By
From the * La Jolla Institute of Allergy and Immunology, San Diego, California 92121; DIBIT,
H.S. Raffaele Institute, I-20132 Milano, Italy; and § Pharmaceutical Research Laboratory, Kirin
Brewery Co., Ltd., Gunma 370-12, Japan
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Abstract |
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Natural killer (NK) T cells are a lymphocyte subset with a distinct surface phenotype, an invariant T cell receptor (TCR), and reactivity to CD1. Here we show that mouse NK T cells
can recognize human CD1d as well as mouse CD1, and human NK T cells also recognize both
CD1 homologues. The unprecedented degree of conservation of this T cell recognition system
suggests that it is fundamentally important. Mouse or human CD1 molecules can present the
glycolipid -galactosylceramide (
-GalCer) to NK T cells from either species. Human T cells,
preselected for invariant V
24 TCR expression, uniformly recognize
-GalCer presented by
either human CD1d or mouse CD1. In addition, culture of human peripheral blood cells with
-GalCer led to the dramatic expansion of NK T cells with an invariant (V
24+) TCR and
the release of large amounts of cytokines. Because invariant V
14+ and V
24+ NK T cells
have been implicated both in the control of autoimmune disease and the response to tumors,
our data suggest that
-GalCer could be a useful agent for modulating human immune responses by activation of the highly conserved NK T cell subset.
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Introduction |
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CD1 molecules are 2-microglobulin (
2m)-associated1 transmembrane proteins that are related to
MHC-encoded antigen presenting molecules. Despite their
association with
2m, comparisons of primary sequences
demonstrate that CD1 molecules are almost as closely related to class II molecules as they are to class I molecules (1). Therefore, CD1 molecules probably diverged from
these other antigen presenting molecules early in vertebrate
evolution, around the time of the class I-class II divergence. CD1 molecules are distinguished from the MHC-encoded classical class I and class II molecules by their lack
of polymorphism. Of the five human CD1 genes, protein
products have been identified for the CD1a, -b, -c, and -d
isoforms (2). The CD1 isoforms are themselves quite divergent, although CD1a, -b, and -c are more closely related to
one another in their amino acid sequences than to CD1d
(1, 3). Only two CD1 genes, CD1d1 and CD1d2, have
been identified in mice. They are highly related to one another and are most similar to human CD1d in sequence (4).
However, there is not an extraordinarily high degree of
conservation between the mouse CD1 (mCD1) and human CD1d (hCD1d) homologues. The overall percentage
of sequence identity between the hCD1d and mCD1
polypeptides in the antigen binding region is 60.4% for the
1 domain and 62.4% for the
2 domain (1, 5).
One of the properties shared by mCD1 and hCD1d
molecules is their ability to be recognized by NK T cells
(6). Recently, much interest has been focused upon the
NK T cell subpopulation on account of its ability to
quickly produce large amounts of cytokines, suggesting a
potential for these T cells to regulate immune responses.
The majority of mouse NK T cells use mainly the V8.2,
V
7, or V
2 chain paired with an invariant V
14J
281 rearrangement (12). The human counterpart of the mouse
NK T cells also expresses a restricted TCR repertoire,
including a homologous, invariant V
24 rearrangement
paired with V
11, the human homologue of mouse V
8
(13). NK T cells in both species are autoreactive in
vitro for CD1 molecules, in the absence of exogenous antigen. In addition to TCR repertoire and CD1 autoreactivity, NK T cells from both species resemble each other in
several additional ways, including expression of intermediate TCR levels, expression of CD4 or the absence of both
CD4 and CD8, expression of cell surface proteins characteristic of memory or activated T cells (16), and the presence of NK receptors, particularly NK1.1 (CD161) in mice
(17, 18) and its homologue, NKRP1, in humans (11, 16).
Despite their relatively restricted TCR repertoire, a minority of NK T cells lack V14 expression. Moreover,
V
14 can be paired in the mouse with several different
V
s (19), and the V
rearrangements expressed by NK T
cells have junctional diversity (12). The combination of
these three factors allows for some diversity in the antigen
receptors expressed by the NK T cell population, and the
results from recent studies in the mouse indicate that
mCD1 autoreactive T cells are in fact heterogeneous in
their ability to recognize different mCD1+ cell lines and
transfectants (20, 21). These data suggest that a diverse set
of autologous ligands may be presented by mCD1, although other interpretations are not ruled out. Consistent
with the requirement for a diverse set of ligands, it has been
shown recently that mouse V
14+ T cells can recognize
the lipoglycan
-galactosylceramide (
-GalCer) presented
by mCD1, whereas V
14
but mCD1-autoreactive T cells
are not responsive to this antigen (22, 23).
In this study, we have uncovered a surprising degree of
conservation in the interaction of invariant NK TCRs
from different species with CD1 molecules despite the extensive divergence in primary sequences of these molecules
between mice and humans. We also demonstrate here that
-GalCer is presented by hCD1d to human NK T cells,
providing the first evidence both for the presentation of a
defined antigen by hCD1d and for a requirement for human NK T cells for a lipoglycan antigen in addition to
hCD1d. As
-GalCer can induce a dramatic hCD1d dependent expansion of human NK T cells, as well as a strong
release of cytokines by these cells, our data further suggest
that this lipoglycan could be a useful agent for the modulation of human immune responses.
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Materials and Methods |
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Gene Cloning and Transfection.
pSRT Cell Hybridomas.
The derivation and characterization of the mCD1 autoreactive T cell hybridomas has been described previously (21, 23, 24). For the stimulation assays, 5 × 104 T hybridoma cells per well were cultured in the presence of 105 mCD1+, hCD1d+, or control stimulator cells. After 16 h, IL-2 release was evaluated in a sandwich ELISA using rat anti-mouse IL-2 mAbs (PharMingen, San Diego, CA).Cloning of Invariant V24+ T Cells.
Activation of V24/V
11+ T Cell Clones by CD1 Transfectants.
Generation of -GalCer-reactive Cell Lines.
Flow Cytometric Analysis.
Biotinylated anti-hCD1d mAb 42.2 was provided by Dr. S. Porcelli. Secondary reagents for mCD1 detection were streptavidin-PE-conjugated (Caltag, South San Francisco, CA). For staining, cells were suspended in buffer comprised of PBS, pH 7.3, containing 2% BSA (wt/vol) and 0.02% NaN3 (wt/vol) and incubated at 4°C for 20-30 min with the primary Ab, washed twice, and then further incubated with secondary reagents for another 20-30 min at 4°C. After two washes, the cells were fixed and analyzed on a FACScan® 440 flow cytometer (Becton Dickinson, San Jose, CA).Cytokine Determination by ELISA.
Supernatants were quantified for IL-4 or IFN- ![]() |
Results |
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The parallels between mouse and human NK T cells led us to test for a possible cross-reactivity of mouse T cell hybridomas with hCD1d. Transfectants in several different cell types were generated and selected for approximately similar levels of surface hCD1d expression (Fig. 1 A). Each of these three transfected cell lines was used as APCs for T cell hybridomas that are mCD1 autoreactive. As shown in Table 1, two of the seven mCD1 autoreactive hybridomas also react with the three different hCD1d transfectants, whereas the other five do not. The hCD1d reactivity of these two NK T cell hybridomas has been confirmed using anti-hCD1d blocking mAb, which inhibited the reactivity to hCD1d A20 transfectants but not to mCD1 transfectants of the same cell line (Fig. 1 B). Similar antibody blocking data have been obtained using hCD1d-transfected Hela and C1R cells (data not shown).
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It is noteworthy that the two hCD1d reactive mouse T
cell hybridomas express the canonical V14/V
8 NK
TCR, whereas the nonreactive ones either express V
14/
V
8 or V
14/V
10 or, in three instances, lack V
14 expression. The lack of hCD1d reactivity of the V
14/V
8+
3C3 hybridoma is not due to a lower level of TCR expression, implicating either V
junctional sequences or some
other factor that distinguishes this hybridoma. Surprisingly,
one of the two cross-reactive T cell hybridomas, DN3A4-1-2, responds much more strongly to hCD1d than to
mCD1 transfectants of A20 cells (Table 1 and Fig. 1 B). Although the amount of IL-2 this cell releases in response to
mCD1 transfectants is well above the background, the
~12-fold greater increase in IL-2 release obtained with
hCD1d was typical of the results from nine different experiments. By contrast, hybridoma 2C12 reacts equally to the
two CD1 homologues (Table 1 and Fig. 1 B).
We then asked whether the interspecies
cross-reactivity of NK T cells for CD1 molecules also
would be observed using human V24/V
11+ clones as
responder cells. The presence or absence of the invariant V
24-J
Q rearrangement in the T cell clones was confirmed by both heteroduplex and oligotyping analysis, and
the diversity in the V
11 junctions was determined by sequencing (data not shown). A total of six clones from three
different donors were analyzed, four of which expressed
the invariant V
24 TCR paired with V
11 and two of
which expressed a noninvariant V
24 also paired with V
11. The ability of these clones to release IFN-
(Table
2) and IL-4 (data not shown) in response to CD1 transfectants was tested. Data from five experiments are combined
and averaged. Consistent with previous data (11), we found
that recognition of hCD1d by human NK T cells required
PMA, and in some cases also required mild aldehyde fixation of the target cells. Therefore, all the experiments
shown in Table 2 had PMA in the cultures, and the Hela
cell APCs also were fixed with glutaraldehyde.
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In agreement with the previous results, all of the clones
with an invariant V24 TCR could respond either to one
or both hCD1d transfectants (Table 2). As we and others
have described for mouse NK T cells (20, 21), the reactivity of different human NK T cell clones is somewhat heterogeneous, and is more dependent on the type of hCD1d
expressing APCs than on the level of hCD1d surface expression. Indeed, clone LG2D3 responds to hCD1d-transfected Hela cells but not to A20-transfected cells, whereas
the other three clones respond similarly to both types of
cells (Table 2). Neither of the two clones that lack the invariant V
24 responded significantly to the hCD1d transfectants, although both showed some background reactivity
against all the APCs when PMA was added. When reactive, each of the clones could synthesize significant quantities of both IFN-
and IL-4 in response to hCD1d stimulation.Three out of the four clones with an invariant V
24
also were stimulated significantly by transfectants expressing
heterologous mCD1 in the presence of PMA (Table 2),
and this reactivity could be inhibited with an anti-mCD1
mAb (data not shown).
In summary, we conclude that not only have NK T cells been conserved throughout evolution, but the ability of the invariant TCR expressed by NK T cells to recognize the CD1d-like molecules mCD1 and hCD1d also has been conserved strictly. Furthermore, if self-ligands are required for this CD1 recognition, these ligands are likely to be similar in mice and humans.
Mouse VWe tested the ability of mouse
NK T cell hybridomas to respond to the lipoglycan -GalCer presented by the heterologous hCD1d molecule. It has
been shown recently that mouse NK T cells with an invariant V
14 TCR can respond in an mCD1-mediated fashion to
-GalCer (22, 23). We therefore used this compound to
determine if hCD1d and mCD1 can present similar compounds to NK T cells.
Using -GalCer-pulsed CD1d transfectants as APCs, we
analyzed the reactivity of the panel of seven mouse T cell
hybridomas described in Table 1. Only three hybridomas
responded to the pulsed APCs, regardless of whether the
hCD1d-expressing cell line used was a transfected C1R,
A20, or Hela cell. The responses of V
14/V
8+ hybridomas 2C12 and DN3A4-1-2 to hCD1d plus
-GalCer were
significantly increased above the level of hCD1d reactivity
in the presence of the vehicle alone. Depending upon the
APC used, the ratio of the IL-2 production in the presence
of
-GalCer compared with the vehicle increased from
1.7- to 3-fold for hybridoma 2C12, and from 1.5- to 9.6-fold for hybridoma DN3A4-1-2. Interestingly, although
the third V
14/V
8+ hybridoma, 3C3, was unresponsive
to hCD1d transfectants in the absence of antigen, it was
strongly stimulated by
-GalCer-pulsed hCD1d cells (Fig.
2 A). Complete inhibition of the IL-2 release induced by
-GalCer pulsed APCs was obtained using an anti-hCD1d mAb, confirming the hCD1-mediated presentation of
-GalCer (Fig. 2 A). Therefore, all three V
14/V
8+ T
cell hybridomas tested respond to hCD1d plus
-GalCer.
By contrast, the V
14/V
10+ hybridoma DN3A4-1-4 responded to
-GalCer-pulsed mCD1-expressing APCs but
not to
-GalCer-pulsed hCD1d-expressing cells (Fig. 2 B).
In summary, these data demonstrate that hCD1d can present the same lipoglycan antigen as its mouse counterpart. Our
previous studies demonstrated that mCD1-mediated recognition of
-GalCer by mouse NK T cells was effective when
V
14 was expressed with any one of these different TCR-
chains (23). The data presented here, in contrast, suggest that
when presented by the heterologous hCD1d molecule
-GalCer responsiveness by mouse NK T cells may be more
highly dependent upon the TCR-
chain.
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We next tested if human NK
T cell clones are responsive to -GalCer presented by
hCD1d. Cultures containing lipoglycan antigen-pulsed APC were carried out in the absence of either PMA or glutaraldehyde fixation. Three NK T cell clones with an invariant V
24 TCR (15.21.2, LG2D3, and PD9) and one
of the V
24/V
11 clones without the invariant junction
(PD18) were tested. In the absence of lipoglycan antigen there was no stimulation by hCD1d because of the absence
of PMA. The results from one representative experiment of
three carried out with clone 15.21.2 are shown in Fig. 2 C.
-GalCer is a potent inducer of both IFN-
and IL-4
release by this T cell clone. The cytokine release was inhibited by an anti-hCD1d mAb (Fig. 2 C) as well as an
anti-V
24 mAb (data not shown), confirming the TCR-mediated recognition of
-GalCer-pulsed hCD1d+ APCs.
Similar data were obtained with clones LG2D3 and PD9.
The reactivity of the 15.21.2 and PD9 human T cell clones
for heterologous mCD1 also could be detected by the
addition of
-GalCer. Clone LG2D3, which did not
respond to mCD1+ APCs in the presence of PMA, likewise did not respond to
-GalCer presented by mCD1
(data not shown).
The results described above demonstrate that long
term T cell clones, selected only on the basis of invariant
V24 and V
11 expression, are specifically activated by
-GalCer presented by hCD1d. To analyze the response of
T cells that have not been subject to long-term culture, we
asked whether
-GalCer would induce the in vitro proliferation of human NK T cells. In these experiments, either
the lipoglycan antigen or the vehicle control was added directly to cultures of unfractionated, fresh PBMCs. The percentage of V
24-positive T cells was determined by flow
cytometry at days 0, 7, 9, 11, and 12. By day 12, we systematically obtained a significant expansion in both the
percentage and number of T cells expressing the V
24/
V
11 TCR. A compilation of all the data from a series of
experiments done with PBMCs from eight different donors
is shown in Table 3. Although on day 0 the V
24/V
11+
T cells were <1% of the total cell number, by day 7-12,
the percentage of V
24+ cells had expanded from 18.5- to
82-fold (Table 3). This increase in the percentage of
V
24+ cells is due to an expansion in cell number, because
the total number of cells in the cultures generally was not
decreased compared with day 0. This expansion required
the presence of IL-2 and
-GalCer, as the number of
V
24/V
11+ T cells did not augment significantly when
either one of these reagents was omitted (data not shown).
PCR-heteroduplex analysis and oligotyping performed on
aliquots of PBMCs, drawn at different time points from the
different culture conditions, confirmed the expansion of
V
24/V
11+ T cells expressing the invariant V
24-J
Q
rearrangement (data not shown). Several of these lines were
maintained in culture beyond day 12, and restimulated
once with
-GalCer-pulsed autologous APCs, and further with
-GalCer-pulsed hCD1d-transfected C1R cells. These two further recalls allowed us to enrich the percentage of V
24-positive T cells to 64% for line XC and 53%
for line PB (Fig. 3). As shown in Fig. 3, lipoglycan-specific
invariant V
24/V
11+ T cells are either CD4+ or CD4
,
consistent with previous reports on the surface phenotype
of this subset (12, 14, 16). A 72% inhibition of the expansion of V
24+ T cells was obtained for line PB when parallel cultures were set up from day 0 in the presence of the
51.1 anti-hCD1d mAb. This inhibition is consistent with
the view that the
-GalCer-induced expansion of fresh T
cells is hCD1d dependent. Similarly, a 62 and 60% reduction of the V
24+ T cell expansion was obtained for lines
MP and PD, respectively, when an anti-V
24 mAb was
added to the culture from day 0. These data suggest that
the
-GalCer-induced T cell expansion was dependent upon engagement of the TCR. Interestingly, when cultured in the presence of
-GalCer-pulsed transfected
APCs, these 2 lines released IFN-
but not IL-4 in an
hCD1d- and V
24-dependent manner (data not shown).
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Discussion |
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The hCD1d molecule is of particular interest on account
of its recognition by human NK T cells and on account of
having a broader expression pattern than do other human
CD1 molecules (26). In this report, we provide the first evidence for the ability of hCD1d to present antigen. The antigen identified here is -GalCer, a structurally well-defined
glycolipid. In the presence of
-GalCer, neither the addition of PMA nor fixation of the APCs is required to stimulate
NK T cell reactivity to hCD1d. Furthermore, preliminary data indicate that
-GalCer can bind in vitro to purified,
soluble hCD1d and mCD1 molecules (Maher, J., O. Naidenko, W. Ernst, R. Modlin, and M. Kronenberg, manuscript in preparation). Together with the antigen presentation and antibody inhibition studies presented here, these
data indicate that the effect of
-GalCer is not likely to be
an indirect one, but rather that
-GalCer forms a complex
with hCD1d that is recognized by the TCR on human NK
T cells. It should be noted that
-GalCer was purified from an extract from a marine sponge, based upon the positive
results obtained with this extract during a screen for compounds that prevent tumor metastases (27). Ceramides with
an
-linked sugar are not abundant in most microbes, and
they are much less abundant than those with a
-linked
sugar in mammalian cells. However,
-galactosylceramide
is not an antigen for CD1d presentation (22, 23). It therefore remains possible that
-GalCer is a mimic for a natural
ligand that normally stimulates NK T cells, although there
are no data to exclude the possibility of a low level of
-GalCer expression in mammalian cells. In mice, a glycosylphosphatidylinositol has been the only natural ligand
bound to mCD1 identified so far (28), although compounds of this type apparently do not stimulate NK T cells
in a CD1-dependent fashion (23).
The lack of polymorphism of nonclassical antigen-presenting molecules has led to the proposal that they may carry out some conserved and essential antigen presenting function. Although this is a plausible hypothesis, with the possible exception of mouse Qa-1b and human HLA-E (29), there is surprisingly little evidence for interspecies conservation of nonclassical class I molecules at either the sequence level or the functional level. In contrast, the CD1 family is demonstrated here to show an extremely high degree of conservation with regard to its interaction with the invariant TCRs that are expressed by NK T cells. This conservation is observed either in the absence of exogenous antigen or together with a lipoglycan antigen. From a functional viewpoint, the mouse and human invariant TCRs and CD1 molecules are nearly equivalent, indicating a strong selection upon this TCR interaction with CD1. These data are consistent with previous reports demonstrating that human and mouse NK T cells are similar in phenotype and function (11, 12, 16). This degree of conservation and cross-reactivity at the antigen recognition level is particularly striking in light of the divergence in primary sequence of both the CD1 molecules and the TCRs expressed by NK T cells (5). We conclude that despite these significant changes in primary structure, the amino acids important for either lipoglycan binding to CD1 or the interaction between the TCR and CD1 must not have diverged significantly.
The results from immune assays of mouse and human T
cells permit the identification of candidate regions of the
TCR that are necessary for the recognition of CD1 plus lipoglycan. Data from a previous study of TCR transgenic
mice expressing V8 and V
14 and of mice deficient for
J
281 as a result of targeted mutation implicated a role for
the invariant V
14 TCR in
-GalCer recognition (22).
Although several analyses of mCD1-reactive T cell hybridomas and cell lines established that V
14 is not absolutely
required for mCD1 autorecognition (20, 24, 30), only
mCD1-autoreactive hybridomas with a V
14 TCR could
respond to
-GalCer plus mCD1 (23). The conservation of
the V
-J
junction in the invariant TCR (14, 15, 18, 31)
implicates this region of the TCR in contacting the CD1
molecule or a combination of CD1 and lipoglycan bound
to it. Consistent with this hypothesis, we found that human T cells that express a V
24 without the invariant V-J junctional sequence were unreactive to hCD1d transfectants in
either the absence or presence of
-GalCer. Furthermore,
there may be a more stringent selection upon the NK T
cell
chain in humans than in mice, as the invariant V
24
is mainly paired with V
11 (16, 32, 33), whereas in mice
there are several predominant V
s (12, 19, 20).
It is unprecedented to find complete cross-reactivity between mice and humans of the interaction of a TCR with
a peptide-MHC complex. However, such a high degree of
conservation is consistent with a superantigen type of recognition mechanism (34). In addition, the high frequency
of -GalCer-reactive cells in humans is consistent with a
superantigen-like mode of action. However, there are two reasons why the data presented here do not favor the possibility that
-GalCer is recognized as a superantigen. First,
the reactive T cells have a restricted V-J junctional diversity
of their
chains, as well as V
gene use. Second, the reactive T cells are selected for both V
and for V
expression,
particularly in humans. These findings favor a more conventional mechanism for the interaction of the
-GalCer
plus CD1 complex with the TCR expressed by NK T
cells.
At the functional level, NK T cells are distinguished by
their ability to produce large amounts of the cytokines
characteristic of memory T cells within a few hours of
stimulation. It was proposed originally that the early expression of IL-4 by NK T cells could be required for Th2-type immune responses (35). Although NK T cells normally may contribute to the induction of Th2 responses, it
is now clear that in many cases they are not required (37, 38). It also is clear from our studies and those of other investigators that NK T cells can secrete large amounts of
IFN- in addition to IL-4 under some circumstances (39,
40). Based upon their relatively high frequency in some
sites and their ability to rapidly secrete large amounts of cytokines, functions for NK T cells in the regulation of autoimmune diseases (33, 41, 42), the response to infectious
agents (43), and the surveillance for tumors (44) have been
proposed. With regard to autoimmune disease progression,
the strongest evidence currently favors a connection between NK T cells and diabetes, in which the results from
mice and humans show a striking degree of similarity (33,
42, 45). The dramatic expansion and activation of human
NK T cells upon stimulation in vitro with
-GalCer is
therefore of a considerable interest. Because we generally
observed both IL-4 and IFN-
in the culture supernatants
of the T cell clones, but only IFN-
from the lines, it
should be possible to identify conditions in which a more
polarized cytokine response develops. Therefore, one
might envision the use of this molecule, or perhaps analogues (22) that might give a more polarized Th1 or Th2
response, as an attractive strategy to modulate human immune response in vivo.
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Footnotes |
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Address correspondence to Mitchell Kronenberg, La Jolla Institute of Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Phone: 619-678-4540; Fax: 619-678-4595; E-mail: mitch{at}liai.org
Received for publication 18 June 1998 and in revised form 20 July 1998.
The authors wish to thank Drs. S. Cardell (Lund University, Lund, Sweden), M. Bix (University of California at San Francisco, San Francisco, CA), and K. Hayakawa (Institute for Cancer Research, Philadelphia, PA) for kindly providing mCD1-restricted hybridomas. We also thank Dr. S. Porcelli for providing the anti-hCD1d mAbs. We thank Drs. S. Tangri, T. Prigozy, L. Gapin, and H. Cheroutre for critical review of the manuscript.
This work was supported by National Institutes of Health research grants CA-52511 and AI-40617 (to M. Kronenberg) and by Progetto Nazionale Tubercolosi, Istituto Superiore di Sanità (to P. Dellabona). This is manuscript no. 244 of the LIAI.
Abbreviations used in this paper
-GalCer,
-galactosylceramide;
2m,
2-microglobulin;
hCD1d, human CD1d;
mCD1, mouse CD1.
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