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CUTTING EDGE |
*
Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, NY 10010; and
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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14+ NK T cells responded to self as
well as foreign (parasite-derived) GPIs in a CD1d-dependent manner. It
further reported that the IgG response to the Plasmodium
berghei malarial circumsporozoite (CS) protein was severely
impaired in CD1d-deficient mice, leading to a model whereby NK T cells,
upon recognition of CD1d molecules presenting the CS-derived GPI
anchor, provide help for B cells secreting anti-CS Abs. We tested
this model by comparing the anti-CS Ab responses of wild-type,
CD1d-deficient, and MHC class II-deficient mice. We found that the IgG
response to the CS protein was solely MHC class II-dependent.
Furthermore, by measuring the response of a broad panel of
CD1d-autoreactive T cells to GPI-deficient CD1d-expressing cells, we
found that GPIs were not required for autoreactive
responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-galactosylceramide
(5, 6) to NK T cells, resulting in potent cellular
activation. However, this compound has only been found in marine
sponges, so there has been great interest in identifying naturally
presented ligands capable of activating NK T cells within a more
physiological context.
NK T cells (7) are the predominant T cells known to be
associated with CD1d-restricted recognition. These
CD4+ or double-negative cells are characterized
by the expression of an invariant TCR -chain (V14-J281) and a
limited TCR ß-chain repertoire, together with the unusual
coexpression of cell-surface markers commonly associated with NK cells.
Upon TCR engagement, NK T cells secrete not only large amounts of IL-4,
IL-5, and IL-10, but also IFN-
and TNF-ß, cytokines which have
opposite effects on Th1/Th2 differentiation. This has generated some
controversy regarding their specific influence in
CD4+ Th cell differentiation and on how the
subsequent adaptive immune response may be biased. Some studies
implicate them in Th2 responses (8), whereas others
associate them with the inhibition of Th2 responses (9) or
with the generation of Th1 responses (10).
Efforts to identify ligands naturally associated with CD1d have relied
on a variety of biochemical approaches. Joyce et al. (11)
found self GPI anchors to be the main natural ligand associated with
mouse CD1d molecules. Using various purified or synthetic GPIs,
Schofield et al. (12) subsequently showed that
V14+ NK T cells were stimulated by self as
well as foreign (parasite-derived) GPIs in a CD1d-dependent manner and
that GPI recognition was mediated by the glycan moiety, in that the
phosphatidylinositol
(PI)3 core by itself
was not stimulatory. In support of these findings, these authors also
reported that the IgG response to the P. berghei
malarial circumsporozoite (CS) Ag, which is believed to be GPI-anchored
(13), was severely reduced in CD1d-deficient mice. This
would indicate that most T cell help for the production of anti-CS
IgG was provided by NK T cell recognition of CD1d/GPI complexes on the
surface of CS-specific B cells. A conclusion from all these studies is
that V14+ NK T cells recognize CD1d complexed
with self or foreign GPIs, and that this specific recognition is linked
to their regulatory roles in autoimmune diseases as well as in a
variety of infectious conditions. In this study, we measured the
response of a broad panel of CD1d-autoreactive T cells to wild-type or
GPI-deficient (deficient in the PIG-A enzyme required for GlcNac-PI
synthesis) CD1d-expressing cells. Contradicting our initial
predictions, we found that CD1d-autoreactive T cells were unaffected by
the dramatic alteration in GPI structure produced by the PIG-A
deficiency. In addition, we compared the anti-CS Ab response of
wild-type and CD1d-deficient mice (of both the B6 and BALB/c genetic
backgrounds) after direct i.v. inoculation of irradiated sporozoites or
after exposure to infected mosquito bites. Our results do not support a
role for CD1d-mediated activation of V14+ NK T
cells as providers of cognate help for IgG anti-CS responses. In
contrast, a comparison of the anti-CS Ab response of wild-type and
MHC class II-deficient mice showed this response to be solely MHC class
II-dependent. This is in line with a previous study that identified
multiple Th cell epitopes in the P. berghei CS protein
(14).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Matched wild-type and Class A mutants of GPI biosynthesis were obtained from Dr. Hyman (Salk Institute) for two tumor lines, BW5147 and S49. The class A mutants (termed BW-Thy-1-a and S49-Thy-1-a) have a block in the transfer of N-acetylglucosamine to the PI acceptor (15). All four cell lines, which constitutively express very low levels of CD1d, were stably transfected with CD1d1 using plasmid pCD113 as described (16) and selected by G418 treatment and multiple cell sortings to ensure stable expression of comparable levels of CD1d1.
In vitro stimulation of CD1d-autoreactive T cells
T cells were cultured for 18 h in the presence of CD1d
transfectants (5 x 104 responders and
5 x 104 transfectants) in 100 µl of a 1:1
mixture of Click’s medium and RPMI 1640 (Biofluids, Rockville, MD)
enriched with 10% heat-inactivated FCS, glutamine, antibiotics, and
5 x 10-5 2-ME. IL-2 or IL-4 released in
the supernatant was measured using the CTLL or CT-4S bioassays,
respectively, as described (17). Fresh T cell responders
were thymocytes from V14-J281 TCR transgenic mice
(18) recovered after 5 days in culture with 2.25 µg/ml
Con A and IL-4 (10 ng/ml), washed, and stimulated as indicated above to
measure IL-4 secretion. CD1d-autoreactive hybridomas have been
described previously (16, 17, 19) and were stimulated as
described above to measure IL-2 release.
Mice
C57BL/6 and BALB/c mice were obtained from the National Cancer Institute (Bethesda, MD). CD1-deficient (CD1D1-null) mice, which do not have NK T cells and have no residual expression of CD1 on B cells (8, 20), were used after six to nine backcrosses onto the C57BL/6 and BALB/c backgrounds. MHC class II-deficient mice (I-Aßb-/-) (21) were used after six backcrosses onto the C57BL/6 background. Eight- to 10-wk-old mice of both sexes were used. All mice were housed in autoclaved cages and were given autoclaved food and water.
Immunizations
P. berghei (NK65 strain) was maintained as described (22). Anesthetized mice were subjected to the bites of gamma-irradiated (15,000 rad; 1 rad = 0.01 Gy) malaria-infected Anopheles stephensi mosquitoes for 10 min/day for 4 (BALB/c background, CD1-deficient mice) or 8 (C57BL/6 background, CD1-deficient mice) days, rested for 10 days, and boosted for 4 more days. For i.v. immunizations, mice were injected in the tail vein with 105 dissected, irradiated salivary gland sporozoites and boosted 2 wk later with the same number of irradiated sporozoites. Sera from the immunized mice were collected 12 days after the last immunization.
ELISA and indirect immunofluorescence assay (IFA)
IgG Ab titers directed against the P. berghei CS protein were determined by coating Immulon-2 plates (Dynatech Laboratories, Alexandria, VA) overnight at 4°C with 0.5 µg/ml of the B8 multiple Ag peptide in PBS. The B8 multiple Ag peptide, described in detail before (23), contains eight copies of the immunodominant epitope (DPPPPNPN)2G of the CS protein of P. berghei. After washing three times with PBS/0.05% Tween 20, plates were blocked for 1 h at 37°C with PBS/3% BSA. Plates were incubated for 1 h with the serum dilutions. After extensive washing, peroxidase-conjugated goat affinity-purified anti-mouse IgG Fc (Cappel, Aurora, Ohio) was added. Plates were developed by adding the substrate 2,2'-azino-di(3-ethylbenzthiazoline-6-sulfonate) (Kirkegaard & Perry, Gaithersburg, MD). End-titers were defined as the last serum dilution (titration) giving values statistically different from those of the preimmune sera. A serum titer of 1/100 was the background cutoff. IFA was performed as described (24).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14 transgenic cells respond similarly to CD1d expressed by
wild-type or GPI-deficient cell lines
PIG-A mutants (15) have a block in the transfer of
N-acetylglucosamine to the PI acceptor. To examine the
effects of this mutation on CD1d autoreactivity, we stably transfected
BW-Thy-1-a and S49-Thy-1-a mutants, as well as the parental tumor lines
BW 5147 and S49, with CD1d1. Fig. 1
shows
that comparable levels of CD1d expression were present in the wild-type
and mutant cell lines used for these experiments. It also shows that
the responses of V14 transgenic cells (18) to these
transfectants, measured as IL-4 released into the supernatant, are
similar. It is important to emphasize that the V14 transgenic cells
constitute a polyclonal population of cells expressing the invariant
TCR -chain associated with a broad range of endogenous TCR
ß-chains (18, 19). Therefore, the results reflect the
overall response pattern of a broad range of V14-based
TCRs.
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We also examined the response of individual, CD1d-autoreactive
hybridomas to CD1d expressed by wild-type or GPI-deficient cell lines,
including one V14-J281/Vß8 hybridoma (DN32D3) as well as
13 non-V14, CD1d-autoreactive hybridomas (Fig. 2). Although there is some level of
variation from experiment to experiment, overall the data conclusively
demonstrate that GPI expression is not required for recognition by a
broad panel of CD1d-autoreactive T cells belonging to both the
V14-positive and V14-negative subsets.
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To examine the effects of CD1d on the induction of IgG anti-CS
Abs, we exposed groups of CD1-deficient (-/-), CD1 heterozygous
(+/-), and wild-type (+/+) mice, in parallel, to the bites of
irradiated mosquitoes infected with P. berghei. The
experiments were conducted using CD1-deficient mice of the C57BL/6
(Fig. 3A) and BALB/c (Fig. 3B) backgrounds. Sera were collected 12 days after the final
boosting, and IgG anti-CS titers were determined by ELISA. No
significant difference was observed between any of the groups.
Identical results were obtained by IFA using sporozoites as an Ag (not
shown). The experiments were also performed after direct i.v.
inoculation of irradiated sporozoites in CD1-deficient mice of the
C57BL/6 background (Fig. 4). Again, no
significant differences were observed. We conclude that the absence of
CD1d expression in knockout mice does not significantly influence the
titers of IgG directed against the CS protein of P.
berghei.
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If the IgG response to the CS protein of P. berghei is
not dependent on CD1d, then it should be predominantly MHC class
II-dependent. We tested this hypothesis by inoculating irradiated
sporozoites into wild-type, CD1-deficient, and MHC class II-deficient
mice, all of the C57BL/6 background. As shown in Fig. 4
, whereas the
mean titers for the wild-type (1/4400) and the CD1-deficient (1/4800)
groups are comparable, the IgG anti-CS titers of the MHC class
II-deficient mice were undetectable (less than 1/100). This result
indicates that the IgG anti-CS response is entirely dependent on
MHC class II molecules.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14-J281/Vß8 or variable, non-V14-based TCR. These two
subsets differ in their requirement for the tyrosine-based endosomal
sorting motif encoded in the cytoplasmic tail of CD1, suggesting that
they recognize distinct families of self Ags loaded in different
cellular compartments (17). The crystal structure of CD1d
revealed a very hydrophobic interior groove with two deep, large
pockets, occupied by discontinuous electron density (25),
apparently an acyl chain-containing ligand (26), and
biochemical analysis (11) identified cellular GPI as a
major natural ligand of CD1d1. Recently, Naidenko et al.
(26) demonstrated binding of a biotinylated phospholipid
to human CD1d by surface plasmon resonance. Although the recognition of
"empty" or lipid-stabilized CD1d molecules by autoreactive T cells
is a formal possibility, the studies mentioned above suggest that self
GPIs could be critical ligands that are intimately involved in the
activation of these autoreactive T cells. In accordance with these
findings, Schofield et al. (12) reported that various self
or foreign parasite-derived GPIs were capable of activating and
expanding V14+ NK T cells in the spleen of
immunized mice. This reactivity was found to be MHC class
II-independent and CD1-restricted, and the glycan moiety was found to
be essential because the PI core by itself was not stimulatory. All
these studies suggest that self and foreign GPIs are critical
determinants of V14+ NK T cell reactivity and
that their specific recognition must be somehow linked to
immunoregulatory roles. Consequently, altering the structure of
cellular GPIs should have a significant effect on the autoreactivity of
V14+ NK T cells. However, we found that both
V14 transgenic cells and CD1d-autoreactive hybridomas responded
similarly to wild-type and GPI-deficient cell lines. Although it
remains possible that some CD1d-autoreactive cells might recognize the
PI core without the glycan moiety (which persists in PIG-A mutants;
Ref. 27) or that they react to other non-GPI glycolipids,
our results raise questions about the claim that NK T cells recognize
GPIs. In addition, we note that the specificity of the anti-V14
mAb used by Schofield et al. (12) to show NK T cell
expansion after GPI injection in vivo has been questioned by
investigators in the field (7). Our results differed from those of Schofield et al. (12), which showed significantly lower anti-CS Ab titers in CD1-deficient mice (mean titers of 1/8192 for wild-type vs 1/832 for CD1-deficient mice). Initially, we thought this difference could be related to the purity of the sporozoite preparation. Dissection of the salivary glands of infected Anopheles mosquitoes, which was the method employed by Schofield et al., can potentially result in the presence of mosquito-derived contaminants in the sporozoite preparation. Because GPI protein anchors are found from lower eukaryotes to mammals (28), we considered the possibility that mosquito-derived GPI anchors or other glycolipids might explain these contrasting results. Mosquito bites, on the other hand, are the natural mode of sporozoite delivery and generally ensure purer sporozoites for the immunization of mice than does their manual isolation from infected salivary glands before i.v. inoculation. Nevertheless, neither method of immunization revealed any significant differences between the anti-CS responses of wild-type and CD1-deficient mice, indicating that the contrasting results are not due to a mosquito-derived glycolipid and that the generation of IgG against the P. berghei CS protein is CD1d-independent. An alternative explanation that could also account for the different results obtained by Schofield et al. (12) relates to the heterogeneous genetic background of the CD1-deficient mice used (129/BALB/c mixture). Thus, it is still possible that the observed differences in the Ab response were governed by genetic disparities other than the CD1 mutation. However, experiments performed with MHC class II-deficient mice showing undetectable Ab response corroborate our claim that CD1d and NK T cells are not key elements for providing cognate help for anti-CS Ab responses. We observed no significant change of NKT phenotype and numbers in mice after immunization with irradiated sporozoites (data not shown). Furthermore, challenge experiments also support the notion that acquired anti-malarial immunity can develop in the absence of CD1d (our unpublished observations). These results also support a previous study (14) that showed immunization with a synthetic peptide representing the repeat region of the P. berghei CS protein failed to induce Abs in 11 strains of mice having different H-2 haplotypes, whereas immunization with a recombinant CS protein, containing the repeat plus short stretches of its flanking regions, overcame the unresponsiveness but with marked differences in Ab levels for the different strains tested.
In conclusion, despite the report that GPIs represent the main natural
ligand presented by CD1d, our results demonstrate that they are not
required for autorecognition of CD1d by V14+
NK T cells or a broad panel of other CD1d-autoreactive T cells. Most
importantly, our studies on IgG production upon sporozoite immunization
do not support the hypothesis that CD1d and
V14+ NK T cells play a role in T cell help to
the anti-CS response but rather indicate that B cell help is
mediated through classical MHC class II/CD4+ T
cell interactions.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. M. Tsuji, Department of Medical and Molecular Parasitology, New York University School of Medicine, 341 East 25th Street, New York, NY 10010.
3 Abbreviations used in this paper: PI, phosphatidylinositol; CS, circumsporozoite; IFA, immunofluorescence assay.
Received for publication January 12, 2000. Accepted for publication March 15, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ T cells. Nature 372:691.[Medline]
14 NK T cells by glycosylceramides. Science 278:1626.-galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype. J. Immunol. 163:2373.14 natural killer cells. J. Exp. Med. 190:783. 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.
T cells contribute to immunity against the liver stages of malaria in ß T-cell-deficient mice. Proc. Natl. Acad. Sci. USA 91:345.This article has been cited by other articles:
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) is expressed as a percentage of the response to wild-type
CD1d-transfected BW and S49. Tested hybridomas include one
V
