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Department of Molecular Biology, Princeton University, Princeton, NJ 08544
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells with
semiinvariant TCRs that promptly releases potent cytokines such as IL-4
and IFN-
upon stimulation. To gain insight into the function of
CD1.1, a panel of nine mAbs was generated and used to biochemically
characterize and monitor the surface expression of CD1.1 on different
cell types. CD1.1 is a heavily glycosylated,
ß2-microglobulin-associated surface protein. Its
recognition by a panel of 12 V14-positive and -negative CD1-specific
ß T cell hybridomas was blocked by two groups of mAbs that bound
to adjacent clusters of epitopes, indicating that different ß TCRs
bind to the same region of CD1.1, presumably above the groove.
Remarkably, CD1.1 was mainly expressed by dendritic cells, B cells, and
macrophages, suggesting a function in Ag presentation to Th cells.
Furthermore, the cell type that expressed the highest levels of CD1.1
was the splenic marginal zone B cell, a distinct subset of B cells that
also expresses CD21 (the C3d receptor) and may be involved in natural
responses to bacterial Ags. Altogether, the results support the idea
that CD1.1 may function in recruiting a form of innate help from
specialized cytokine producer ß T cells to APCs, a role that might
be important at the preadaptive phase of immune responses to some
microbial pathogens. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cells.
Human CD1b-expressing monocytic and dendritic cells could present
mycobacterial lipids loaded in an endosomal compartment to double
negative ß T cells (6, 7, 8). In addition, elucidation of the
structure of mouse CD1.1 revealed a very hydrophobic groove that
could potentially accommodate hydrophobic lipid or peptide ligands (9).
Indeed, a set of synthetic peptides containing a hydrophobic motif was
shown to bind to CD1.1 in vitro (10).
Although CD1-specific cells expressing variable TCR - and ß-chains
have been reported (11), a remarkable feature of the mouse system and
its human CD1d homologue is the existence of a conserved set of
CD1-specific T cells that utilize TCRs made of an invariant
V14-J281 (human V24-JQ) -chain paired with distinct
families of TCRß-chains such as mouse Vß8 (human Vß11) (12, 13).
These CD1-specific ß T cells, which are CD4-positive or
CD4/CD8-negative, also express NK receptors and have been referred to
as NK1.1+ T cells (5, 14, 15). Mouse (16, 17) and human
(18) CD1-specific cells exhibit a high frequency of autoreactivity to
CD1-expressing cells, and are dependent on CD1 for selection (19, 20, 21).
Their unusual property of very rapidly releasing potent cytokines such
as IL-4 and IFN- upon TCR engagement has led to the speculation that
they might constitute an innate regulatory or effector immune
pathway, but the conditions and consequences of their recruitment in
vivo remain undefined.
Previous experiments established that CD1 is mainly expressed by cells of hemopoietic origin and by hepatocytes (4, 22, 23, 24, 25). We have now generated a panel of nine anti-CD1 mAbs and examined the form and the pattern of CD1.1 and CD1.2 surface expression by hemopoietic cells. The CD1.1 and CD1.2 genes are 95% identical, yet are differentially transcribed in different tissues (23). Although most mAbs recognized the products of both the CD1.1 and CD1.2 genes, we were able to focus on CD1.1 by making use of our observation that the C57BL/6 strain only expresses CD1.1 (50). The results presented in this paper demonstrate that CD1.1 is expressed as a heavily glycosylated, ß2m-associated protein in transfected lines as well as in fresh mouse CD1-expressing cells. Five mAbs that blocked CD1.1 recognition by all members of a panel of 12 CD1-specific T cell hybrids delineated two adjacent clusters of CD1.1 epitopes, presumably centered around the groove. In strong support of the hypothesis that CD1.1 is directly or indirectly involved in Ag presentation to Th cells, we found that it was conspicuously expressed at high levels on dendritic cells, MHC class II+ macrophages, and B cells. In addition, we identified the splenic marginal zone B (MZB) cell, a minor subset of B lymphocytes that is believed to be involved in the natural response to complement-coated bacterial Ags, as the cell type that expressed the highest constitutive levels of CD1.1. These results further support the idea that NK1.1 T cells and other CD1-specific cells might be involved in some form of innate immunity to microbial pathogens.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6-, C57BL/6.ß2m-deficient (26) (backcrossed 10 times to C57BL/6), and C57BL/6.TAP-1-deficient (27) mice (backcrossed four times to C57BL/6) were maintained under specific pathogen-free conditions in our barrier facility. Other mouse strains were purchased from The Jackson Laboratory (Bar Harbor, ME).
Generation of CD1.1 transfectants
The generation of the CD1.1-transfected cell lines C57SV-CD1.1 (mouse B6 fibroblast), CR1-CD1.1 (human B cell), and RBL-CD1.1 (rat basophil) is described elsewhere.4
Generation of anti-CD1 mAbs
Male Wistar rats, purchased from Charles River (Wilmington, DE) were immunized with C57BL/6 thymocytes, boosted three times with the RBL-CD1.1-transfected rat cell line, once with BALB/c thymocytes, and received a final boost with CR1-CD1.1 cells 3 days before fusion with Sp2/0. Hybridoma supernatants were screened for CD1 specificity by FACS analysis on CD1.1-transfected and untransfected cells. mAbs were purified using protein G beads (Pharmacia Biotech, Piscataway, NJ). For flow cytometry, purified mAbs were biotinylated with aminohexannoyl-biotin N-hydroxy Succinimide ester (Zymed, San Francisco, CA). Ab isotypes were determined by flow cytometry using rat isotype-specific reagents (Caltag, San Francisco, CA).
Generation of CD1-specific T cell hybridomas
The derivation and characterization of the CD1.1-specific T cell hybridomas has been described in detail elsewhere (13, 17).4 Stimulation by CD1.1-expressing thymocytes or splenocytes was assayed by measuring the IL-2 released in the supernatant of 24-h cultures as described (13, 17). Ab blocking was performed with 2 µg/ml of purified mAbs, a concentration that did not affect the stimulation of a CD1-unreactive control T cell hybridoma.
Immunoprecipitation of CD1.1
Cell surface proteins were biotinylated with 0.5 mg/ml sulfo-NHS-SS-biotin (Pierce, Rockford, IL) for 30 min at room temperature. In metabolic labeling experiments, cells were pulsed for 2 h with 1 mCi of 35S-cysteine/methionine (Pro-Mix; Amersham, Arlington Heights, IL) per 1 to 2 x 107 cells. In some cases, cells were previously cultured for 12 h in medium containing 1 µg/ml of tunicamycin (Calbiochem, La Jolla, CA) to prevent addition of N-linked carbohydrates. Labeled cells were then harvested after treatment with 0.05% trypsin (Biofluids, Rockville, MD), and washed twice in PBS before lysing in 10 mM Tris, pH 7.4, 150 mM NaCl, 1% Triton X-100 at 5 x 107 cells per ml for 20 min at 4°C. Nuclei were removed by pelleting immediately after lysis and the lysate precleared overnight on Protein G beads (Pharmacia) coated with an irrelevant isotype-matched Ab. Specific immunoprecipitation was conducted for 3 h at 4°C by incubation with mAb-coated Protein G beads, and immunoprecipitates washed twice with 50 mM Tris, pH 7.4, 100 mM NaCl, 2 mM EDTA, 2% Triton X-100 and once with 50 mM Tris, pH 8.0, 120 mM NaCl, 0.5% Nonidet P-40. Beads were resuspended in loading buffer (10 mM Tris, pH 8.0, 1 mM EDTA, 2.5% SDS, 20% glycerol, bromophenol blue) and boiled for 5 min before loading onto SDS-PAGE gels.
FACS analysis
Biotinylated anti-CD1 Abs were prepared as described above and titrated to establish optimal concentrations for use in flow cytometry. Anti-B220-CyChrome (RA6-3B2), -CD5-FITC (53-7.3), -CD8-FITC (53-6.7), -CD11b-FITC (M1/70), -CD11c-FITC (HL3), -CD21-FITC (7G6), -CD23-FITC (B3B4), -HSA-FITC (M1/69), -I-Ab-FITC (Y3P), -IgM-FITC (R6-60.2), and -CD1-biotin (1B1) were purchased from PharMingen (San Diego, CA). 3C11 anti-CD1 was a gift of Dr. Terhorst (Harvard Medical School, Boston, MA). Anti-CD4-tricolor (CT-CD4) and streptavidin-phycoerythrin (PE) were purchased from Caltag. Multicolor staining was conducted after FcR blocking with 2.4G2 (American Type Culture Collection, Rockville, MD), and analysis was performed on a FACScan (Becton Dickinson, San Jose, CA) using Cellquest software (Becton Dickinson). Analyses presented as panel sets of a given figure are from the same experiment so that fluorescence intensities can be compared. Comparison of relative levels of CD1.1 were made using the mean fluorescence intensity of the histogram profiles on a FACScan calibrated with standard fluorescent beads. For competition experiments, purified blocking Abs were used at 30-fold or greater excess over the biotinylated Abs.
Generation of dendritic cells
Enriched dendritic cell populations were prepared by adherence/de-adherence of spleen cells on plastic culture dishes as described (28).
Immunohistochemistry
Preparation and staining of frozen C57BL/6- and CD1-deficient spleen sections were conducted as previously described (29) using PNA-HRP (ICN, Costa Mesa, CA) and 19G11-biotin detected with streptavidin-alkaline phosphatase (Southern Biotechnology Associates, Birmingham, AL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of nine hybridomas specific for CD1.1-transfected cells
was isolated, eight of which were IgG2b and one IgG1 (20H2). All mAbs
cross-reacted onto CD1.2-transfected cells, except 15F7 (not shown).
However, we have observed that the C57BL/6 mouse strain carries a
frameshift mutation at the 5' end of the exon encoding the 3
domain4 that is predicted to abolish surface
expression. Since all experiments reported in this paper utilized cells
from the C57BL/6 strain, the analysis is focused on CD1.1, thereby
avoiding the ambiguities that might arise from the simultaneous
detection of the products of two differently regulated genes. As
reported previously by others (22, 30) and shown in Figure 1
for a representative mAb, 19G11,
staining of ß2m knockout thymocytes was reduced by at
least 10-fold, down to almost background levels for nine of nine
anti-CD1.1 mAbs, whereas staining of TAP knockout cells was
unaltered. A similar result was obtained with spleen cells (not shown).
These results therefore further support the conclusion that CD1.1
depends on ß2m but does not require TAP-dependent peptide
loading for surface expression. It remains possible, however, that a
ß2m-independent form of CD1 that would escape detection
by all nine mAbs exists at the surface of some cell types
(31).
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B for two mAbs and was observed with all mAbs (not
shown). The larger size of the immunoprecipitated heavy chain band
relative to the predicted 36 kDa size of an unmodified CD1.1 protein
has been previously reported to be due to N-linked
glycosylation based upon Endo F treatment experiments (25). Likewise,
when CD1.1 was immunoprecipitated from fresh, biotin-labeled C57BL/6
thymocytes, we also observed a highly glycosylated heavy chain and
ß2m (data not shown).
The very high level of glycosylation of CD1.1 raised the possibility
that some mAbs recognized only a subset of surface CD1.1 molecules
based upon their particular glycosylation status. To test whether
recognition of CD1.1 by the anti-CD1 mAbs of our panel was
dependent upon N-linked carbohydrates, CD1.1 was immunoprecipitated
from metabolically labeled C57SV-CD1.1 grown in the presence of
tunicamycin. Tunicamycin blocks the transfer of N-linked carbohydrate
to the protein. Thus, protein synthesized in the presence of
tunicamycin lacks N-linked carbohydrate. As shown in Figure 1C for 19G11 and 16G9 (and also observed with each of two
additional mAbs, 20H2 and 14F5), immunoprecipitates of lysates from
metabolically labeled tunicamycin-treated C57SV-CD1.1 cells resulted in
a sharp 36-kDa band as predicted for the core CD1.1 protein (Fig. 1C). The isotype-matched anti-Kb mAb
R1.21.2 immunoprecipitated the expected glycosylated (47-kDa) and
unglycosylated (40-kDa) Kb heavy chain bands from the
control and tunicamycin-treated cells, respectively. These results
therefore suggest that these anti-CD1.1 mAbs are binding primarily
to the core protein rather than to carbohydrate determinants.
Using a flow cytometric competition assay, we next determined the
spatial relationship of the epitopes recognized by the different Abs.
Excess purified Abs were used as cold competitors for biotinylated Abs.
In addition, the rat IgG2b anti-CD1 mAb 1B1 (22) that became
commercially available during the course of this study, as well as the
IgM anti-CD1 Ab 3C11 (detected by an anti-rat IgM reagent),
were included in the competition analysis. A summary of the results,
graphically presented in the upper panel of
Figure 2, identifies at least four
distinct clusters of epitopes recognized by 3C11/1B1/14F5/15C6/17F5,
15F7/19G11/20H2, 16G9/4C4, and 19F8.
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We previously reported that 3C11, the first anti-CD1.1 mAb available, could block the stimulation of two CD1-specific T cell hybridomas by C57BL/6 thymocytes, but could not block a third one (13). One possible explanation for this split blocking pattern was that 3C11 did not recognize CD1.2 and therefore would not block T cell hybridomas that cross-reacted onto CD1.2. However, our recent observation that C57BL/6 mice only expressed CD1.1 due to a frameshift mutation in CD1.24 contradicted this hypothesis, suggesting instead that 3C11 either failed to bind the relevant form of CD1.1 (for example, differently glycosylated or ligand associated CD1.1) or that it bound to a region that did not contribute major interactions with the TCR of the resistant CD1-specific T cell hybridoma.
Using our extended panels of 11 mAbs and 12 CD1-specific T cell
hybridomas, we have now performed a systematic analysis of the patterns
of mAb-mediated blocking of T cell recognition of CD1.1. The results
are graphically summarized in the lower panel of
Figure 2. They indicate that only the five mAbs 15C6, 17F5, 15F7,
19G11, and 20H2 invariably blocked T cell recognition of CD1.1. These
mAbs all belonged to two relatively well-demarcated clusters of
epitopes (see black squares in Fig. 2). Furthermore, the fact that some
mAbs of one cluster could partially block binding of mAbs of the other
cluster indicated that, although separate, the two clusters were
adjacent. Altogether, the results support the conclusion that all
ß TCRs contact CD1.1 in the same region, presumably above the
groove, and that the two mAb clusters are located at adjacent positions
in this region. Conversely, 19F8, which defines its own cluster, failed
to block CD1.1 recognition by any of the ß TCRs, suggesting that
its binding site is located away from the CD1.1 groove.
Interestingly, several mAbs behaved like 3C11 in that they failed to
block some CD1-specific TCRs and completely blocked others. This was
unlikely to result simply from differences in binding affinities, as
reciprocal patterns of blocking were observed. For example, the mAb
3C11 blocked 1C8.DC1 but not SBC12, whereas mAb 16G9 blocked SBC12 but
not 1C8.DC1. Rather, in accordance with our demonstration that the mAbs
bind to distinct regions of CD1.1, the results may suggest that
different regions of CD1.1 contribute interactions of variable
importance for binding of individual ß TCRs. Alternatively, it is
possible that a modified form of CD1.1 that is recognized by an
individual TCR-ß may not be recognized by a particular mAb.
Although the tunicamycin experiments suggested that glycosylation did
not modify CD1.1 binding by the members of the panel of anti-CD1.1
mAbs examined (19G11, 16G9, 14F5, and 20H2), the possibility that some
mAbs recognize subsets of CD1.1 associated with particular ligands, as
recently shown with anti-MHC II mAbs (32, 33), remains to be
tested.
The expression pattern of CD1.1
Previous functional and expression assays indicated that CD1 was
expressed by thymocytes and splenocytes (4, 22, 23, 25), although the
relative levels of expression between different subsets of cells were
not precisely compared or were obscured by limitations inherent to the
use of a single mAb or by the potential recognition of both CD1.1 and
CD1.2. In particular, the report that some CD1.1-specific T cell
hybridomas recognized CD1.1-expressing thymocytes but not splenocytes
suggested that CD1.1 was expressed at significantly lower levels by
splenocytes. Surprisingly, however, histogram analyses of total
lymphoid populations in the spleen and thymus stained with the various
mAbs showed that a large proportion of splenocytes expressed CD1.1 at
levels similar to those of thymocytes (Fig. 3, compare A and
B). Multicolor analysis using B cell- and T
cell-specific markers allowed us to determine the relative levels of
CD1.1 expression of B cells and T cells in the spleen (Fig. 3, B–D and Fig. 4C). Additional
experiments have now established that CD1.1 recognition by some T cells
is tissue and cell specific, so that there exist T cells that respond
to CD1.1 expressed by cortical thymocytes and not B cells. Conversely,
other T cells respond to B cells and not cortical
thymocytes.4 Altogether, these results strongly suggest
that it is preferential recognition of modified forms of CD1.1,
possibly associated with tissue-specific self-ligands, rather than
simple differences in CD1.1 expression levels that accounts for the
differential responses of these T cell clones.
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, C and D show that
CD4/CD8 double positive (DP) thymocytes expressed high levels of CD1.1,
single positive CD4 thymocytes expressed levels of CD1.1 similar to
that of DP thymocytes, and single positive CD8 thymocytes expressed
approximately twofold less CD1.1. Mature CD4 T cells found in
peripheral organs such as spleen (CD4, Fig. 3C) or
lymph node (data not shown) had on average a twofold decrease in CD1.1
levels compared with DP and single positive CD4 thymocytes. Mature,
peripheral CD8 T cells in the spleen (CD8, Fig. 3D)
or lymph node (data not shown) also showed a further twofold reduction
in CD1.1 levels compared with single positive CD8 thymocytes. Thus,
similar to what was previously reported for the various human CD1
isotypes (34), levels of mouse CD1.1 decrease as thymocytes mature and
become peripheral T cells.
We also examined the relative levels of CD1.1 expression by various
classes of APCs. Adherent/de-adherent, in vitro-purified splenic
dendritic cells expressed very high levels of CD1.1, approximately
three times above that of the majority of splenic B cells (Fig. 4, compare A and C). Among fresh peritoneal
macrophages (Mac-1+), the I-A+ subpopulation
expressed higher levels of CD1.1 (Fig. 4B),
suggesting that subsets of macrophages that are naturally activated
also overexpress CD1.1. Finally, the bulk of splenic B cells
(B220+) expressed CD1.1 at levels similar to those of
cortical thymocytes (Fig. 4C, and compare Fig. 3, A and B), although approximately 6 to 8%
of splenic B cells expressed CD1.1 at very high levels (Fig. 4C, and see below).
We next investigated the relative levels of expression of CD1.1 on B
cell subsets in the spleen and other sites, using B220 to identify B
cells. CD5 was also used to exclude T cells in the spleen and lymph
node and to define the B1 B cell lineage (Ly1, or CD5+, B
cells (35)) in the peritoneum. CD1.1 levels may decrease slightly as B
cells develop into mature B cells, since the levels of CD1.1 on (mostly
immature) bone marrow B cells were slightly higher (1.7 fold) than on
(mostly mature) lymph node B cells (Fig. 5, compare A and
C). Both conventional B2 B cells and B1 (Ly1) B cells
in the peritoneum expressed CD1.1 at levels equivalent to bone marrow B
cells (Fig. 5D). B cells in the spleen showed three
distinguishable levels of CD1.1 expression (Fig. 5B,
arrows). The largest population of splenic B cells expressed a level of
CD1.1 that was equivalent to that observed on the mature lymph node B
cells. A second population of B cells in the spleen expressed CD1.1 at
levels comparable to that of B cells in the bone marrow. Finally, a
small but distinct B cell population expressed very high levels of
CD1.1.
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, HSAhigh,
CD1int). In conjunction with an HSAlow
phenotype, the CD21int, CD23high, and
IgMlow phenotype of the bulk population of splenic B cells
(Fig. 6) indicated that they were mature follicular B cells
(37, 38, 39, 40).
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B and 6;
see also Figs. 3A and 4C). These
CD1.1high cells, which expressed seven times more CD1.1
than the bulk population of B cells, were also clearly distinguished by
their HSAint, CD21high, CD23low,
IgMhigh, IgDlow phenotype (Fig. 6, and data not
shown for IgD), and by their larger size (mean FSC of 428 vs 321 for
the rest of B cells, data not shown). They did not appear to be B1 B
cells based on CD5 expression (data not shown). Furthermore, the
HSAint and CD21high phenotype of these cells
clearly distinguishes them from the immature B cells that have recently
emigrated from the bone marrow. Thus, the phenotype of the
CD1high B cells is most consistent with that of MZB cells
(37, 38, 39, 40). This conclusion is in accordance with the fact that C3H mice,
which were reported to have an increased number of MZB cells (40), also
had an increased proportion of CD1.1high B cells (32% of
C3H B cells are CD1.1high, as detected by the
CD1.1-specific mAb 15F7, compared with 12% of C57BL/6 B cells, data
not shown). Finally, immunohistochemistry (Fig. 7) confirmed that the cells that were
CD1high did indeed localize to the splenic marginal zone.
In conclusion, the results demonstrate that the CD1high
phenotype is characteristic and specific of splenic MZB cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An important step toward understanding the enigmatic immune function of CD1.1 is to define its pattern of expression in normal tissues and cells, and to identify the cell types that express the highest surface levels. In this study, we described the largest panel of mAbs to CD1.1 produced to date, and we defined at least four clusters of CD1.1 epitopes. Taking advantage of our observation that the nearly identical CD1.2 molecule is not expressed at the surface of C57BL/6 cells4 and seems to be poorly if at all expressed in other mouse strains (S.-H.P. and A.B., unpublished observations), we could focus on the expression of the relevant CD1.1 molecule in vivo.
Using mAbs that recognized CD1.1 independently of N-linked carbohydrates, we confirmed that CD1.1 was expressed on the surface of transfected cell lines as well as fresh thymocytes as a ß2m-associated, heavily N-glycosylated protein. Surprisingly, although five of the mAbs of the panel consistently and completely blocked CD1.1 recognition by all members of a panel of 12 autoreactive T cell hybridomas, we found that the two previously reported anti-CD1.1 mAbs, 3C11 and 1B1, as well as three mAbs of our own panel could only block CD1.1 recognition by some, but not other, T cell hybrids. The molecular basis of this unusual observation remains to be established. It is possible that these mAbs only recognize a subset of the CD1.1 molecules expressed on the surface, possibly because they are sensitive to glycosylation or to ligand-induced conformational changes. In any case, this result emphasizes the value of assessing CD1.1 expression with a larger panel of mAbs, and most importantly from a functional point of view, with mAbs that consistently block T cell recognition of CD1.1 molecules.
We confirmed the previously reported conclusion (22) that CD1.1 is expressed by cells of hemopoietic origin. In addition, we examined the relative levels of expression among the different cell types of hemopoietic origin, and made the observation that they vary in a manner that is suggestive of function. Although mature T cells expressed low levels of CD1.1, cell types endowed with the ability to introduce foreign Ags to the immune system, including dendritic cells, MHC class II+ macrophages, and B cells, expressed the highest levels of CD1.1.
Most remarkably, a minor subset of B cells expressing very high levels
of CD1.1 was found and identified as the splenic MZB cell population.
This observation may shed light on the enigmatic function of CD1.1.
Indeed, the MZB cell is a phenotypically and functionally distinct cell
type (44) that may be involved in some innate forms of B cell responses
(45, 46). Unlike dendritic cells, which can survey the peripheral
tissues and return to the lymphoid system displaying foreign Ag and
costimulatory molecules, the MZB cell is a fixed resident of the
spleen. Nonetheless, the histologic location of MZB cells is at the
point where blood enters the spleen through the marginal sinuses, so
that MZB cells are well situated for the capture of blood-borne
pathogens. In addition, marginal zone B cells express high levels of
the complement receptor CD21 (37), which greatly enhances the B cell
response to complement-coated Ags (47). The strategic location of MZB
cells and their expression of CD21 make them remarkably well suited
therefore for the capture of complement-coated bacteria. A number of
studies suggest that MZB cell responses could be amplified or switched
through cytokines released by nonconventional helper cells. Such help
could be provided by NK cells (48), which seem to localize
preferentially to the splenic marginal zone (46), or might come from
CD1-restricted T cells, which are known to very promptly secrete
cytokines such as IL-4 and IFN-. Indeed, NK1.1+
CD1-specific T cells share with at least some MZB cells (49) several
unusual characteristics, including the expression of self-reactive,
germline-encoded Ag receptors, and of receptors associated with the
innate immune system, suggesting a function at the early, innate, phase
of immune responses. The fact that CD1 family members may specialize in
presenting bacterial glycolipids (3) further strengthens the idea that
CD1high MZB cells and CD1-specific NK1.1+ T
cells could be involved in some important aspects of innate responses
to blood-borne microbial pathogens.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Albert Bendelac, Department of Molecular Biology, Princeton University, Princeton, NJ 08544. E-mail address:
3 Abbreviations used in this paper: ß2m, ß2-microglobulin; MZB, marginal zone B cell; DP, double positive; HSA, heat-stable antigen; PE, phycoerythrin.
Received for publication September 17, 1997. Accepted for publication December 1, 1997.
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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 MHC class I-specific CD4+ and CD4-8- T cells in mice and humans. J. Exp. Med. 180:1097.ß cells: new clues to their origin, specificity, and function. J. Exp. Med. 182:633.This article has been cited by other articles:
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  L. Bai, Y. Sagiv, Y. Liu, S. Freigang, K. O. A. Yu, L. Teyton, S. A. Porcelli, P. B. Savage, and A. Bendelac Lysosomal recycling terminates CD1d-mediated presentation of short and polyunsaturated variants of the NKT cell lipid antigen {alpha}GalCer PNAS, June 23, 2009; 106(25): 10254 - 10259. [Abstract] [Full Text] [PDF]
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 C. H. Tripp, F. Sparber, I. F. Hermans, N. Romani, and P. Stoitzner Glycolipids Injected into the Skin Are Presented to NKT Cells in the Draining Lymph Node Independently of Migratory Skin Dendritic Cells J. Immunol., June 15, 2009; 182(12): 7644 - 7654. [Abstract] [Full Text] [PDF]
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 L. Moens, A. Jeurissen, S. Nierkens, L. Boon, L. Van Kaer, A. Kasran, G. Wuyts, J. L. Ceuppens, and X. Bossuyt Generation of Antibody Responses to Pneumococcal Capsular Polysaccharides Is Independent of CD1 Expression in Mice Infect. Immun., May 1, 2009; 77(5): 1976 - 1980. [Abstract] [Full Text] [PDF]
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 P. CHOPRA, P. DIIORIO, S. C. PINO, S. B. WILSON, N. E. PHILLIPS, J. P. MORDES, A. A. ROSSINI, D. L. GREINER, L. D. SHULTZ, and R. BORTELL Failure of {alpha}-Galactosylceramide to Prevent Diabetes in Virus-inducible Models of Type 1 Diabetes in the Rat In Vivo, March 1, 2009; 23(2): 195 - 201. [Abstract] [Full Text] [PDF]
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R. Racine, M. Chatterjee, and G. M. Winslow CD11c Expression Identifies a Population of Extrafollicular Antigen-Specific Splenic Plasmablasts Responsible for CD4 T-Independent Antibody Responses during Intracellular Bacterial Infection J. Immunol., July 15, 2008; 181(2): 1375 - 1385. [Abstract] [Full Text] [PDF]
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P. Barral, J. Eckl-Dorna, N. E. Harwood, C. De Santo, M. Salio, P. Illarionov, G. S. Besra, V. Cerundolo, and F. D. Batista B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo PNAS, June 17, 2008; 105(24): 8345 - 8350. [Abstract] [Full Text] [PDF]
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N. W. Kin, D. M. Crawford, J. Liu, T. W. Behrens, and J. F. Kearney DNA Microarray Gene Expression Profile of Marginal Zone versus Follicular B Cells and Idiotype Positive Marginal Zone B Cells before and after Immunization with Streptococcus pneumoniae J. Immunol., May 15, 2008; 180(10): 6663 - 6674. [Abstract] [Full Text] [PDF]
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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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N. Schrantz, Y. Sagiv, Y. Liu, P. B. Savage, A. Bendelac, and L. Teyton The Niemann-Pick type C2 protein loads isoglobotrihexosylceramide onto CD1d molecules and contributes to the thymic selection of NKT cells J. Exp. Med., April 16, 2007; 204(4): 841 - 852. [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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S. Seo, T. Asai, T. Saito, T. Suzuki, Y. Morishita, T. Nakamoto, M. Ichikawa, G. Yamamoto, M. Kawazu, T. Yamagata, et al. Crk-Associated Substrate Lymphocyte Type Is Required for Lymphocyte Trafficking and Marginal Zone B Cell Maintenance J. Immunol., September 15, 2005; 175(6): 3492 - 3501. [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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A. A. Belperron, C. M. Dailey, and L. K. Bockenstedt Infection-Induced Marginal Zone B Cell Production of Borrelia hermsii-Specific Antibody Is Impaired in the Absence of CD1d J. Immunol., May 1, 2005; 174(9): 5681 - 5686. [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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M. S. Duthie, M. Kahn, M. White, R. P. Kapur, and S. J. Kahn Both CD1d Antigen Presentation and Interleukin-12 Are Required To Activate Natural Killer T Cells during Trypanosoma cruzi Infection Infect. Immun., March 1, 2005; 73(3): 1890 - 1894. [Abstract] [Full Text] [PDF]
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K. O. A. Yu, J. S. Im, A. Molano, Y. Dutronc, P. A. Illarionov, C. Forestier, N. Fujiwara, I. Arias, S. Miyake, T. Yamamura, et al. Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of {alpha}-galactosylceramides PNAS, March 1, 2005; 102(9): 3383 - 3388. [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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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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J. L. Amprey, J. S. Im, S. J. Turco, H. W. Murray, P. A. Illarionov, G. S. Besra, S. A. Porcelli, and G. F. Spath A Subset of Liver NK T Cells Is Activated during Leishmania donovani Infection by CD1d-bound Lipophosphoglycan J. Exp. Med., October 4, 2004; 200(7): 895 - 904. [Abstract] [Full Text] [PDF]
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F. Burke, A. J. Stagg, P. A. Bedford, N. English, and S. C. Knight IL-10-Producing B220+CD11c- APC in Mouse Spleen J. Immunol., August 15, 2004; 173(4): 2362 - 2372. [Abstract] [Full Text] [PDF]
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C. S. Goodyear and G. J. Silverman Staphylococcal toxin induced preferential and prolonged in vivo deletion of innate-like B lymphocytes PNAS, August 3, 2004; 101(31): 11392 - 11397. [Abstract] [Full Text] [PDF]
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K. Roelofs-Haarhuis, X. Wu, and E. Gleichmann Oral Tolerance to Nickel Requires CD4+ Invariant NKT Cells for the Infectious Spread of Tolerance and the Induction of Specific Regulatory T Cells J. Immunol., July 15, 2004; 173(2): 1043 - 1050. [Abstract] [Full Text] [PDF]
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M. M. S. Huang, P. Borszcz, S. Sidobre, M. Kronenberg, and K. P. Kane CD1d1 Displayed on Cell Size Beads Identifies and Enriches an NK Cell Population Negatively Regulated by CD1d1 J. Immunol., May 1, 2004; 172(9): 5304 - 5312. [Abstract] [Full Text] [PDF]
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S. Camelo, A. Shanley, A. S. P. Voon, and P. G. McMenamin The Distribution of Antigen in Lymphoid Tissues following Its Injection into the Anterior Chamber of the Rat Eye J. Immunol., May 1, 2004; 172(9): 5388 - 5395. [Abstract] [Full Text] [PDF]
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K. Benlagha, S.-H. Park, R. Guinamard, C. Forestier, L. Karlsson, C.-H. Chang, and A. Bendelac Mechanisms Governing B Cell Developmental Defects in Invariant Chain-Deficient Mice J. Immunol., February 15, 2004; 172(4): 2076 - 2083. [Abstract] [Full Text] [PDF]
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C. Forestier, S.-H. Park, D. Wei, K. Benlagha, L. Teyton, and A. Bendelac T Cell Development in Mice Expressing CD1d Directed by a Classical MHC Class II Promoter J. Immunol., October 15, 2003; 171(8): 4096 - 4104. [Abstract] [Full Text] [PDF]
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S.-i. Fujii, K. Shimizu, C. Smith, L. Bonifaz, and R. M. Steinman Activation of Natural Killer T Cells by {alpha}-Galactosylceramide Rapidly Induces the Full Maturation of Dendritic Cells In Vivo and Thereby Acts as an Adjuvant for Combined CD4 and CD8 T Cell Immunity to a Coadministered Protein J. Exp. Med., July 21, 2003; 198(2): 267 - 279. [Abstract] [Full Text] [PDF]
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L. Sfondrini, D. Besusso, M. T. Zoia, M. Rodolfo, A. M. Invernizzi, M. Taniguchi, T. Nakayama, M. P. Colombo, S. Menard, and A. Balsari Absence of the CD1 Molecule Up-Regulates Antitumor Activity Induced by CpG Oligodeoxynucleotides in Mice J. Immunol., July 1, 2002; 169(1): 151 - 158. [Abstract] [Full Text] [PDF]
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M. Mempel, C. Ronet, F. Suarez, M. Gilleron, G. Puzo, L. Van Kaer, A. Lehuen, P. Kourilsky, and G. Gachelin Natural Killer T Cells Restricted by the Monomorphic MHC Class 1b CD1d1 Molecules Behave Like Inflammatory Cells J. Immunol., January 1, 2002; 168(1): 365 - 371. [Abstract] [Full Text] [PDF]
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C. M. Grimaldi, D. J. Michael, and B. Diamond Cutting Edge: Expansion and Activation of A Population of Autoreactive Marginal Zone B Cells in a Model of Estrogen-Induced Lupus J. Immunol., August 15, 2001; 167(4): 1886 - 1890. [Abstract] [Full Text] [PDF]
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B. Wang, T. Chun, I. C. Rulifson, M. Exley, S. P. Balk, and C.-R. Wang Human CD1d Functions as a Transplantation Antigen and a Restriction Element in Mice J. Immunol., March 15, 2001; 166(6): 3829 - 3836. [Abstract] [Full Text] [PDF]
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T. J. D'Orazio, E. Mayhew, and J. Y. Niederkorn Ocular Immune Privilege Promoted by the Presentation of Peptide on Tolerogenic B Cells in the Spleen. II. Evidence for Presentation by Qa-1 J. Immunol., January 1, 2001; 166(1): 26 - 32. [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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 C. D. D'Souza, A. M. Cooper, A. A. Frank, S. Ehlers, J. Turner, A. Bendelac, and I. M. Orme A Novel Nonclassic beta 2-Microglobulin-Restricted Mechanism Influencing Early Lymphocyte Accumulation and Subsequent Resistance to Tuberculosis in the Lung Am. J. Respir. Cell Mol. Biol., August 1, 2000; 23(2): 188 - 193. [Abstract] [Full Text]
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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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K.-H. Sonoda, M. Exley, S. Snapper, S. P. Balk, and J. Stein-Streilein Cd1-Reactive Natural Killer T Cells Are Required for Development of Systemic Tolerance through an Immune-Privileged Site J. Exp. Med., November 1, 1999; 190(9): 1215 - 1226. [Abstract] [Full Text] [PDF]
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 A. Melian, Y.-J. Geng, G. K. Sukhova, P. Libby, and S. A. Porcelli CD1 Expression in Human Atherosclerosis : A Potential Mechanism for T Cell Activation by Foam Cells Am. J. Pathol., September 1, 1999; 155(3): 775 - 786. [Abstract] [Full Text] [PDF]
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G. Szalay, C. H. Ladel, C. Blum, L. Brossay, M. Kronenberg, and S. H. E. Kaufmann Cutting Edge: Anti-CD1 Monoclonal Antibody Treatment Reverses the Production Patterns of TGF-{beta}2 and Th1 Cytokines and Ameliorates Listeriosis in Mice J. Immunol., June 15, 1999; 162(12): 6955 - 6958. [Abstract] [Full Text] [PDF]
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A. M. Oliver, F. Martin, and J. F. Kearney IgMhighCD21high Lymphocytes Enriched in the Splenic Marginal Zone Generate Effector Cells More Rapidly Than the Bulk of Follicular B Cells J. Immunol., June 15, 1999; 162(12): 7198 - 7207. [Abstract] [Full Text] [PDF]
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T. Chun, K. Wang, F. A. Zuckermann, and H. R. Gaskins Molecular Cloning and Characterization of a Novel CD1 Gene from the Pig J. Immunol., June 1, 1999; 162(11): 6562 - 6571. [Abstract] [Full Text] [PDF]
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Y.-H. Chiu, J. Jayawardena, A. Weiss, D. Lee, S.-H. Park, A. Dautry-Varsat, and A. Bendelac Distinct Subsets of CD1d-restricted T Cells Recognize Self-antigens Loaded in Different Cellular Compartments J. Exp. Med., January 4, 1999; 189(1): 103 - 110. [Abstract] [Full Text] [PDF]
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M. H. Levine, A. M. Haberman, D. B. Sant'Angelo, L. G. Hannum, M. P. Cancro, C. A. Janeway Jr., and M. J. Shlomchik A B-cell receptor-specific selection step governs immature to mature B cell differentiation PNAS, March 14, 2000; 97(6): 2743 - 2748. [Abstract] [Full Text] [PDF]
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