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*
Division of Immunology and Rheumatology, Department of Medicine, and
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305; and
La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
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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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CD1 molecules present Ags to T cells like class I MHC molecules. The
CD1-associated Ags are unusual and include hydrophobic peptides as well
as glycolipids (12, 13, 14). The CD1 molecule itself or in combination with
endogenous Ags appears to be recognized by an autoreactive subset of T
cells expressing the NK1.1 surface marker (15, 16). This T cell subset
has a restricted TCR repertoire that is made up predominantly of an
invariant rearrangement of the V
14 and J281 gene segments
associated with Vß2, Vß7, or Vß8 receptors (16, 17). The
NK1.1+ T cell subset in the thymus is positively selected
by CD4+CD8+ thymocytes that express CD1 (18).
However, T cells that express neither the NK1.1 marker nor the V14
TCR are able to recognize CD1 on syngeneic APCs (19).
T cells are capable of recognizing both ß2m-dependent and
independent forms of CD1 (19, 20). The TCR with the invariant
V14-J281 rearrangement expressed by NK1.1+ T cells
recognizes only the ß2m-dependent form of CD1 on
syngeneic B cells (20). However, non-V14 TCRs are able to recognize
both the ß2m-dependent and -independent forms of CD1 on
syngeneic B cells and other APCs as judged by the in vitro responses of
T cell hybridomas (19, 20). The anti-CD1 mAb, 1B1, is able to
inhibit T cell responses to the ß2m-dependent form of CD1
but not to the ß2m-independent form (20). This
observation suggests that the 1B1 mAb recognizes only the
ß2m-dependent form.
Previous studies indicated that almost all murine B cells express CD1 on their cell surface (20, 21). In the current study, we determined the levels of CD1 expression on subsets of B cells by multicolor immunofluorescent staining with two anti-CD1 mAbs, 1B1 (IgG2b) and 3C11 (IgM). Although dull staining of CD1 was observed on most T and B cells, two subsets of CD1high B cells with characteristics of marginal zone and follicular B cells, respectively, were found in the spleen. Staining with the two anti-CD1 mAbs showed a markedly reduced expression of CD1 on T and B cells from ß2m-/- mice, but a ß2m-independent form was detected on these cells by a T cell clone that recognized CD1. This T cell recognition of the ß2m-independent form was inhibited by the 3C11 mAb.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male and female C57BL/6 and BALB/c mice of 8 to 12 wk of age were obtained from the Stanford University Department of Comparative Medicine (Stanford, CA). ß2m-/- C57BL/6 mice of similar age and sex were purchased from Taconix (Germantown, NY). The single-cell suspensions of spleens and peripheral lymph nodes (LNs) obtained from these mice were prepared by gentle passage through nylon mesh. E from the spleen were lysed by incubation in chilled 0.14 M NH4Cl and 20 mM Tris (pH 7.4) for 2 min. Single-cell suspensions of bone marrow (BM) from the femur and tibia were prepared by flushing the marrow cavities with tissue culture medium.
Abs and cell lines
The following mAbs used in immunofluorescent staining were harvested from hybridomas, purified, and conjugated to the appropriate fluorochromes as described previously (22, 23): Cy7-allophycocyanin anti-IgD (1126), allophycocyanin anti-CD5 (53-7.3), Cascade Blue (CB) anti-IgM (331), CB anti-CD4 (G.K. 1.5), CB anti-CD8 (53-6.7), CB anti-CD3 (2C11), CB anti-F4/80 (F4/80), phycoerythrin (PE) anti-CD43 (S7), FITC anti-CD24 (heat stable Ag; 30F1), FITC anti-B220, and allophycocyanin anti-B220 (RB3-6B2). Biotinylated rat anti-CD1 (1B1), FITC anti-CD21/CD35 (complement receptor (CR)1/CR2;7G-6), PE anti-CD23 (low affinity IgER; B3B4), PE-streptavidin (SA), biotinylated control rat IgM and IgG2b, and unconjugated anti-CD16/32 (2.4G2) were purchased from PharMingen (San Diego, CA). Texas Red-SA (TR-SA) and tetramethylrhodamine isothiocyanate (TRITC)-SA were obtained from Southern Biotechnology (Birmingham, AL). Immunohistologic staining was performed with FITC anti-IgD (1126) and allophycocyanin anti-IgM (331) purified and conjugated as described previously (22). Another anti-CD1 mAb (3C11; rat IgM) was purified from the supernatants of hybridoma cells that were obtained from Dr. C. Terhorst (Harvard University, Cambridge, MA). The IgM fraction was isolated using an E-Z Sep bioreactor IgM size exclusion separator kit (Pharmacia, Uppsala, Sweden) followed by separation on Biogel A-5 m beads (Bio-Rad, Hercules, CA). Biotinylation was performed as described previously (23).
The cloned BALB/c CD4-CD8- Vß9 and V4.4
T cell lines (TLI-2.C4 and TLI-2.C7) that were used for the
proliferation assays have been described previously (24). A
nontransfected BALB/c B cell lymphoma line, A20 (25), and A20 cells
transfected with CD1 cDNA were used as stimulator cells.
Immunofluorescent staining
Fresh single-cell suspensions of lymphoid cells were incubated
with various combinations of fluorochrome- or biotin-conjugated Abs at
saturation for 20 min at 4°C. In the case of the biotin-conjugated
reagents, counterstaining for 15 min with fluorochrome-conjugated SA
was performed. Stainings were performed in the presence of saturating
concentrations of anti-CD16/CD32 mAb to block Fc
RII/IIIRs.
Stained samples were washed twice and resuspended in staining medium
with calcium- and magnesium-free PBS containing 3% FBS (HyClone,
Logan, UT) and 0.05% NaN3 (Fisher Scientific, Fairlawn,
NJ) with propidium iodide (PI) at 0.5 µg/ml (Sigma, St. Louis, MO).
Up to eight-color flow cytometric analysis was performed using a highly modified triple laser (488 nm argon, 408 nm krypton, 599 nm dye), FACStar (Becton Dickinson, Mountain View, CA), with four-decade logarithmic amplifiers (26). Data were analyzed with Flow Jo software (Green Star, San Carlos, CA) using 5% probability plots; cells staining for PI (dead cells) were excluded from analysis in all cases.
Immunohistology
Spleens were frozen in OCT compound (Miles, Elkhart, IN) and cut into 9-µm thick sections. Tissue sections were fixed at -20°C in acetone for 15 min and dried at room temperature. The nonspecific binding of staining Abs was blocked by incubating each slide with 10% rat serum in PBS for 15 min at room temperature. Abs were added to each slide and incubated for 1 h at room temperature. After washing out excess Abs, TRITC-SA was added to visualize biotinylated Abs. The slides were analyzed with a laser confocal microscope (CLSM2010, Molecular Dynamics, Sunnyvale, CA) at the Cell Science Imaging Facility at Stanford University.
T cell proliferation assays
Cloned Vß9/V4.4 T cells (1 x 104)
were incubated in flat-bottom, 96-well, plastic plates in triplicate
cultures with graded numbers of nontransfected or CD1-transfected A20 B
cells that had been irradiated in vitro (4000 cGy) immediately before
culture. In other experiments, the cloned T cells were incubated
with similarly irradiated spleen cells (5 x 104) from
wild-type (wt) BALB/c, wt C57BL/6, or
ß2m-/- C57BL/6 mice and stimulated for
48 h with 20 µg/ml LPS (Boivan type, Difco, Detroit, MI).
Control cultures contained responder and stimulator cells alone. Cells
were incubated for 48 h at 37°C in 5% CO2 in RPMI
1640 tissue culture medium supplemented with 10% FBS (HyClone), 1
x 10-5 M 2-ME, 2 mM glutamine, and 100 µg/ml penicillin
and streptomycin. [3H]thymidine (1 µCi/well) (New
England Nuclear, Boston, MA) was added to the cultures at 18 h
before harvest. [3H]thymidine incorporation was measured
using a beta-plate counter (Beckmann Instruments, Fullerton, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The specificity of two anti-CD1 mAbs, 3C11 (rat IgM) and 1B1
(rat IgG2b), was confirmed by immunofluorescent staining of a BALB/c B
cell line (A20) that was nontransfected or had been transfected with
CD1 cDNA (A20/CD1). Figure 1
shows the
flow cytometric analysis of the two cell lines that had been stained
with the two anti-CD1 mAbs and the isotype-matched control mAbs.
The staining of the nontransfected A20 line with both anti-CD1 mAbs
was similar to background controls, whereas the staining of the A20/CD1
line with those mAbs resulted in bright staining.
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. All staining was performed in the
presence of saturating concentrations of anti-FcRII/III mAb. The
analysis revealed higher levels of autofluorescence for
B220+ cells than for B220- cells. A
subpopulation of B cells (enclosed in boxes), which accounted for 10.9
to 15.3% of all B220+ cells, expressed high levels of CD1.
Non-B cells (B220-) stained dully with the 1B1 mAb but did
not stain with the 3C11 mAb.
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). A total of <1% of spleen B cells stained with 3C11 or 1B1 mAbs
above the background thresholds that had been set using the isotype
controls. In addition, the dull staining of the non-B cells that was
observed with the 1B1 mAb in wt mice was not observed in the spleens of
ß2m-/- mice. Thus, both the bright staining
for CD1 on B cells and the dull staining on non-B cells in the spleen
were markedly reduced in ß2m-/- mice.
Spleen cell staining for CD1 and B220 was compared with that of
cells in the peritoneal cavity (PerC), LNs, and BM in Figure 3. To achieve an optimal resolution of
CD1+ and CD1- cells, counterstaining for the
biotinylated 3C11 mAb was performed with a PE-SA conjugate instead of
with the TR-SA conjugate used in Figure 2. This staining revealed the
presence of B cells expressing high and low levels of CD1 staining
(enclosed in boxes) in the spleens of wt C57BL/6 mice. The spleen cells
from ß2m-/- mice showed some residual
staining of dull cells (3.0% of B cells) and <1% of bright cells
(Fig. 3). Background staining with control rat IgM showed staining of
<1% of B cells in both the bright and dull boxes. Although, a bright
CD1 (CD1high) subset of B cells was found in the spleen, it
accounted for 1% or fewer B cells in the PerC, LNs, or BM (Fig. 3). On
the other hand, 14 to 51% of B cells in the three latter sources
showed dull staining for CD1, which was clearly above background
controls. In ß2m-/- mice, some residual
CD1dull cells were observed in the three sources that
accounted for 
2.8% of all B cells (Fig. 3). Using the bright
counterstain PE-SA, some dull staining of non-B cells was observed with
the 3C11 mAb. This was not seen in ß2m-/-
mice or with control IgM mAb (Fig. 3).
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To determine whether the CD1high B cells represent a
previously described B cell subset, seven-color fluorescent analysis
was performed with mAbs that identify follicular, B-1 (Ly-1), immature,
and marginal zone B cells (27, 28, 29, 30, 31). Figure 4 shows the phenotype of
CD1high splenic B cells that had been identified with
either 3C11 (Fig. 4, E and F) or 1B1 mAb (Fig. 4, H and I) compared with the phenotype of total
splenic B cells (Fig 4, B and C) from normal
C57BL/6 mice. Fig. 4B shows the staining pattern of gated
B220+ cells (Fig. 4A, enclosed in the box) for
CD23 vs CD24. The upper box in Figure 4B encloses
CD23+ B cells (73%), which are mostly CD24low
and consequently represent the follicular subset (27, 30, 31). The
lower box encloses
CD23-CD24low/intermediate and
CD23-CD24high B cells. The former contain
marginal zone and B-1 cells, and the latter contain immature B cells
(27, 31). As shown in Figure 4, E and H,
B220+CD1high cells were enriched for
CD23- cells, which represented 60% and 67% of all
CD1high cells. Most of the
CD1highCD23- cells were
CD24intermediate, which is consistent with them being
either marginal zone or B-1 cells. Staining for IgD and IgM supported
this notion by demonstrating a higher frequency (69% and 62%) of
IgMhigh IgDdull cells among CD1high
B cells (Fig. 4, F and I, lower box)
compared with splenic B cells. Follicular B cells are mainly
IgMdull IgDhigh (Fig. 4C,
upper box). Thus, roughly 70% of CD1high B
cells contained either immature, marginal zone, or B-1 cell subsets,
and 30% contained follicular B cells. Interestingly, most
B220+ CD1high IgDhigh (follicular)
B cells also expressed high levels of IgM.
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B shows that 0.4% of gated
B220+ cells (Fig. 5A, enclosed in the box) were
CD43+ and CD5+. A similar percentage (0.3%) of
gated CD1high B cells (Fig. 5, C and
E, enclosed in the boxes) were CD43+
CD5+ (Fig. 5, D and F, enclosed in
the boxes).
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H (upper box) shows that 15% of gated
B220+ cells (Fig. 5G, enclosed in the box)
expressed high levels of CD21. CD21-CD23- B
cells that included immature and B-1 cells accounted for 11% (Fig. 5H, lower box) of B220+ cells, and
the remainder of B cells expressed intermediate levels of CD21. The
latter cells were CD23+ and were members of the follicular
subset (27, 30, 31). Gated CD1high B cells (Fig. 5, I and K, enclosed in the boxes) were
predominantly (76%) CD21highCD23- marginal
zone B cells (Fig. 5J, enclosed in the upper
box). Consistent with data shown in Figure 4, 25 to 30%, of
CD1high B cells were CD23+ and therefore
follicular B cells, but these cells also expressed high levels of CD21
(Fig. 5, J and L). A small percentage (1.9% and
3.0%) of the CD1high B cells were
CD21-CD23- (Fig. 5, J and
L). Gating on marginal zone B cells
(B220+CD23-CD24low/intermediateCD43-)
showed that 
50% were CD1high (data not shown).
Next, we next determined the frequency of follicular CD23+
IgM+ IgDhigh
CD21highCD43- B cells in wt and
ß2m-/- C57BL/6 mice. The results shown in
Figure 6 demonstrate that the percentage
of follicular-type (IgDhigh) B cells expressing high levels
of CD21 and low levels of CD43 was similar in wt and
ß2m-/- mice (27% and 24%, respectively).
These CD21high follicular cells had the same intensity of
staining for CD21 and CD43 as the marginal zone B cells shown in Figure 6C for wt and ß2m-/- mice.
Approximately 60% of the CD21high follicular cells (15%
of B cells) from both mice also expressed high levels of IgM (data not
shown) and therefore showed all of the characteristics of the marginal
zone CD1high subset. In normal mice, 20% of these
follicular CD21high cells (3% of B cells) coexpressed high
levels of CD1 (data not shown).
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To determine the location of CD1high B cells in the
spleen, laser confocal microscopy was employed. Figure 7 shows three-color immunofluorescent
staining of frozen spleen sections from wt C57BL/6 mice (Fig. 7A) and ß2m-/- C57BL/6 mice
(Fig. 7B). The primary follicles in Figure 7, A
and B, stained blue-green, expressing high levels of IgD
(green) and low levels of IgM (blue). CD1 (red) was expressed strongly
on the outer rims of these primary follicles in wt C57BL/6 mice (Fig. 7A, arrows). These CD1+ cells were
IgDlow and IgMhigh, and their location
indicated that they are marginal zone B cells. A scattering of
red-staining cell aggregates was seen in the follicles. The latter
cells may correspond to the minority of
CD1highCD23+CD21high B cells
identified by flow cytometry.
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B)
showed that marginal zone B cells are still present as judged by
IgDlow (faint green) and IgMhigh (bright blue)
cells at the follicular rims (arrows). However, CD1 expression was not
detected. In the ß2m-/- mouse, the
periarteriolar lymphatic sheaths (PALS) that were detected by staining
with anti-Thy-1.2 mAb were enlarged as compared with the wt mouse
(Fig. 7A) (data not shown). In Figure 7B,
a central arteriole is indicated by the yellow arrowhead, and multiple
B cell follicles can be seen around the PALS. Very strong staining with
the 3C11 mAb was observed in the walls of blood vessels and on other
scattered cells in the red pulp in both
ß2m-/- and wt mice. The latter staining was
specific as judged by background control staining with rat IgM myeloma
protein (data not shown), but the nature of these positively stained
cells was not determined. T cell recognition of CD1 is not associated with ß2m
We previously established a panel of
CD4-CD8- T cell clones with invariant
rearrangements of the Vß7, Vß9, or Vß15 genes from the
spleens of BALB/c mice (32). Clones with the invariant Vß9
rearrangement were associated with an invariant V4.4-Ja24
rearrangement (24). Figure 8A
shows that a Vß9/V4.4 T cell clone recognized CD1, because it
vigorously proliferated in response to the CD1-transfected B cell line
A20 but did not proliferate in response to nontransfected A20 cells.
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A) but not by an isotype-matched control mAb.
Similarly, LPS-activated, wt C57BL/6 spleen cells induced T cell
proliferation that was inhibited by the 3C11 mAb. In the absence of LPS
activation, neither BALB/c nor C57BL/spleen cells stimulated a response
above background (data not shown). Surprisingly, LPS-activated spleen
cells obtained from ß2m-/- mice on the
C57BL/6 background also stimulated a response that was inhibited by
3C11 mAb. The same concentration of 3C11 mAb failed to inhibit the
[3H]thymidine incorporation of the cloned T cells in
response to various concentrations of rIL-2 (data not shown). The 1B1
mAb failed to inhibit the response of the cloned T cells to
LPS-activated, wt, and ß2m-/- C57BL/6
spleen cells (data not shown).
Most LPS-activated, wt C57BL/6 spleen cells expressed CD1 (Fig. 8B), but <1% of LPS-activated cells from
ß2m-/- mice stained above background (Fig. 8C). A similar staining pattern was observed with the 3C11
mAb, but the intensity of staining of the LPS-activated cells was not
as high as that seen with the 1B1 mAb (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of CD1 on some B cell subsets in humans has been described previously (7, 8), and recent studies of both of CD1-/- and CD1+/+ mice indicate that CD1 is expressed on most T and B lymphocytes in the spleen (20, 21). In the current study, we used two anti-CD1 (3C11 and 1B1) mAbs for the fluorescent analysis of various B cell populations. The specificity of these mAbs was confirmed by demonstrating their staining of CD1-transfected but not nontransfected B cell lymphoma A20 cells. A striking heterogeneity of CD1 expression was observed on B cell tumor lines, since another BALB/c B cell lymphoma line, BCL1, stained brightly for CD1 (33) in the absence of transfection with CD1 cDNA.
The staining of normal splenic B cells with both anti-CD1 mAbs
identified a distinct population, accounting for 15% of B
(B220+) cells, that stained brightly for CD1. The remaining
B cells in the spleen, LNs, BM, and PerC showed either dull staining or
no staining above background. The majority of non-B cells (mainly T
cells) in the spleen stained above background using the 1B1 mAb, but
this dull staining was less apparent when the 3C11 mAb was used. In all
instances, saturating concentrations of unconjugated anti-FcR
(anti-CD16/32) mAb were used to block nonspecific staining via the
FcR, and dead cells were excluded from analysis using PI staining.
Furthermore, both bright and dull staining of B cells and dull staining
of T cells, as seen with the 1B1 mAb, were markedly reduced in spleen
cells from ß2m-/- mice.
Multicolor, flow cytometric analysis demonstrated that 70 to 75% of
CD1high B cells are marginal zone B cells. These cells
expressed high levels of IgM, low levels of IgD, and lacked expression
of CD23, a phenotype that is found on B-1, immature, and marginal zone
B cells (27, 29, 30). Furthermore, the cells lacked expression of CD43
and CD5, which are markers for B-1 cells (28, 29), and expressed high
levels of CD21, which is a CR marker found on marginal zone B cells but
not on B-1 and immature B cells (31). Further evidence was obtained
from immunohistology data, which showed that the majority of
CD1high IgMhigh IgDlow B cells were
localized to the marginal zone of spleen tissue sections. The staining
of the tissue sections of ß2m-/- mice
showed that a rim of IgMhigh IgDlow cells still
surrounded the follicles; however, these cells did not stain for CD1,
which is consistent with the failure to detect CD1high B
cells among spleen cells from these mice by FACS. Gating for marginal
zone B cells (B220+
CD24low/intermediate CD23-
CD43-) revealed that 50% of these cells expressed high
levels of CD1 (data not shown), and virtually all CD1high
cells were also CD21high (Fig. 5).
Approximately 25 to 30% of B220+CD1high cells expressed the IgDhigh CD23+ phenotype of follicular B cells (27, 29). Interestingly, these cells also expressed high levels of CD21, and most cells were IgMhigh, which is a phenotype not previously associated with follicular B cells (29, 31). Based on both their high expression of IgD and CD23 and on immunohistology data, which showed occasional aggregates of CD1high cells in splenic primary follicles, we suggest that these CD1high IgDhigh IgMhigh CD23+CD21high cells are a subset of follicular B cells. Further immunohistologic data are required to confirm the presence of B cells with this phenotype in splenic follicles. Thus, approximately two-thirds of CD1high B cells expressed the phenotypic characteristics of marginal zone B cells, one-third expressed the characteristics of a novel follicular B cell subset, and the remainder included cells with characteristics of immature B cells, B-1 cells, and B cells that could not be identified with a previously described subset. Both, marginal zone B cells and CD21high IgDhigh IgMhigh follicular B cells were found in comparable numbers in ß2m-/- mice, suggesting that the expression of CD1 might not be required for the development of these B cell populations. Very bright CD1-staining cells were also detected by immunohistology in the red pulp, which is consistent with previous reports of expression on blood vessels (34).
Although CD1 expression by splenic cells from
ß2m-/- mice was markedly reduced (Figs. 2 and 3), LPS-activated spleen cells from these mice stimulated the
proliferation of a CD1-restricted Vß9/V4.4 T cell clone. This T
cell proliferation was CD1-dependent, because it was inhibited by the
anti-CD1 mAb 3C11 and was also induced by CD1-transfected but not
nontransfected A20 cells. Thus, either a ß2m-independent
form of CD1 itself or a molecule that cross-reacts with the 3C11 mAb is
expressed on the surface of LPS-activated B cells. This possibility is
consistent with recent studies on anti-CD1 T cell hybridomas that
have shown that some Vß14--expressing T cells recognize
a ß2m-independent form of CD1, whereas
Vß14+ hybridomas only recognize a
ß2m-dependent form (20). As T cell proliferation was not
blocked by 1B1, which was the second anti-CD1 mAb used here, the
current study confirms previous data showing that 1B1 recognizes only a
ß2m-dependent form of CD1 (20) and indicates that the
3C11 mAb recognized both the ß2m-dependent and the
ß2m-independent forms of CD1. The failure of 3C11 to
demonstrate a significant expression of CD1 on B cells from wt or
ß2m-/- mice as assessed by FACS could
suggest that the ß2m-independent form is expressed below
the threshold level of detection on most B cells, or that only a small
subset (<1%) of B cells in the spleen expresses this form. It is of
note that 3% of splenic B cells in ß2m-/-
mice showed dull staining for CD1 when a bright counterstain was used
in conjunction with the 3C11 mAb (Fig. 3). A
ß2m-independent form of CD1d has been reported previously
in human gastrointestinal epithelial cells (11).
The T cell recognition of CD1 on the surface of B cells may play an
important role in the pathogenesis of systemic lupus. CD4+
and CD8+ T cells expressing anti-CD1 TCR transgenes,
which were obtained from the Vß9/V4.4 T cell clone noted above,
will induce lupus when transferred into syngeneic BALB/c nude hosts
(33). These mice develop anti-dsDNA Abs, proteinuria, and ascites
(33). Furthermore, the transgenic T cells can activate wt BALB/c B
cells via the cross-linking of surface CD1 to secrete both IgM and IgG
in vitro (33). Thus, the interaction between anti-CD1 T cells and B
cells expressing surface CD1 leads to a mutual activation of both cell
types that results in hypergammaglobulinemia and systemic autoimmunity
in vivo (33). More recent studies have shown that the spontaneous
secretion in vitro of both IgM and IgG by spleen cells from lupus-prone
New Zealand Black/New Zealand White mice is mediated by the
CD1high subset of B cells (D. Zeng et al., manuscript in
preparation).
It is of interest that the CD21 molecule, which is coexpressed with high levels of CD1 on marginal zone and follicular B cells according to this study, can trap polysaccharides from microorganisms after binding to complement (35). This mechanism, as well as that provided by the mannose receptor (36), may provide a pathway by which B cells expressing CD1 can trap nonprotein Ags and process them via a TAP-independent pathway for presentation on the cell surface via CD1 (37). T cells that recognize such nonprotein Ags in association with CD1 (13, 14) may interact in particular with the CD1/CD21-expressing marginal zone B cells so as to augment their Ab responses to these nonprotein Ags. Thus, the marginal zone may be a critical site for interactions between T and B cells for certain subsets of microbial Ags.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Samuel Strober, Division of Immunology and Rheumatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5111.
3 Abbreviations used in this paper: ß2m, ß2-microglobulin; wt, wild-type; LN, lymph node; CB, Cascade Blue; PE, phycoerythrin; CR, complement receptor; SA, streptavidin; TR, Texas Red; TRITC, tetramethylrhodamine isothiocyanate; PI, propidium iodide; BM, bone marrow; PerC, peritoneal cavity; PALS, periarteriolar lymphatic sheaths.
Received for publication January 6, 1998. Accepted for publication April 15, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ T cells. Nature 372:691.[Medline]
-chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J. Exp. Med. 180:1097.
R. Ann. N. Y. Acad. Sci. 651:84.[Medline]
ß T cells. J. Immunol. 151:5348.[Abstract]
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L. Benatuil, J. Kaye, N. Cretin, J. G. Godwin, A. Cariappa, S. Pillai, and J. Iacomini Ig Knock-In Mice Producing Anti-Carbohydrate Antibodies: Breakthrough of B Cells Producing Low Affinity Anti-Self Antibodies J. Immunol., March 15, 2008; 180(6): 3839 - 3848. [Abstract] [Full Text] [PDF]
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 E. Marino, M. Batten, J. Groom, S. Walters, D. Liuwantara, F. Mackay, and S. T. Grey Marginal-Zone B-Cells of Nonobese Diabetic Mice Expand With Diabetes Onset, Invade the Pancreatic Lymph Nodes, and Present Autoantigen to Diabetogenic T-Cells Diabetes, February 1, 2008; 57(2): 395 - 404. [Abstract] [Full Text] [PDF]
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A. Cariappa, C. Boboila, S. T. Moran, H. Liu, H. N. Shi, and S. Pillai The Recirculating B Cell Pool Contains Two Functionally Distinct, Long-Lived, Posttransitional, Follicular B Cell Populations J. Immunol., August 15, 2007; 179(4): 2270 - 2281. [Abstract] [Full Text] [PDF]
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 A. A. Belperron, C. M. Dailey, C. J. Booth, and L. K. Bockenstedt Marginal Zone B-Cell Depletion Impairs Murine Host Defense against Borrelia burgdorferi Infection Infect. Immun., July 1, 2007; 75(7): 3354 - 3360. [Abstract] [Full Text] [PDF]
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K. Kumazaki, B. Tirosh, R. Maehr, M. Boes, T. Honjo, and H. L. Ploegh AID-/-{micro}s-/- Mice Are Agammaglobulinemic and Fail to Maintain B220-CD138+ Plasma Cells J. Immunol., February 15, 2007; 178(4): 2192 - 2203. [Abstract] [Full Text] [PDF]
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 B. Srivastava, W. J. Quinn III, K. Hazard, J. Erikson, and D. Allman Characterization of marginal zone B cell precursors J. Exp. Med., November 7, 2005; 202(9): 1225 - 1234. [Abstract] [Full Text] [PDF]
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Y. Geng, P. Laslo, K. Barton, and C.-R. Wang Transcriptional Regulation of CD1D1 by Ets Family Transcription Factors J. Immunol., July 15, 2005; 175(2): 1022 - 1029. [Abstract] [Full Text] [PDF]
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J. S. Bezbradica, A. K. Stanic, N. Matsuki, H. Bour-Jordan, J. A. Bluestone, J. W. Thomas, D. Unutmaz, L. Van Kaer, and S. Joyce Distinct Roles of Dendritic Cells and B Cells in Va14Ja18 Natural T Cell Activation In Vivo J. Immunol., April 15, 2005; 174(8): 4696 - 4705. [Abstract] [Full Text] [PDF]
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J. Rolf, V. Motta, N. Duarte, M. Lundholm, E. Berntman, M.-L. Bergman, L. Sorokin, S. L. Cardell, and D. Holmberg The Enlarged Population of Marginal Zone/CD1dhigh B Lymphocytes in Nonobese Diabetic Mice Maps to Diabetes Susceptibility Region Idd11 J. Immunol., April 15, 2005; 174(8): 4821 - 4827. [Abstract] [Full Text] [PDF]
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L. J. Kobrynski, A. O. Sousa, A. J. Nahmias, and F. K. Lee Cutting Edge: Antibody Production to Pneumococcal Polysaccharides Requires CD1 Molecules and CD8+ T Cells J. Immunol., February 15, 2005; 174(4): 1787 - 1790. [Abstract] [Full Text] [PDF]
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 Y. Lin, T. J. Roberts, P. M. Spence, and R. R. Brutkiewicz Reduction in CD1d expression on dendritic cells and macrophages by an acute virus infection J. Leukoc. Biol., February 1, 2005; 77(2): 151 - 158. [Abstract] [Full Text] [PDF]
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N. Kanayama, M. Cascalho, and H. Ohmori Analysis of Marginal Zone B Cell Development in the Mouse with Limited B Cell Diversity: Role of the Antigen Receptor Signals in the Recruitment of B Cells to the Marginal Zone J. Immunol., February 1, 2005; 174(3): 1438 - 1445. [Abstract] [Full Text] [PDF]
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I. Girkontaite, V. Sakk, M. Wagner, T. Borggrefe, K. Tedford, J. Chun, and K.-D. Fischer The Sphingosine-1-Phosphate (S1P) Lysophospholipid Receptor S1P3 Regulates MAdCAM-1+ Endothelial Cells in Splenic Marginal Sinus Organization J. Exp. Med., December 6, 2004; 200(11): 1491 - 1501. [Abstract] [Full Text] [PDF]
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 A. R. Ferguson, M. E. Youd, and R. B. Corley Marginal zone B cells transport and deposit IgM-containing immune complexes onto follicular dendritic cells Int. Immunol., October 1, 2004; 16(10): 1411 - 1422. [Abstract] [Full Text] [PDF]
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E. C. Whipple, R. S. Shanahan, A. H. Ditto, R. P. Taylor, and M. A. Lindorfer Analyses of the In Vivo Trafficking of Stoichiometric Doses of an Anti-Complement Receptor 1/2 Monoclonal Antibody Infused Intravenously in Mice J. Immunol., August 15, 2004; 173(4): 2297 - 2306. [Abstract] [Full Text] [PDF]
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S. Atencio, H. Amano, S. Izui, and B. L. Kotzin Separation of the New Zealand Black Genetic Contribution to Lupus from New Zealand Black Determined Expansions of Marginal Zone B and B1a Cells J. Immunol., April 1, 2004; 172(7): 4159 - 4166. [Abstract] [Full Text] [PDF]
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C. S. Goodyear, M. Narita, and G. J. Silverman In Vivo VL-Targeted Activation-Induced Apoptotic Supraclonal Deletion by a Microbial B Cell Toxin J. Immunol., March 1, 2004; 172(5): 2870 - 2877. [Abstract] [Full Text] [PDF]
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L. Heltemes-Harris, X. Liu, and T. Manser Progressive Surface B Cell Antigen Receptor Down-Regulation Accompanies Efficient Development of Antinuclear Antigen B Cells to Mature, Follicular Phenotype J. Immunol., January 15, 2004; 172(2): 823 - 833. [Abstract] [Full Text] [PDF]
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N. Lee and D. E. Geraghty HLA-F Surface Expression on B Cell and Monocyte Cell Lines Is Partially Independent from Tapasin and Completely Independent from TAP J. Immunol., November 15, 2003; 171(10): 5264 - 5271. [Abstract] [Full Text] [PDF]
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C. M. Witt, W.-J. Won, V. Hurez, and C. A. Klug Notch2 Haploinsufficiency Results in Diminished B1 B Cells and a Severe Reduction in Marginal Zone B Cells J. Immunol., September 15, 2003; 171(6): 2783 - 2788. [Abstract] [Full Text] [PDF]
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H. Amano, E. Amano, T. Moll, D. Marinkovic, N. Ibnou-Zekri, E. Martinez-Soria, I. Semac, T. Wirth, L. Nitschke, and S. Izui The Yaa Mutation Promoting Murine Lupus Causes Defective Development of Marginal Zone B Cells J. Immunol., March 1, 2003; 170(5): 2293 - 2301. [Abstract] [Full Text] [PDF]
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 T. Samardzic, D. Marinkovic, P. J. Nielsen, L. Nitschke, and T. Wirth BOB.1/OBF.1 Deficiency Affects Marginal-Zone B-Cell Compartment Mol. Cell. Biol., December 1, 2002; 22(23): 8320 - 8331. [Abstract] [Full Text] [PDF]
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 S.-J. Kang and P. Cresswell Calnexin, Calreticulin, and ERp57 Cooperate in Disulfide Bond Formation in Human CD1d Heavy Chain J. Biol. Chem., November 15, 2002; 277(47): 44838 - 44844. [Abstract] [Full Text] [PDF]
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W.-J. Won and J. F. Kearney CD9 Is a Unique Marker for Marginal Zone B Cells, B1 Cells, and Plasma Cells in Mice J. Immunol., June 1, 2002; 168(11): 5605 - 5611. [Abstract] [Full Text] [PDF]
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K. M. Tumas-Brundage, E. Notidis, L. Heltemes, X. Zhang, L. J. Wysocki, and T. Manser Predominance of a novel splenic B cell population in mice expressing a transgene that encodes multireactive antibodies: support for additional heterogeneity of the B cell compartment Int. Immunol., April 1, 2001; 13(4): 475 - 484. [Abstract] [Full Text] [PDF]
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T. Dao, M. Exley, W. Z. Mehal, S. M. A. Tahir, S. Snapper, M. Taniguchi, S. P. Balk, and I. N. Crispe Involvement of CD1 in Peripheral Deletion of T Lymphocytes Is Independent of NK T Cells J. Immunol., March 1, 2001; 166(5): 3090 - 3097. [Abstract] [Full Text] [PDF]
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M. Batten, J. Groom, T. G. Cachero, F. Qian, P. Schneider, J. Tschopp, J. L. Browning, and F. Mackay Baff Mediates Survival of Peripheral Immature B Lymphocytes J. Exp. Med., November 20, 2000; 192(10): 1453 - 1466. [Abstract] [Full Text] [PDF]
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H. Kumar, A. Belperron, S. W. Barthold, and L. K. Bockenstedt Cutting Edge: CD1d Deficiency Impairs Murine Host Defense Against the Spirochete, Borrelia burgdorferi J. Immunol., November 1, 2000; 165(9): 4797 - 4801. [Abstract] [Full Text] [PDF]
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D. Zeng, M.-K. Lee, J. Tung, A. Brendolan, and S. Strober Cutting Edge: A Role for CD1 in the Pathogenesis of Lupus in NZB/NZW Mice J. Immunol., May 15, 2000; 164(10): 5000 - 5004. [Abstract] [Full Text] [PDF]
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D. Zeng, G. Gazit, S. Dejbakhsh-Jones, S. P. Balk, S. Snapper, M. Taniguchi, and S. Strober Heterogeneity of NK1.1+ T Cells in the Bone Marrow: Divergence from the Thymus J. Immunol., November 15, 1999; 163(10): 5338 - 5345. [Abstract] [Full Text] [PDF]
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H. S. Kim, J. Garcia, M. Exley, K. W. Johnson, S. P. Balk, and R. S. Blumberg Biochemical Characterization of CD1d Expression in the Absence of beta 2-Microglobulin J. Biol. Chem., April 2, 1999; 274(14): 9289 - 9295. [Abstract] [Full Text] [PDF]
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K. Somnay-Wadgaonkar, A. Nusrat, H. S. Kim, W. P. Canchis, S. P. Balk, S. P. Colgan, and R. S. Blumberg Immunolocalization of CD1d in human intestinal epithelial cells and identification of a ß2-microglobulin-associated form Int. Immunol., March 1, 1999; 11(3): 383 - 392. [Abstract] [Full Text] [PDF]
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