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*
Immunology Section, Department of Cell and Molecular Biology, Lund University, Lund, Sweden; and
Gwen Knapp Center for Lupus and Immunology Research, Committee on Immunology and Department of Pathology, University of Chicago, Chicago, IL 60637
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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14-J281
rearrangement and a limited set of TCR Vß segments, implying
recognition of a limited set of CD1d-associated ligands. A second group
of CD1d-reactive T cells use diverse TCR potentially recognizing a
larger diversity of ligands presented on CD1d. In TCR-transgenic mice
carrying rearranged TCR genes from a CD1d-reactive T cell with the
diverse type receptor (using V3.2/Vß9 rearrangements), the
majority of T cells expressing the transgenic TCR had the typical
phenotype of NKT cells. They expressed NK1.1, CD122, intermediate TCR
levels, and markers indicating previous activation and were CD4/CD8
double negative or CD4+. Upon activation in vitro, the
cells secreted large amounts of IL-4 and IFN-
, a characteristic of
NKT cells. In mice lacking CD1d, TCR-transgenic cells with the NKT
phenotype were absent. This demonstrates that a CD1d-reactive TCR of
the "non-V 14" diverse type can, in a ligand-dependent way,
direct development of NK1.1+ T cells expressing expected
functional and cell-surface phenotype
characteristics. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß+ T cells have been described that
recognize CD1d in the absence of added Ag (6, 7, 8, 9, 10). Some of
these CD1d-reactive T cells express the NK1.1 marker (6).
NK1.1 was first described as a NK cell marker and is present on NK
cells and a subpopulation of T cells (termed NKT
cells)3 in some mouse
strains, like C57BL/6 (B6) mice (11). To date the
described CD1d-reactive T cells known to derive from the
NK1.1+ population had an invariant TCR -chain
consisting of a particular V14-J281 rearrangement and used TCR
ß-chains having primarily Vß8.2, Vß7, or Vß2 segments with
diverse rearrangements (12). The use of this semiinvariant
TCR for CD1d recognition has been conserved through evolution
(13, 14, 15, 16, 17). A very similar human TCR, with an invariant TCR
-chain and using the corresponding human TCR Vß segments,
recognizes the human homologue CD1d, and there is cross-recognition
between the murine and human system (15). Others described
murine CD1d-reactive T cells used diverse TCR - and ß-chains
(7, 8, 9, 10). These cells appear to share some of the
characteristic features of the NK1.1+ T cells of
B6 mice (7, 9, 18), but whether these cells belong to the
NK1.1+ T cell subset is not clear.
The role of NKT cells, or CD1d-reactive T cells, in the immune system
is not well understood, although their potent functional capacities,
like rapid production of large amounts of IL-4 and IFN- upon in vivo
stimulation (19), have been described. Their absence or
aberrant function in certain murine and human autoimmune disorders
indicate that they might be involved in the regulation of harmful
autoimmune reactions (20, 21, 22, 23, 24, 25). There is also evidence for
a role of NKT cells during bacterial infections (26, 27),
in IL-12-dependent rejection of tumors (28), and as helper
T cells for IgG production (3).
To analyze further the function and differentiation of CD1d-reactive T
cells, we have established a TCR-transgenic system expressing as
transgene-rearranged TCR genes from a CD1d-autoreactive T cell
hybridoma with the diverse-type TCR. Hybridoma VIII24 had been derived
from the CD4+ population in MHC class
II-deficient mice, used V3.2 and Vß9 TCR rearrangements, and was
reactive to endogenous CD1d on splenocytes and different
CD1d-transfected cell lines (7). This report describes the
phenotype and functional capacity of the TCR-transgenic T cells, their
appearance in the thymus, and demonstrates their dependence on the
ligand CD1d.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The variable regions of the TCR genes from the VIII24 hybridoma
were first cloned and sequenced from mRNA as previously detailed
(29). Using appropriate oligo nucleotides, genomic DNA
fragments containing the rearranged variable genes, V3.2J20 and
Vß9Jß1.4, were amplified by PCR from the hybridoma and cloned into
TCR expression cassette vectors as described in detail
(30). Linearized DNA constructs from the TCR and TCRß
cassette vectors, with prokaryotic sequences eliminated, were injected
into fertilized (B6 x SJL)F2 embryos.
Transgenic founders were screened for by Southern blot hybridization of
tail DNA, and progeny of positive founders typed by flow cytometry for
transgene expression on PBLs. Transgene-carrying founder mice were
backcrossed to B6 mice. Mice were 5 wk to 6 mo of age unless otherwise
stated, and from the first to fifth backcross generation. The NK1.1 Ag
is present in both SJL and B6 mice (11). For some
experiments, the 24ß transgenic line had been crossed with mice
lacking CD1d (31), backcrossed five generations to the B6
genetic background.
Flow cytometry
Cells were stained with conjugates and Abs of the following
specificities: Vß9-FITC, CD3-FITC, TCRß-PE, CD44-PE, IL-2Rß
(CD122) -PE, NK1.1-PE, NK1.1-biotin, TCRß-biotin, V3.2-biotin,
CD4-allophycocyanin, CD8-allophycocyanin (PharMingen, San Diego, CA),
TCRß-FITC, CD4-PE, CD8-PE, streptavidin-tricolor (Caltag, San
Fransisco, CA), and streptavidin-PE (Southern Biotechnology Associates,
Birmingham, AL). Abs to CD4 (GK1.5), CD8 (YTS169.4), CD24 (M1/69),
CD62L (Mel-14), Vß9 (MR10.2), V3.2 (RR3.16), and B220 (RA3.6B2)
had been purified and conjugated to FITC or biotin using standard
procedures or to Cy5 according to the manufacturers instructions
(Amersham Life Sciences, Little Chalfont, U.K.). The samples were
analyzed using FACSort or FACSCalibur flow cytometers (Becton
Dickinson, Mountain View, CA) and CellQuest software. Fluorescence is
displayed on a log10 scale.
T cell activation
Spleen or lymph node cells were stimulated in vitro at
105 cells/well in 96-well plates in complete RPMI
1640 medium (supplemented with 1 mM L-glutamine, 50 µm
2-ME, 1 mM sodium pyruvate, penicillin-streptomycin, and 10%
heat-inactivated FCS) in the presence of 2.5% of supernatant from the
X63Ag8 cells transfected to produce IL-2. The plates (nontissue culture
grade) had been precoated with KT3 (anti-CD3
) Abs at 10 µg/ml.
Supernatants were harvested at different times and analyzed as
described below. For activation of NKT cells in vivo (19),
mice were injected i.v. with a single dose of 1.5 µg of
anti-CD3 Ab (2C11) in HBSS or only HBSS. After 90 min, mice were
sacrificed, spleens were removed, and single-cell suspensions were
prepared. A total of 5 x 106 spleen
cells/ml/well of 24-well plates were cultured in complete RPMI 1640
medium for 90 min without further stimulation before supernatants were
harvested and analyzed for IL-4 and IFN-.
Detection of secreted cytokines by ELISA
Supernatants were collected as indicated and frozen at -70°C
until the day of the assay. Briefly, ELISA plates were coated with
11B11 (anti-IL-4) or R4-6A2 (anti-IFN-) Abs, incubated with
several dilutions of each supernatant or recombinant cytokine standards
(ImmunoKontact, Bioggio, Switzerland), followed by biotinylated AN18
(anti-IFN-) or BVD6 (anti-IL-4, ImmunoKontact) Abs and
streptavidin-alkaline phosphatase (Sigma, St. Louis, MO) and revealed
with the enzyme substrate.
Serum Ig isotypes
Standard sandwich ELISA were used to determine serum levels of Igs. For the detection of total IgG, plates were coated with goat anti-mouse IgG (Southern Biotechnology Associates), incubated with dilutions of serum, and revealed with a HRP-conjugated rabbit anti-mouse Ig antisera (Dako, Glostrup, Denmark). IgE was assayed using monoclonal anti-IgE reagents from Serotec (Oxford, U.K.) and an IgE standard from PharMingen. IgG1 and IgG2a were analyzed using the mouse monoclonal isotyping reagents ISO-2 (Sigma).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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3.2+ TCR
For the construction of mice carrying a transgenic CD1d-reactive
TCR, we selected a well-characterized CD4+ T cell
hybridoma, VIII24 (7), as donor of rearranged TCR genes.
VIII24 belongs to a set of CD1d-reactive hybridomas generated from
CD4+ T cells from MHC class II-deficient mice,
which were shown to respond to CD1d in the absence of added Ags
(7). The reactivity of VIII24 was dependent on the
expression by the APC of ß2-microglobulin
(ß2m), but not the TAP molecule
(7), consistent with the requirements for CD1d expression
(32, 33, 34). Stimulation could be inhibited by Abs to CD1d,
or to either of the TCR V-segments, V3.2 or Vß9 (S. Cardell,
unpublished data). Rearranged genomic variable region fragments from
the VIII24 hybridoma were cloned into expression cassette vectors
containing natural promoter and enhancer regions (30).
Separate lines were established for the transgenic TCR -chain and
the TCR ß-chain constructs, respectively, and the two were crossed to
obtain transgenic mice expressing the full CD1d-reactive TCRß
(Fig. 1
). The two single transgenic lines
are referred to as 24 and 24ß below, and the double transgenic
mice as 24ß.
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3.2. Either transgenic TCR chain expressed alone
resulted in an increased proportion of CD8+ vs
CD4+ T cells in the spleen (Fig. 1
a).
In contrast, in 24ß mice the CD8+ population
was severely reduced, and there was a decrease in the frequencies of
splenic CD4+ cells. Among
CD8+ cells, <10% expressed both transgenes at
high levels (Fig. 1b), while total TCRß levels were
homogenous (Fig. 1c), indicating a pronounced expression of
endogenous both TCR - and ß-chains. Also in the
CD4+ population, there was a marked expression of
endogenous TCR - and ß-chains (Fig. 1b). Cells
expressing both TCR transgenes were primarily found in a population of
CD4/CD8 double negative (DN) T cells, with no signs within this subset
of endogenous TCR chains on the surface (Fig. 1b, and
demonstrated by costaining for CD3 and transgenic TCR chains, data not
shown). The TCR levels were slightly reduced on both
CD4+ and CD8+ 24ß T
cells compared with cells from single transgenic and transgene-negative
littermate mice, suggesting an influence of low levels of the
transgenic CD1d-reactive TCR also on these cells. The TCR levels on the
DN population were even lower and similar to those of NKT cells from
wild-type (WT) mice (Fig. 1c). Transgene-expressing T cells exhibited a surface phenotype of NKT cells
In 24ß mice, the NK1.1+
TCRß+ population increased 5- to 10-fold
compared with WT or B6 mice (Fig. 2a), both in frequencies and
absolute numbers. NKT cells made up 12.6% (±3.1, n =
7) of total spleen cells and 35.6% (±12.5, n = 5) of
the TCRß+ population. In B6 or WT mice,
1.9% (±0.5)of splenocytes were NK1.1+
TCRß+. In mice expressing only one of the
transgenic TCR chains, the frequency of NK1.1+
TCRß+ cells were similar or slightly lower
than in control mice. In 24ß mice, the majority of
transgene-expressing cells (V3.2+
Vß9+ cells in gate R2 in the first upper panel
of Fig. 2b) were DN, although a substantial population,
somewhat variable between mice, expressed graded levels of CD4 (Fig. 2b). A heterogenous CD4 expression was seen also on
NK1.1+ T cells from WT mice. This can be directly
compared between WT and 24ß CD4+ cells in
Fig. 1 and the TCRß+
NK1.1+ population displayed in Fig. 2b
(in Fig. 2b an additional gate has been added for
CD4low cells, while the upper gate is the same as
that in Fig. 1). The majority of transgene-expressing cells (R2 gate)
were CD44high, CD62Llow,
and positive for the NK1.1 marker and CD122 (IL-2R ß-chain) (Fig. 2b), a surface phenotype similar to that of NKT cells of
normal mice (gate R3 in the lower panel), although they
expressed only low levels of CD69 while NKT cells of B6 mice were
positive (not shown). Thus,
24+ß+ T cells present
in the periphery of the 24ß-transgenic mice posess a surface
marker phenotype very similar to NKT cells from normal B6
mice.
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NKT cells have been shown to display a particular profile of
cytokines when stimulated in vitro (12, 18, 35) and
further to rapidly secrete high amounts of cytokines upon in vivo
induction (19). To analyze the potential of transgenic T
cells to produce cytokines, lymph node or spleen cells were
polyclonally stimulated in vitro. T cells in the 24ß-transgenic
mice responded well to TCR ligation in vitro by proliferation (not
shown) and secretion of large amounts of IL-4 and IFN- (a 15- and
2-fold increase, respectively, compared with WT, Fig. 3a), while single transgenic
controls were similar to WT.
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ß and control (single transgenic and B6) mice were injected with
anti-CD3 Ab. Ninety minutes after anti-CD3 injection, spleen
cells were prepared and cultured in medium for 90 min in vitro before
supernatants were harvested and analyzed for cytokines. In B6 mice,
production of IL-4 and IFN- was induced by the in vivo injection,
while the results were variable for the 24ß mice (Fig. 3b). Clearly, the IL-4 production induced in 24ß mice
by this protocol was not increased to the extent seen in
V14-J281-transgenic mice (36). In the latter mice,
serum IgE levels were elevated, thought to be the consequence of the
high frequency of IL4-producing NKT cells. In 24ß mice, serum IgE
was only slightly elevated, while total IgG, IgG1, and IgG2 levels were
similar to control mice (Fig. 4).
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Thymi of 24ß mice contained 5–10% the number of cells
compared with WT, 24 thymi contained around 20%, and 24ß thymi
were similar to WT (not shown). The CD4/CD8 double positive (DP)
population was greatly reduced in 24ß thymi but the CD4/CD8 DN
subset enlarged (Fig. 5), generally also
in absolute numbers (up to 2.5-fold). A population of DN thymocytes
(Fig. 5) expressing the transgenic TCR -chain, but lacking the NKT
phenotype (not shown), was present in 24 mice. DN T cell populations
have been found in some other TCR-transgenic systems and have been
proposed to contain cells of the 
lineage (37, 38).
Twenty-five to 50% of the TCR+ cells in 24ß
thymi were NK1.1+ (Fig. 5), corresponding to an
2.5-fold increase in numbers compared with WT, while either of the
two transgenic chains alone rather decreased the number of
NK1.1+ TCRß+
thymocytes. The great majority of cells in the 24ß DN population,
65–75%, expressed both TCR transgenes (Fig. 6a), with very few cells
expressing endogenous TCR on the surface as determined by costaining
for CD3 expression and transgenic TCR chains (not shown). In the
24ß DP population, low levels of the transgenic TCR could be
detected on some of the cells. There was a prominent expression of
endogenous TCR - and ß-chains in the thymic
CD4+ and CD8+ single
positive (SP) subsets, just like in the peripheral SP subsets.
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ß DN thymocytes, most TCRß+
cells were CD122+, and around 40% of the DN
TCRß+ population was
CD24+ (heat shock Ag) (Fig. 6, b and
c). NK1.1 expression was found on a subset of
TCRß+ cells, mostly within the
CD24- fraction (Fig. 6c), and their
level of TCRß was slightly lower than that of the major DN
TCRß+ population (Fig. 6b).
CD122-expressing cells were very rare, and NK1.1+
cells are absent among DP cells of both WT and 24ß mice (Fig. 6d). Early appearance of the NKT phenotype on TCR-transgenic cells
Like in adult mice, thymi of 1-wk-old 24ß mice contained
10% the number of cells compared with WT thymi. One-week-old
24ß thymi contained very few SP cells, a reduced DP population,
and a large DN population (Fig. 7a), of which most cells
expressed the transgenic TCR (not shown). At this age, only 3–5% of
DN TCR+ thymocytes were
NK1.1+ (Fig. 7b), all residing within
the CD24- fraction (not shown), but the majority
were CD122+ (Fig. 7b). In the
periphery at 1 wk of age, 6% of splenocytes expressed the two
transgenic TCR chains, and 10% of these were
NK1.1+ (determined by V3.2 vs NK1.1 expression
in Fig. 7c).
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To investigate whether the appearance of TCR-transgenic NKT cells
were dependent on the CD1d ligand, 24ß mice were crossed with mice
lacking CD1d (CD1d° mice) (31). In the absence of CD1d,
TCRß+ T cells expressing the NK1.1 marker
were virtually absent both in the thymus and spleen (Fig. 8a). Transgene-positive T
cells were present in CD1d° mice (Fig. 8b), but they had a
phenotype very different from that of transgenic T cells on the control
CD1d+/° background, as well as higher TCR
levels (note the position of the population within the gates of the
first dotplots in Fig. 8b). The
24ß+CD1d° cells were preferentially DN,
resembling the DN population in 24-transgenic mice (37, 38), or CD8+, negative for the CD122 and
NK1.1 markers, and had a naive phenotype
(CD62Llow, CD44high, Fig. 8b). Thus, 24ß-transgenic T cells with the typical NKT
phenotype appeared in the thymus and periphery only in the presence of
the CD1d ligand.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß mice expressing a transgenic CD1d-reactive TCR using
V3.2 and Vß9, the majority of peripheral
24+ß+ T cells, and a
high proportion of
24+ß+ thymocytes,
expressed the NK1.1 marker. Peripheral
24+ß+ T cells shared
characteristic features with NKT cells, including a phenotype of
previous activation (CD44high,
CD62Llow), expression of CD122/IL-2Rß,
intermediate levels of the TCR, and synthesis of high amounts of
cytokines, IL-4 and IFN-, upon activation (12, 18, 35).
The appearance of
24+ß+ T cells of the
typical NKT phenotype required the presence of CD1d and the expression
of both chains of the CD1d-reactive TCR. Further, in contrast to what
was reported for mice transgenic for the V14-type NKT TCR chain
(36), 24ß NKT cells did not respond to activation in
vivo with rapid production of high amounts of cytokines, and serum IgE
levels in 24ß mice were close to normal despite the capacity of
24ß NKT cells to produce IL-4 upon activation in vitro. The latter
may be due to the high production of IFN- by the same population, as
IL-4 and IFN- have diverse effects on Ig isotype switch in B cells
(39). Alternatively, recognition of different
CD1-associated ligands, presented on different APC or in distinct
locations, by the 24ß- and V14-type TCR, may result in
dissimilar behavior of the cells in vivo. Regardless of some functional
discrepancy, our results demonstrate that CD1d-reactive T cells with
diverse TCR (TCRdiv) may be contained within the
NK1.1+ TCRß+
population and potentially share at least some immune functions with
CD1d-reactive TCRV14 T
cells.
Although -galactosylceramide has been shown to be a common ligand
for TCRV14 cells
(2), the broad TCR repertoire of
TCRdiv CD1d-reactive T cells may reflect a
potential to recognize a variety of ligands presented on CD1d. In line
with this, recent reports have described ligand-specific reactivity to
several distinct GPI molecules by NKT cells (3) and
reactivity to cellular phospholipids (40), demonstrating
the existence of a diversity of ligands recognized by CD1-restricted T
cells. The 24ß TCR recognizes a putative unknown CD1-bound ligand
not requiring endosomal loading (41) and distinct from the
ceramide based ligands activating the V14-type T cells (2, 40, 42, 56).
The major 24+ß+
TCR-positive T cell population in the thymus and periphery of
transgenic mice was DN, and a minor subset CD4+,
while the original T cell hybridoma carried the CD4 marker
(7). Thus, transgenic T cells with identical TCR could
have either phenotype. Similarly, CD1d-reactive T cells of the V14
type have been demonstrated among DN as well as
CD4+ NKT cells (6). This implies
that CD4 expression on NKT cells is not a phenotype dictated by the TCR
specificity. In fact, it has been demonstrated both that the CD4
molecule can be up-regulated on DN splenic T cells (43),
and down-regulated on CD4+ NKT cells
(44), by activation.
24+ß+ T cells
expressed CD4 at heterogenous levels similar to those of
CD4+ NK1.1+ T cells in WT
B6 mice, a pattern different from what is found on conventional
(NK1.1-) CD4+ T cells.
Although CD4+ and DN NKT populations may harbor
shared TCR specificities, there may be important differences between
the two cell types. In normal mice, we have demonstrated that DN, but
not CD4+, NKT cells of spleen and liver express
inhibitory NK markers of the Ly-49
type,4 and it has been
reported that IL-4 production upon stimulation was found preferentially
in the CD4+ subset (Ref. 12 and M.
Sköld and S. Cardell, manuscript in preparation).
Current views hold that NKT cells can develop both in the thymus
(12) and extrathymically (45). The majority
of thymocytes expressing the transgenic TCR were found in the DN
subset, and a substantial fraction of these cells were immature
(CD24+), suggesting that the thymus was a site of
maturation for 24ß-transgenic T cells. In 24ß mice, the size
of the transgenic thymi was 5–10% of WT, and the DP population was
severely reduced. In TCRVa14-transgenic mice, a
reduction in thymocyte numbers was also seen (36, 46). The
number of thymocytes was reconstituted in the absence of the ligand
CD1d, compatible with a deletion of cells during thymic selection due
to CD1d autoreactivity of the transgenic TCR (47). The
finding that 24+ß+
CD8+ cells were extremely rare suggests a
deletion of 24+ß+
cells expressing a CD8 coreceptor increasing the avidity of interaction
with CD1d, as proposed for NKT cells (34). But, the low
number of DP cells may also be the result of killing of
CD1d+ DP cells by mature CD1d-reactive
24ß+ thymocytes (48).
The majority of TCR+ß+
DN thymocytes expressed CD122. This marker is induced on conventional
MHC class I-restricted TCRß+ cells during
thymic selection by high-affinity TCR-ligand interaction
(49). CD122 expression on
24+ß+ thymocytes was
thus not surprising considering the apparent autoreactive nature of the
24ß TCR (7) and suggests that the majority of DN
TCR+ thymocytes had undergone TCR selection
events. Also, the NK1.1+ phenotype appears to
correlate with high-affinity TCR-ligand interaction (50, 51). Not all of the DN CD122+ cells
expressed the NK1.1 marker. Part of the NKT phenotype (display of
CD122/IL-2Rß) appears to be a result of the selection process, while
expression of the NK1.1 marker itself may result from an independent
event taking place at a later time. Findings from various mutant mice
suggest a division of NKT development into a first step of
CD1d-dependent selection (31, 52, 53), leading to the
CD122+ phenotype, and a second,
cytokine-dependent step resulting in final maturation of NKT cells
characterized by the expression of NK1.1 (54, 55).
Further, some of the
24+ß+
CD122+ NK1.1- cells may
have lost expression of the NK1.1 marker during activation
(44).
We demonstrate in the 24ß TCR-transgenic system that a
CD1d-reactive TCR of the diverse type can direct development of NKT
cells expressing most of the expected functional and surface phenotype
characteristics. Thus, the TCRdiv (represented by
the 24ß NKT cells) and
TCRV14 NKT cells have
many similarities: the reactivity to CD1d in the absence of exogenous
ligands, the activated cell surface phenotype, and the profile of
cytokines secreted upon activation. But there are also important
distinctions, such as the recognition of distinct CD1d-bound ligands
and, in the case of 24ß NKT cells, the lack of rapid cytokine
secretion in response to TCR stimulation in vivo. This implies that the
TCRdiv NKT cells may have the capacity to perform
the same immune regulatory functions as suggested for the
TCRV14 NKT cells, but
possibly that they are induced in different situations. Identification
of the endogenous ligands activating NKT cells in vivo will shed some
light on this issue, as well as further analysis of the precise
functions of NKT cell subsets during the immune responses in which
their importance has been implied.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Susanna Cardell, Immunology Section, Department of Cell and Molecular Biology, Lund University, Sölvegatan 21, 223 62 Lund, Sweden,
3 Abbreviations used in this paper: NKT cell(s), T cell(s) expressing the NK1.1 marker; ß2m, ß2-microglobulin; B6, C57BL/6; DN, double negative; DP, double positive; SP, single positive; TCRdiv, T cell(s) with diverse TCR; TCRV14, T cell(s) using the semiinvariant V14-J281 TCR; WT, wild type; CD1d°, CD1d deficient.
4 M. Sköld and S. Cardell. Differential regulation of Ly-49 expression on CD4+and CD4-CD8- (double-negative) NK1.1+ T cells. Submitted for publication.
Received for publication April 23, 1999. Accepted for publication April 20, 2000.
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 L. Rogers, S. Burchat, J. Gage, M. Hasu, M. Thabet, L. Wilcox, T. A. Ramsamy, and S. C. Whitman Deficiency of invariant V{alpha}14 natural killer T cells decreases atherosclerosis in LDL receptor null mice Cardiovasc Res, April 1, 2008; 78(1): 167 - 174. [Abstract] [Full Text] [PDF]
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 E. Ambrosino, M. Terabe, R. C. Halder, J. Peng, S. Takaku, S. Miyake, T. Yamamura, V. Kumar, and J. A. Berzofsky Cross-Regulation between Type I and Type II NKT Cells in Regulating Tumor Immunity: A New Immunoregulatory Axis J. Immunol., October 15, 2007; 179(8): 5126 - 5136. [Abstract] [Full Text] [PDF]
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H. Wakao, H. Kawamoto, S. Sakata, K. Inoue, A. Ogura, R. Wakao, A. Oda, and H. Fujita A Novel Mouse Model for Invariant NKT Cell Study J. Immunol., September 15, 2007; 179(6): 3888 - 3895. [Abstract] [Full Text] [PDF]
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M. S. Vincent, X. Xiong, E. P. Grant, W. Peng, and M. B. Brenner CD1a-, b-, and c-Restricted TCRs Recognize Both Self and Foreign Antigens J. Immunol., November 15, 2005; 175(10): 6344 - 6351. [Abstract] [Full Text] [PDF]
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Y.-T. Chen and J. T. Kung CD1d-Independent Developmental Acquisition of Prompt IL-4 Gene Inducibility in Thymus CD161(NK1)-CD44lowCD4+CD8- T Cells Is Associated with Complementarity Determining Region 3-Diverse and Biased V{beta}2/V{beta}7/V{beta}8/V{alpha}3.2 T Cell Receptor Usage J. Immunol., November 15, 2005; 175(10): 6537 - 6550. [Abstract] [Full Text] [PDF]
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S. C. Kent, Y. Chen, S. M. Clemmings, V. Viglietta, N. S. Kenyon, C. Ricordi, B. Hering, and D. A. Hafler Loss of IL-4 Secretion from Human Type 1a Diabetic Pancreatic Draining Lymph Node NKT Cells J. Immunol., October 1, 2005; 175(7): 4458 - 4464. [Abstract] [Full Text] [PDF]
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N. Duarte, M. Stenstrom, S. Campino, M.-L. Bergman, M. Lundholm, D. Holmberg, and S. L. Cardell Prevention of Diabetes in Nonobese Diabetic Mice Mediated by CD1d-Restricted Nonclassical NKT Cells J. Immunol., September 1, 2004; 173(5): 3112 - 3118. [Abstract] [Full Text] [PDF]
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D. Mayerova and K. A. Hogquist Central Tolerance to Self-Antigen Expressed by Cortical Epithelial Cells J. Immunol., January 15, 2004; 172(2): 851 - 856. [Abstract] [Full Text] [PDF]
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T. Yoshimoto, B. Min, T. Sugimoto, N. Hayashi, Y. Ishikawa, Y. Sasaki, H. Hata, K. Takeda, K. Okumura, L. Van Kaer, et al. Nonredundant Roles for CD1d-restricted Natural Killer T Cells and Conventional CD4+ T Cells in the Induction of Immunoglobulin E Antibodies in Response to Interleukin 18 Treatment of Mice J. Exp. Med., April 21, 2003; 197(8): 997 - 1005. [Abstract] [Full Text] [PDF]
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M. Capone, D. Cantarella, J. Schumann, O. V. Naidenko, C. Garavaglia, F. Beermann, M. Kronenberg, P. Dellabona, H. R. MacDonald, and G. Casorati Human Invariant V{alpha}24-J{alpha}Q TCR Supports the Development of CD1d-Dependent NK1.1+ and NK1.1- T Cells in Transgenic Mice J. Immunol., March 1, 2003; 170(5): 2390 - 2398. [Abstract] [Full Text] [PDF]
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S.-H. Park, A. Weiss, K. Benlagha, T. Kyin, L. Teyton, and A. Bendelac The Mouse CD1d-restricted Repertoire Is Dominated by a Few Autoreactive T Cell Receptor Families J. Exp. Med., April 9, 2001; 193(8): 893 - 904. [Abstract] [Full Text] [PDF]
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) or HBSS alone (
) as a
control. After 90 min, mice were sacrificed. Spleen cells were prepared
from injected mice and cultured in medium in vitro for another 90 min
before supernatants were harvested and analyzed for IL-4 and IFN-
) mice, and levels of total IgG, IgG1, IgG2a, and IgE were measured
in ELISA. Each box represents the value from one mouse.
