By
From the * Department of Molecular Biology, Princeton, New Jersey 08544; and the Institut Pasteur,
Unite de Biologie des Interactions Cellulaires, 75724 Paris Cedex 15, France
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Abstract |
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Although recent studies have indicated that the major histocompatibility complex-like, 2-microglobulin-associated CD1 molecules might function to present a novel chemical class of antigens, lipids and glycolipids, to
/
T cells, little is known about the T cell subsets that interact
with CD1. A subset of CD1d-autoreactive, natural killer (NK)1.1 receptor-expressing
/
T
cells has recently been identified. These cells, which include both CD4
CD8
and CD4+ T
cells, preferentially use an invariant V
14-J
281 T cell receptor (TCR)
chain paired with a
V
8 TCR
chain in mice, or the homologous V
24-J
Q/V
11 in humans. This cell subset
can explosively release key cytokines such as interleukin (IL)-4 and interferon (IFN)-
upon
TCR engagement and may regulate a variety of infectious and autoimmune conditions. Here,
we report the existence of a second subset of CD1d-restricted CD4+ T cells that do not express
the NK1.1 receptor or the V
14 TCR. Like the V
14+ NK1.1+ T cells, these T cells exhibit
a high frequency of autoreactivity to CD1d, use a restricted albeit distinct set of TCR gene
families, and contribute to the early burst of IL-4 and IFN-
induced by intravenous injection
of anti-CD3. However, the V
14+ NK1.1+ and V
14
NK1.1
T cells differ markedly in
their requirements for self-antigen presentation. Antigen presentation to the V
14+ NK1.1+
cells requires endosomal targeting of CD1d through a tail-encoded tyrosine-based motif,
whereas antigen presentation to the V
14
NK1.1
cells does not. These experiments suggest
the existence of two phenotypically different subsets of CD1d-restricted T cells that survey self-antigens loaded in distinct cellular compartments.
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Introduction |
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Classical MHC class I and class II molecules in vertebrates capture pathogen-derived peptides in the endoplasmic reticulum or in the endosomal compartment,
and present them on the cell surface for recognition by
CD8+ or CD4+ /
T lymphocytes, respectively (1). In
contrast, CD1 molecules, a family of MHC-like, non-
MHC-encoded molecules, seem to present a novel antigenic universe, made of lipids rather than peptides, to T
cells (2). Human CD1b and CD1c molecules can present
various lipid and glycolipid components of mycobacterial
cell walls (3). CD1d, a conserved isotype that is expressed by all mammals studied to date, and the only one
that is expressed by mice and rats, may also bind various
glycolipids, including glycosyl phosphatidyl inositols (6)
and glycosylated ceramides (7).
Although little is known about the frequency and phenotype of T cells that use CD1 as a presenting molecule, or
about the antigen presentation pathways associated with
CD1, several observations suggest that they differ from
those defined in the classical MHC system. In humans, a
few CD1b- and CD1c-restricted T cell lines have been reported. Most of them have an unusual CD4/CD8 double negative phenotype (3), while some are CD8+ (8). Their
recognition of mycobacterial lipid antigens depends on a
tyrosine-based motif encoded in the cytoplasmic tail of
CD1b itself that targets CD1b to the endosome, a different
mechanism of endosomal trafficking than that of the MHC
class II pathway (9, 10). CD1d, the only CD1 isotype in
mice, interacts with a prominent subset of CD1d-restricted
T cells that has been identified in vivo on the basis of its
unique phenotype and functional properties. This subset
comprises the NK1.1 receptor-expressing /
T cells (NK
T cells) that preferentially use an invariant V
14-J
281
TCR
chain paired with a V
8 TCR
chain in mice
(11, 12) or the homologous V
24-J
Q/V
11 in humans
(11, 13, 14). This cell subset, which includes both double
negative and CD4 T cells, accounts for 15% of mature thymocytes, 5% of spleen T cells, and 30% of liver T cells. The
unusual functional properties of these NK T cells (15),
which include their ability to explosively release key cytokines such as IL-4 and IFN-
upon TCR engagement, are
thought to be the basis for their role in various intracellular infections (16, 17), in tumor rejection (18), and in autoimmune diseases (19, 20). A large fraction of these cells can be shown to be autoreactive to CD1d-expressing cells (12).
Thus, a recent report showing that alpha galactosyl ceramide,
a component of marine sponges, can specifically stimulate
most V
14-J
281/V
8 T cells in a CD1d-restricted fashion (7) suggests that these cells might survey a single, yet
unidentified family of self-glycolipids with homology to alpha galactosyl ceramide. There have been reports of other
CD1d-autoreactive T cell hybridomas that do not use
V
14 TCRs (11, 12, 21), but the phenotype and the functional properties of their precursor cell type have not been
characterized in vivo. Therefore, we asked whether these
hybridomas belonged to the NK1.1+ subset or were perhaps a window into a new T cell subset.
Here, we report the existence of a novel, prominent
subset of CD1d-restricted T cells that do not express the
NK1.1 receptor or the V14 TCR. Like V
14+ NK1.1+
T cells, these T cells exhibit a high frequency of autoreactivity to CD1d, use a restricted set of TCR gene families,
and contribute to the early burst of IL-4 and IFN-
induced by intravenous injection of anti-CD3. However,
V
14+ NK1.1+ and V
14
NK1.1
T cells differ markedly in their requirements for self-antigen presentation.
V
14+ NK1.1+ cells require endosomal targeting of CD1d
through a tail-encoded tyrosine-based motif for antigen
recognition, whereas V
14
NK1.1
T cells do not. Altogether, these experiments suggest that there are two phenotypically different subsets of CD1d-restricted T cells that
survey antigens loaded in distinct cellular compartments. These results have significant implications for the antigen
presenting functions of CD1 molecules.
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Materials and Methods |
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Mice.
C57BL/6 and C57BL/6 IAT Cell Subset Staining and Purification.
Pooled splenocytes obtained from 10 C57BL/6.MHC IIIn Vitro T Cell Stimulation Assay.
T cells were cultured for 18 h in the presence of CD1d-expressing cells (5 × 104 responders and 5 × 104 transfectant or 5 × 105 thymocyte or splenocyte stimulators, unless otherwise stated) in 100 µl of a 1:1 mixture of Click's medium and RPMI (Biofluids) enriched with 10% heat-inactivated FCS, glutamine, antibiotics, and 5 × 10T Cell Hybridoma Generation.
Purified T cell subsets were cultured for 5 d with anti-CD3 and IL-2 and fused with BW5147Competitive Reverse Transcription PCR Quantification of Cytokine mRNA.
Messenger RNA was purified from 105 FACS®-sorted cells using the RNeasy Mini Kit (QIAGEN), reverse transcribed, and PCR amplified using IL-4, IFN-TCR Gene Sequencing.
Reverse transcription (RT)-PCR, primers, and methods were as described previously (11).CD1d Tail-mutant Constructs and Transfectants.
Complementary DNA for CD1-TD was generated by PCR using full-length CD1d cDNA (25) as template. First, primers S3 (5'-CCCTGGGAATGCTTCGG-3') and tR2 (5'-GGCAGGTGTAAGGAAGAGTCATCTCCTTCTCCAGATATAGTA-3') were used to amplify the 600-bp fragment A, and primers tNotI (5'-AAAAAGCGGCCGCGCAGGTACGCACATTTGCAGTT-3') and tF2 (5'-TACTATATCTGGAGAAGGAGATGACTCTTCCTTACACCTGCC-3') were used to amplify the 240-bp fragment B. The sequences of the tR2 and tF2 primers are complementary to each other. Fragments A and B were then used together as templates to amplify the chimeric PCR fragment C using the S3 and tNotI primers. To generate the CD1-TD plasmid Tdel2, fragment C was digested by BstEII and NotI and then subcloned into pCD113 (25) to replace its wild-type counterpart CD1-WT. The cDNA for Y332F was generated by PCR using pCD113 as template. Primers used were t-F332 (5'-GGAGAAGGAGAAGCGCTTTTCAAGACATCCGG-3') and CD1-R (5'-AAACTCGAGGCAGGTACGCACATTTGCAGT-3'). A single mutation introduced in the t-F332 primer is underlined. The amplifed 270-bp fragment was digested with Eco47III and XhoI and then subcloned into pCD113 to replace its wild-type counterpart. The sequence mutations were confirmed by sequencing. Plasmids (pCD113, Tdel2, and Y332F) were linearized by PvuI and XmnI before transfection. Transfection and selection of stable transfectants were as described (25).Confocal Microscope Analysis.
Labelings were performed essentially as described (26). Cells washed twice in cold PBS were fixed in 4% paraformaldehyde and 4% sucrose in PBS for 20 min at room temperature. Subsequent steps were performed at room temperature. After quenching for 20 min in 50 mM NH4Cl in PBS, the cells were washed once in PBS and permeabilized for 5 min in 0.05% saponin in the buffer used for washing. Cells were then incubated with anti-LAMP-1 (PharMingen) in the permeabilizing buffer for 45 min. After two washes in this permeabilizing buffer, the presence of anti-LAMP-1 antibodies was revealed by incubating the cells for 45 min in permeabilizing buffer containing Rhodamine-labeled rabbit secondary antibodies (1:50; DAKO). After two washes in permeabilizing buffer, the cells were incubated for 45 min with FITC-labeled rat anti-CD1d mAb 19G11 (27). After three washes in permeabilizing buffer and one wash in PBS, the cells were mounted in 100 µg/ml 1,4 diacylbicyclo (2.2.2) octane (Dabco; Sigma Chemical Co.), 100 µg/ ml moviol (Calbiochem Corp.), 25% (vol/vol) glycerol, 100 mM Tris-HCl, pH 8.5. The samples were examined under an LSM 510 confocal microscope attached to an axiovert microscope equipped with an argon and a helium-neon laser (Carl Zeiss, Inc.). The Rhodamine and FITC emissions were recorded sequentially. Optical sections were recorded with a 63× lens and a pinhole aperture such that the thickness of the sections was ~0.7 µm. No immunofluorescence staining was observed when second antibodies were used without the first antibody or with an irrelevant first antibody. ![]() |
Results |
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To determine
whether there are CD1d-restricted CD4 cell subsets other
than the NK T cell subset, we reexamined the residual CD4 cell population found in C57BL/6 mice bearing a targeted mutation of MHC class II (IAb
/
, referred to as
MHC II
/
). Fig. 1 shows that the residual 2 or 3% CD4+
cells in MHC II
/
mice could be divided into CD4+
NK1.1+ (one third) and CD4+NK1.1
(two thirds) cells,
as reported previously (21, 28). To examine these cells at
the single cell level, we generated separate panels of T cell
hybridomas from these sorted cell subsets. The hybrids were screened for autoreactivity to CD1d-transfected cells
or to cells that naturally express CD1d, such as thymocytes
and splenocytes, and for expression of the canonical V
14-J
281 TCR
chain. Significant numbers of CD1d-autoreactive cells were found in both NK1.1+ (27%) and
NK1.1
(32%)-derived subsets (Fig. 1). Most of the hybrids derived from NK1.1+ cells used the V
14-J
281
TCR
chain (81%), as expected, whereas most of those
derived from NK1.1
cells (86%) did not. Though the
NK1.1
CD1d-autoreactive subset does not use the canonical V
14-J
281 TCR, it is nevertheless not a highly
heterogeneous set but expresses a rather restricted set of
TCR genes. For example, out of 13 such V
14-negative
CD1d-autoreactive hybridomas collected in several independent fusion experiments and used in the experiments
depicted below in Fig. 4, 5 used V
8, and 3 of them, derived from 2 different mice, had the V
8 gene rearranged
to the same J
19 segment. Studies in progress on larger
panels of hybridomas confirm that CD4+NK1.1
cells
have a biased use of V
gene families (data not shown). In
addition, a majority of the V
14-negative CD1d-autoreactive hybrids (9 out of 13), like the V
14-positive hybrids
(11), used V
8.2 (see legend to Fig. 4) with diverse junctional regions (not shown). Thus, the results demonstrate
the existence of a second novel, phenotypically distinct set
of CD1d-restricted T cells that are NK1.1
, use limited
sets of TCRs, are autoreactive to CD1d, and whose frequency is comparable to that of V
14+ NK1.1+ cells.
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The use of a limited set of TCR families by both sets of CD1d-autoreactive cells suggests that they might recognize a limited number of CD1d-associated self-antigens. To examine the origin of self-molecules potentially presented by CD1d, we took advantage of the existence of a targeting motif in the cytoplasmic tail of CD1d that gives it access to the endosomal compartment (9, 31). We constructed a tail-deleted variant (CD1-TD) lacking the SAYQDIR COOH-terminal end of the cytoplasmic tail which contains the endosomal targeting motif (underlined), and generated stable transfectants expressing CD1-TD or the wild-type CD1 (CD1-WT) using two different cell lines, mouse C57SV fibroblasts (32) and rat RBL basophils (33). CD1-TD was well expressed on the plasma membrane (Fig. 2 a) in a highly glycosylated form similar to that of CD1-WT (not shown). Fig. 2 b shows that CD1-WT exhibited a prominent intracytoplasmic distribution with a diffuse vesicular pattern that colocalized extensively with LAMP-1, indicating that a significant fraction of the CD1 molecules pass through a late endosome/lysosome location. A similar distribution was found in BCL-1, a B cell line that naturally expresses CD1d (not shown). In contrast, most LAMP-1-positive vesicules were devoid of CD1d in CD1-TD-transfected cells, despite the matched expression levels of surface CD1d. These results, shown in Fig. 2 for C57SV, a mouse fibroblast cell line, are identical to those recently reported for a mouse B cell line, A20, transfected with CD1-WT or CD1-TD (31), and are similar to those established previously in the human CD1b system (9).
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To determine whether the CD1d molecules trafficking
through the endosome pick up a distinct set of self-antigens, we compared the ability of CD1-WT and CD1-TD
transfectants to stimulate CD1d-autoreactive T cells. To
achieve a dose titration of the CD1d molecules, we used
multiple rounds of FACS® sorting to select several sublines
expressing different surface levels of CD1-WT or CD1-TD. Fig. 3 shows that DN32.D3, a canonical V14-J
281/V
8 hybridoma, responded 10-fold less well to
CD1-TD than to CD1-WT, whether the CD1d molecule
was expressed by rat RBL basophils or by mouse C57SV fibroblasts. In contrast, 1C8.DC1, a V
14-negative hybridoma, showed identical responses to CD1-WT and CD1-TD over a wide range of surface concentrations, indicating that the CD1d-associated antigens recognized by 1C8.DC1
were essentially unaffected by the drastic changes in intracellular trafficking associated with the tail truncation, and
therefore that they are most likely loaded in the secretory
pathway. Again, identical results were obtained for both
C57SV and RBL transfectants, as shown in Fig. 3, left and
right, respectively, and confirmed in independent transfection experiments. An additional mutant of CD1d, CD1-Phe, which contains a Tyr to Phe mutation in the cytoplasmic tail motif, reproduced the CD1-TD phenotype (not
shown, and see Table I below).
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These results suggested the existence of two separate
pathways of antigen presentation by CD1d, one dependent
on and one independent of endosomal trafficking, and therefore the existence of two separate pools of self-antigens
loaded in distinct intracellular compartments. To test whether
the differences in recognition exhibited by DN32.D3 and
1C8.DC1 were characteristic of their representative subsets, we tested an extended panel of CD1d-autoreactive T cell hybridomas generated from normal or MHC II/
splenocytes or thymocytes over the course of 3 yr in seven fusion experiments. Fig. 4 is a compilation of several experiments
comparing their recognition of C57SV and RBL transfectants expressing matched levels of CD1-TD and CD1-WT.
We found that none of the 13 V
14-negative hybridomas
discriminated between CD1-WT and CD1-TD, whereas
10 out of 14 (71%) V
14-positive hybridomas clearly did,
exhibiting a 3-15-fold impaired recognition of CD1-TD.
These patterns of recognition of CD1-WT and CD1-TD
suggest that there is a systematic difference between the
two T cell subsets in their antigen presentation requirements.
A few (4 out of
14) V14-positive hybridomas were able to recognize
CD1-TD as well as CD1-WT, possibly because of residual access of CD1-TD to the endosomal compartment, or because they crossreacted with other antigens. To assay a
larger population of V
14-positive T cells, and to rule out
potential biases associated with studies of in vitro-derived
hybridomas, we studied cells from a transgenic mouse
where the invariant V
14-J
281 TCR
chain is expressed by all T cells, in association with endogenous, polyclonal TCR
chains (22). These T cells constitute a fresh
polyclonal population of V
14-J
281-positive CD1d-autoreactive T cells. Table I shows that V
14-J
281 transgenic thymocytes responded strongly to CD1-WT- and
poorly to CD1-TD-transfected cells. The response of 5 × 104 transgenic cells to RBL.CD1-TD was much lower
than the response of 104 cells to RBL.CD1-WT, suggesting that >80% of fresh V
14-positive cells specifically see
endosomally loaded antigens. The control V
14-negative
T cell hybridoma 1C8.DC1 used in this experiment responded equally to both. We next compared fresh NK1.1+
and NK1.1
CD4+ cells purified from the spleens of MHC
II
/
mice. Although these are not pure populations of
V
14-positive and -negative cells, they are significantly biased, containing 81 vs. 14% V
14-positive cells, respectively (see Fig. 1). Here again, the NK1.1+ (V
14-rich)
subset responded much more strongly to CD1-WT than to
CD1-Phe (or CD1-TD, not shown), whereas the NK1.1
(V
14-poor) subset responded well to both (Table I).
In a recent study, a single hybridoma out of two V14+
hybrids tested was found to react less well to CD1-TD than
to CD1-WT (31). The reaction patterns of our 27 hybridomas as well as those of fresh V
14 transgenic and fresh
NK1.1+ and NK1.1
cells conclusively demonstrate that
the ability to discriminate CD1-TD from CD1-WT is the
common, characteristic pattern of the V
14 T cell subset.
A hallmark of NK T cells is their extraordinary ability to synthesize and secrete large amounts of cytokines, especially IL-4, at peak levels very quickly after anti-CD3 injection in vivo, a unique property that is likely to influence the outcome of
the responses in which they are involved (22, 34). To determine whether CD4+NK1.1 cells can contribute to this
early cytokine burst, we purified CD4+NK1.1
and CD4+
NK1.1+ splenocytes 1.5 h after intravenous injection of 1 µg of 2C11 anti-CD3 antibody to MHC II
/
mice, and
measured their IL-4 and IFN-
mRNA using a competitive RT-PCR procedure (24). Fig. 5 shows that both subsets contributed significantly to the early cytokine burst, although NK1.1+ T cells tended to produce two to three
times more IL-4 and IFN-
mRNA than NK1.1
T cells
within this short time-frame. In conventional in vitro mitogen stimulation assays, both subsets released the same
amount of both IL-4 and IFN-
proteins after a period of
48 h (not shown). Thus, we conclude that both subsets can
produce IL-4 and IFN-
upon primary stimulation, although the kinetics of in vivo production may be faster for
NK T cells.
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Discussion |
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We have identified the in vivo counterpart of the non-
V14-expressing CD1d-autoreactive
/
T cell hybridomas reported previously by several laboratories, and
showed that they belong to a novel subset of T cells that
shares some characteristics with the V
14+NK1.1+ T cells
but differs in many others. Like V
14-positive NK T cells, these T cells exhibit a high frequency of autoreactivity to
CD1d, use restricted families of TCRs, and contribute to
the early burst of IL-4 and IFN-
induced by intravenous
injection of anti-CD3. However, they do not express the
NK1.1 receptor. In addition, they recognize different subsets of CD1d molecules. We showed using a large panel of
hybridomas as well as polyclonal fresh populations of
V
14-positive and -negative T cells that the V
14+
NK1.1+ T cells require endosomal targeting of CD1d
through a tail-encoded tyrosine-based motif for recognition of CD1d, whereas the newly discovered V
14
NK1.1
T cells do not. This dichotomy between NK1.1-positive and -negative T cells is independent of the expression of NK1.1, because NK T cell-derived hybridomas fail
to express NK1.1 (35; and data not shown). Altogether,
these experiments clearly establish that there are two phenotypically different subsets of CD1d-restricted T cells that
survey antigens loaded in distinct cellular compartments.
The results imply that CD1d may load self-antigens in
the two cellular compartments that are sampled separately
by the classical MHC class I and class II molecules. To sample the endosome, it uses an endosomal targeting motif
without which it can efficiently only sample the secretory
pathway. In support of the existence of a secretory pathway
of antigen loading is the recent report that a soluble, secretory form of CD1d could be loaded with endogenous cellular glycosyl phosphatidyl inositols (6). The existence of a
second, endosomal pathway has also been previously suggested by the finding that presentation of alpha galactosyl
ceramide, a mimic of the self-antigen recognized by V14
cells, is chloroquine dependent (7). As suggested (9), CD1d
may differ from MHC class II in that it might reach the cell
surface first and only secondarily be internalized, using its
tail-encoded tyrosine-based motif to access the endosome,
load new antigens, and recycle to the cell surface. Indeed,
experiments in progress in our laboratory indicate that the
rate of internalization of CD1-TD is significantly reduced
compared with that of CD1-WT (data not shown)
Therefore, like MHC class I and class II-restricted CD8
and CD4 T cells, CD1d-restricted V14-negative and
V
14-positive cells may survey different pathways of antigen presentation. This dichotomy is reinforced by the distinct phenotypes of the two subsets, in particular with
respect to the expression of the NK1.1 receptor. The
emerging picture is that CD1d-restricted T cells constitute at least two subsets of
/
T lymphocytes, comparable in
numbers to the NK cells (on the order of 1-20% of the
lymphocyte compartment in various tissues), that are particularly enriched in some tissues, such as the liver, spleen,
and bone marrow, and that use a limited number of TCRs
to focus on a limited number of distinct self- and foreign
antigens. Although the self-antigens recognized by the two
subsets of CD1d-restricted T cells described here remain to
be characterized, the evidence that the T cells can recognize both mouse and rat CD1-WT- and CD1-TD-transfected cells indicates that the nature and the cellular distribution of these self-antigens are conserved. An intriguing
possibility, suggested by current models of CD1/antigen/
TCR interactions (7, 36), is that the CD1d-restricted T
cells survey glycosylation changes in some conserved families of glycolipids, and thus act as sentinels in various conditions of stress, infection, or tumor growth where glycosylation processes may be affected. The finding that the phenotypic properties of these cells are distributed according to the antigens they recognize raises interesting developmental and functional issues.
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Footnotes |
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Address correspondence to Albert Bendelac, Department of Molecular Biology, Princeton, NJ 08544. Phone: 609-258-5454; Fax: 609-258-2205; E-mail: abendelac{at}molbio.princeton.edu
Received for publication 15 September 1998 and in revised form 28 October 1998.
We thank C. Carnaud and P. Matzinger for reviewing the manuscript, A. Beavis for cell sorting, and D. Hasara and L. Antonucci for managing the mouse colonies.
This work was supported by grants from American Cancer Society IM 788, a Cancer Research Institute Investigator Award (A. Bendelac), a grant from the Mallinckrodt Foundation, and a postdoctoral fellowship from the Cancer Research Institute (Y.-H. Chiu). The confocal microscope was purchased thanks to a donation from Marcel and Liliane Pollac.
Abbreviations used in this paper HPRT, hypoxanthine ribosyl transferase; mfi, mean fluorescent intensity; RT, reverse transcriptase.
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