated
that these primordial T cells recognize some self Ags in the context of
monomorphic MHC Ags. Since primordial T cells preferentially mediate
self-reactivity against abnormal (or rapidly proliferating) self cells,
these T cells might play a role in innate immunity, as proposed by
C. A. Janeway, Jr. (33). lpr mice produce such abnormal
self cells, and such cells are therefore recognized by primordial T
cells. Due to the abnormality of Fas Ag (6, 7, 8), such Fas-
targets are not killed appropriately by Fas ligand+
primordial T cells. Therefore, despite intensive expansion of DN
CD4-8-B220+ ß T cells in
lpr mice, the autoimmune disorder is limited (1, 2, 3, 4, 5). In any
case, the appendix is an interesting immune organ. The lymphocytes
isolated from the lymphoid follicles in the appendix of normal mice
were the same as those in the lymph nodes (data not shown). Therefore,
the isolation of IEL from the appendix in this study was important for
the detection of DN CD4-8-B220+
ß T cells in normal mice.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Toru Abo, Department of Immunology, Niigata University School of Medicine, Asahimachidori 1-757, Niigata 951, Japan.
3 Abbreviations used in this paper: DN, double-negative; DP, double-positive; IEL, intraepithelial lymphocyte; int, intermediate; LPL, lamina propria lymphocytes; Mls, minor lymphocyte-stimulating antigen; MNC, mononuclear cell; PE, phycoerythrin; sIg, surface immunoglobulin; SPF, specific pathogen-free.
Received for publication August 4, 1997. Accepted for publication November 20, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J. Immunol. 143:103.[Abstract]
ß-T cells expanded in autoimmune lpr mice are probably a counterpart of normal T cell in the liver. J. Immunol. 147:1214.[Abstract]
ßintermediate T cells in the liver of normal adult mice: implication for lpr pathogenesis. Int. Immunol. 6:533. CD8+ intraepithelial T cell receptor /ß+ lymphocytes reveals a major extrathymic pathway of T cell differentiation. J. Exp. Med. 173:483.This article has been cited by other articles:
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  D. B. Ascon, M. Ascon, S. Satpute, S. Lopez-Briones, L. Racusen, R. B. Colvin, M. J. Soloski, and H. Rabb Normal mouse kidneys contain activated and CD3+CD4-CD8- double-negative T lymphocytes with a distinct TCR repertoire J. Leukoc. Biol., December 1, 2008; 84(6): 1400 - 1409. [Abstract] [Full Text] [PDF]
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 M. S. Ford, Z.-X. Zhang, W. Chen, and L. Zhang Double-Negative T Regulatory Cells Can Develop Outside the Thymus and Do Not Mature from CD8+ T Cell Precursors. J. Immunol., September 1, 2006; 177(5): 2803 - 2809. [Abstract] [Full Text] [PDF]
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M. Minagawa, H. Watanabe, C. Miyaji, K. Tomiyama, H. Shimura, A. Ito, M. Ito, J. Domen, I. L. Weissman, and K. Kawai Enforced Expression of Bcl-2 Restores the Number of NK Cells, But Does Not Rescue the Impaired Development of NKT Cells or Intraepithelial Lymphocytes, in IL-2/IL-15 Receptor {beta}-Chain-Deficient Mice J. Immunol., October 15, 2002; 169(8): 4153 - 4160. [Abstract] [Full Text] [PDF]
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H. Kawamura, T. Kawamura, Y. Kokai, M. Mori, A. Matsuura, H. Oya, S. Honda, S. Suzuki, A. Weerashinghe, H. Watanabe, et al. Expansion of Extrathymic T Cells as Well as Granulocytes in the Liver and Other Organs of Granulocyte-Colony Stimulating Factor Transgenic Mice: Why They Lost the Ability of Hybrid Resistance J. Immunol., May 15, 1999; 162(10): 5957 - 5964. [Abstract] [Full Text] [PDF]
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