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*
Institut National de la Santé et de la Recherche Médicale Unité 25, Hôpital Necker, Paris, France; and
Laboratoire d’Immunologie-Immunopathologie, Centre Hospitalier Universitaire, Poitiers, France
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) lymphokines (17). Besides a numerical and functional deficit of NKT cells (12), NOD mice present multiple defects of innate immunity, including poor NK function, which explains the remarkable permissiveness NOD.SCID (18) and NOD.RAG1°/° mice (19) to xenografts. Whether such defects contribute to the autoimmune profile of the strain is still not clear, but indirect arguments suggest that this might be the case. For instance, most microbiological or pharmacological agents that boost innate immune defenses such as viruses (20), bacillus Calmette-Guérin (21), poly(I:C) (21, 22, 23), or IL-12 (24) also exert an influence upon the onset of type 1 diabetes in NOD mice. In many cases they delay or totally prevent the disease, in a few situations they may accelerate the process, but they are never neutral. Another indirect argument comes from genetic studies. A region of disease susceptibility, referred to as Idd6, has been recurrently mapped on the distal portion of chromosome 6 (25) in an interval that overlaps the NK complex (NKC) (26). This 2-Mb segment contains all the critical genes involved in the physiology and the regulation of NK and NKT cells, including the Nkrp1 gene cluster, the set of inhibitory and activating Ly49 genes (27), Cd69, Cd94 (28), and a number of functional genes providing NK-mediated innate resistance against mouse CMV (Cmv1) (29), ectromelia poxvirus (Rmp1) (30), and Chinese hamster ovary xenotransplants Chok (28).
A few years ago, we started backcrossing onto NOD mice the cell surface marker NK1.1, a receptor of the NKR-P1 family expressed in the C57BL/6 (B6) but not in the NOD strain. There were two main purposes to this breeding. One was to tag NK and NKT cells with NK1.1, which is specifically recognized by the mAb PK136 (31). The second was to construct a NOD strain congenic for the Idd6 genetic interval, to explore the impact of this locus upon the pathogenesis of type 1 diabetes and the functional defects of innate immunity in this strain.
The NOD.NK1.1 congenic strain obtained after 10 backcrosses has already
been successfully used for discriminating FcRs on NK cells and
macrophages of NOD mice (32) and for identifying NKT cells
in V
14J281-transgenic NOD mice (16). Here we report
data directly connected to the objectives for which this congenic
strain was initially produced, namely 1) the expression of the NK1.1
marker on NK and NKT cells, 2) the diabetic profile of the strain, and
3) the impact of B6 gene introgression upon the functional deficit of
NK and NKT cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The NOD.NK1.1 congenic strain was initiated from an outcross
between NOD/Necker and C57BL/6/J/Orl (B6). For the first five backcross
(BC) generations, NK1.1 heterozygous breeders were selected by
phenotyping NK cells from small spleen biopsies performed under general
anesthesia. For the five next BC generations, tail DNA was genotyped
with a set of microsatellites delimiting an interval of 
10 cM
between D6 Mit 254 and D6 Mit 14. Informative markers for NKR-P1 were
D6 Mit 52 and D6 Mit 135. Additional microsatellites ordered upstream
downstream were D6 Mit 13, 25, 339, 291, and 259 (33). The
genetic interval was maintained relatively broad in the absence of more
precise information upon Idd6. An homozygous line was
initiated from the progeny of the intercross at BC 10. NOD.NK1.1, NOD
wild-type, and B6 mice were bred behind a barrier, under strict
specific pathogen-free conditions. The mice were kept under the same
sanitary situation during the whole time of the experimentation.
Assessment of diabetes
Mice were followed for glycosuria (Glukotests; Boerhinger Mannheim, Roche, France) once a week, starting at week 10. After two consecutive positive urine tests, the mice were bled for glycemia (Haemoglucotest; Boerhinger Mannheim) and recorded as diabetic when the blood glucose concentration reached 3 g/L.
For histopathology, pancreas samples were fixed in formalin, paraffin-embedded, and stained as 4-µm sections in hematoxylin and eosin.
Cyclophosphamide (CY)-accelerated diabetes
Seven-week-old females received a single i.p. injection of 300 mg/kg CY (Endoxan-Asta, Colombes, France) extemporaneously dissolved in saline. Glycosuria was checked three times a week for eight consecutive weeks, and diabetes was assessed as described above.
Enrichment for mature thymocytes
Thymic lobes were carefully extirpated from the thoracic cavity of exsanguinated mice and homogenized in loose fitting glass pestles. Thymocytes were washed and resuspended in RPMI 1640 medium plus 5% FCS (Life Technologies, Cergy-Pontoise, France) at 20 x 106 cells/ml. A mAb cocktail of Y169 (rat anti-mouse CD8) and J11d (rat anti-mouse heat-stable Ag; anti-HSA) plus rabbit complement at 1/10 (Low-Tox; Cedarlane, Ontario, Canada) was added to the suspension, which was left for 40 min at 37°C with continuous agitation. After extensive washings, live cells were recovered by centrifugation at 2000 rpm for 20 min on Ficoll (J. Prep; Techgen, Les Ulis, France). HSA-CD8- thymocytes were restained with a second anti-HSA mAb (clone M.1/69) to gate out by flow cytometry the few remaining immature cells.
Flow cytometry
Anti-NK1.1 (clone PK136) anti-DX5, anti-CD44 (clone 1
M7.8), and anti-TCR
(clone H57-597) were purchased from BD
PharMingen (San Diego, CA). Anti-CD4 (clone MT4) was purified from
ascites fluid by ammonium-sulfate precipitation and gel chromatography
on DEAE cellulose. Biotinylation was performed according to standard
procedures. We used exclusively PerCP conjugates for FL3, because of
the nonspecific binding of fluorochromes such as Tricolor on NOD
lymphoid cells.
Fluorescent cells were passed on a FACScan or a FACSCalibur (BD Bioscience, San Jose, CA) and analyzed with the CellQuest software (BD Bioscience). Statistics presented are based on at least 1500–2000 events gated on the population of interest.
Cytotoxicity assay for NK cells
Cytotoxicity was measured by conventional 4-h
51Cr release assay against YAC-1 target cells. NK
spleen cells had been boosted with 150 µg poly(I:C) 16 h before
the assay. They were serially diluted and distributed as triplicates in
0.1 ml RPMI 1640–10% FCS into U-shaped microtiter plates (Nunclon;
Nunc, Roskilde, Denmark). 51Cr-labeled YAC-1
cells (200 µCi/5 x 106 cells) were added
at 1 x 104 cells/well in 0.1 ml medium.
Supernatant (0.1 ml) was collected at the end of the assay, and isotope
release was measured in a counter. Percent specific release was
calculated according to the general formula: [(experimental cpm
- spontaneous cpm)/(maximal cpm - spontaneous cpm)] x 100.
Spontaneous release was consistently below 15% of maximal
incorporated cpm.
A lytic unit (LU25) was defined as the number of effector cells required to achieve 25% specific release. It was deduced from the linear function relating release to the number of effector cells. The results are given as the number of LU25 present in 1 x 106 effector cells.
NKT cell stimulation by -galactosylceramide (-GC)
(2S, 3S,
4R)-1-O-(-D-galactopyranosyl)-2-(N-hexacosanoylamino)-1,3,4-octadecanetriol
was synthesized by Pharmaceutical Research Laboratories, Kirin Brewery
(Gunma, Japan) and generously made available by Dr. Y. Koezuka. Mice
were injected concomitantly i.p. and i.v. with 2 µg -GC. Controls
received an identical volume of vehicle (0.025% polysorbate solution).
Mice were killed 2 h after injection and bled under general
anesthesia. Sera were carefully decanted from the clot and immediately
frozen.
ELISA for IL-4 and IFN-
Serum contents in the two cytokines were determined by sandwich
ELISA. Plates were coated with capture mAbs (11B11 for IL-4 and R46A2
for IFN-), blocked with PBS-1% BSA and incubated for 2 h with
serial dilutions of the sera. Detection was achieved with biotinylated
mAbs (BVD6 for IL-4 and AN18 for IFN-) and streptavidin-peroxidase
(Amdex; Amersham, Les Ulis, France). The colorimetric reaction used
o-phenylenediamine as substrate plus hydrogen peroxide
(Sigma, France). IFN- and IL-4 concentrations, expressed in
picograms per milliliter, are deduced from serial dilution curves of
mouse recombinant standards (R&D Systems, Abingdon, U.K.) run in
parallel in each assay. The sensitivity for IL-4 and IFN- is in the
order of 20–40 pg/ml.
Statistical analyses
Comparisons between groups of mice for cumulative disease incidence were plotted as survival curves and treated by log rank test. Statistical significance between groups of mice for NK cytotoxicity and NKT lymphokine release was treated with the unpaired two-tail Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NKT cell phenotype was analyzed first in the thymus (Fig. 1
), after depletion of immature
CD8+/HSA+ thymocytes by mAb
plus complement and restaining with a second anti-HSA mAb to gate
out the few remaining immature cells. The three colors left were used
for TCR, NK1.1, and V8 or CD44. As shown in the dot-plot (Fig. 1A), a double-positive NK1.1/TCR population could be
as easily resolved in NOD.NK1.1 as in B6 thymocytes processed in
parallel. NK1.1 density per cell was not different in the two strains.
In contrast, as expected from literature (2), the
expression of TCR was intermediate compared with that of mainstream
mature thymocytes.
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-chain, NKT cells overuse V8.2 gene segment
(34). As shown in the histograms Fig. 1
B, 65%
of NOD.NK1.1 and 70% of B6 NKT cells express V8, vs 15–25% only
in mainstream mature thymocytes. CD44 expression is another typical
feature of NKT cells (35). As shown in Fig. 1C,
87% of NOD.NK1.1 and 98% of B6 NKT cells were
CD44+, vs 15–25% in mainstream thymocytes. The
only significant difference between NOD.NK1.1 and B6 NKT cells was of
quantitative nature. The ratio between NKT and mainstream mature
thymocytes was systematically lower in NOD.NK1.1 mice (7/78 vs 18/75 in
B6) due to a numerical defect of NKT cells. Even at older ages, the
defect remained visible. We also noticed a higher proportion of
TCR-/NK1.1+ cells in
NOD.NK1.1 samples. This could just reflect a more active circulation of
conventional NK cells through the thymus of NOD mice. Alternatively,
and although it has been shown that NKT cell differentiation is not
necessarily linked to NKR-P1 receptor expression (36, 37),
it is possible that the accumulation of NK1.1+
TCR- cells reflects a maturation arrest at some
stage of NKT cell ontogeny. Further studies on the thymic
differentiation pathways of NKT cells will be necessary for clearing
this issue.
NKT cells could be also visualized in total spleen, using the same
triple staining combination (Fig. 2A). Here, however, NKT cells
represented <1% of the total population—0.48% and 0.80%,
respectively, in NOD.NK1.1 and B6 spleen samples—and were less
homogeneously clustered on the NK1.1 by TCR dot-plot.
Conventional NK cells
(NK1.1+TCR-) are also
clearly visible.
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8 gene segments could be easily demonstrated
in the population gated in the upper right quadrant, as compared with
mainstream T cells (histograms in Fig. 2B). Splenic NKT
cells presented also an overactivated phenotype as demonstrated by the
high percentage of CD44+ cells. There was indeed
an increased percentage of CD44+ cells among
NOD.NK1.1 NKT cells (in the order of 60%), yet when compared with B6
NKT cells, the percentage of the latter was systematically higher in
every experiment done (in the order of 90%), suggesting a possible
defect of activation of NOD NKT cells that might account for the
functional deficit described in NOD mice.
Conventional NK cells were reanalyzed per se by double staining with
PK136 and DX5 mAbs, the latter staining indiscriminately the vast
majority of NK cells. CD3+ T lymphocytes were
gated out using a third color. As can be seen from Fig. 3, the distribution of NK cells with
respect to the two classical NK markers is quasi-identical in NOD.NK1.1
and B6 mice. In both samples, double-positive NK1.1/DX5 cells are
predominant and constitute an homogeneous, well-resolved population
amounting to 3% of the splenocytes. Interestingly, in contrast to
NKT cells, there was no obvious numerical deficit in NOD.NK1.1 mice. If
anything, conventional NK cells seemed slightly more abundant in some
NOD.NK1.1 spleens as compared with B6 (see Fig. 2A and
3).
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Cumulative incidence was followed over a 9-mo period, in a cohort
of 300 males and 300 females. The mice were the progeny of a large
intercross between BC 10 mice. They were individually genotyped at the
boundaries of the foreign B6 segment, D6 Mit 254 upstream and D6 Mit14
downstream. Mice that had recombined within this interval were excluded
from the analyses. The global results are presented in Fig. 4A for females and 4B for males.
Differences between congenic and wild-type mice are clearly observed.
Time of onset is not affected, but incidence is lowered in BB
(homozygous B6) compared with NN (homozygous NOD) mice. The differences
are statistically significant by log rank test, well below 0.01%, and
can be demonstrated both in females and males, suggesting that the
protection afforded by the B6 alleles (or the lost susceptibility) is
not linked to the sexual dimorphism of the strain. The fact that we
compared littermates, bred under the same conditions and housed in
common cages, genotyping being done after weaning, made unlikely an
implication of environmental factors.
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However, when histology was examined at 10–12 wk, i.e., at a preclinical stage, there was no significant difference in insulitis severity between congenic NK1.1 and wild-type NOD islets (data not shown). In both strains, the proportion of intact, peri-, and intrainfiltrated islets was identical.
The two strains showed absolutely identical susceptibility to disease acceleration by CY at 7 wk of age (data not shown). Thus the protection afforded by the B6 alleles from distal chromosome 6 is sex independent and does not seem to affect the early stages of the disease such as islet infiltration or precocious effectors still under control. B6 genes rather seem to regulate the late developments of autoimmune diabetes, at a time when effector T cells are probably expanding and accumulating around or within the islets.
NK and NKT cell functions in NOD.NK1.1 congenic mice
As mentioned above, NKT cells were not numerically restored in NOD.NK1.1 mice, neither in the thymus nor in the spleen, when compared with the same subsets in B6 mice. We also measured the capacity of NKT cells from NOD.NK1.1 mice to release explosively cytokines and of NK cells to lyse YAC-1 target cells in a standard chromium assay and found that neither functions were restored to the levels achieved by the same subsets in B6 mice (data not shown). Thus, as reported for SJL mice (37), the introduction of a B6 NKC was not sufficient to reconstitute the functional deficit of innate immunity in NOD congenic mice.
Yet, because we had found significant differences in disease
susceptibility between NOD.NK1.1 and NOD wild-type mice, we decided to
give a closer look at the two NOD strains and to compare their
performances at an individual level. We assayed first the lytic
potential of poly(I:C)-boosted NK cells from NOD wild-type and NK1.1
mice (Fig. 5A). Despite a
definite dispersion of the latter group,
LU25/1 x 106 effector
cells was on the average higher among congenic mice with a
p < 0.001. The percentages of DX5-positive cells,
measured by flow cytometry in every sample, was not different in the
two groups of mice, eliminating trivial quantitative differences in NK
cell numbers.
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, 2 hours after in vivo challenge with -GC
(38). Here again (Fig. 5, B and C),
despite some dispersion, the amounts of lymphokine released was
significantly higher in the congenic mice compared with the wild-type
controls. As a matter of comparison, the lymphokine contents found in
the sera of B6 mice challenged under the same conditions were 2- to
3-fold higher. Thus the presence of B6 genes, including the NKC, had a
partial but definite impact upon the functional performances of both NK
and NKT cell subsets in NOD mice. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14J281-transgenic NOD mice (16), NK1.1
expression is not inhibited in the NOD context. Here we confirm that
the marker is spontaneously expressed on thymic NKT cells whose
ontogeny has not been transgenically enforced by the canonical
-chain rearrangement. Furthermore, we show that NK1.1 expression
coincides with the subset of mature thymocytes that overexpresses
V8, that is predominantly CD44+, and that has
an intermediate display of TCR. In the periphery, too, the T cells that
stain with PK136 mAb respond to the definition of NKT cells:
preponderant usage of V8, CD44 positivity, and intermediate TCR
display. We know also that the subset contains both
CD4+ and double-negative T cells (data not
shown). The numerical deficit in thymic NKT cells reported by the group
of Baxter and our own group (11, 12), and hypothesized as
being one of the defects responsible for deleterious autoimmunity in
NOD mice, is confirmed with the NK1.1 marker and can also be observed
within the small population of splenic NKT cells.
Spleen phenotyping shows in addition that the PK136 mAb properly
identifies the majority of NOD NK cells that coexpress DX5. Thus, the
NOD.NK1.1 congenic mouse fulfills one of its initial purposes, namely
to provide an experimental tag for NK and NKT cell subsets. These
latter populations will be more easily followed in inflamed tissues,
more easily deleted in vivo by treatment with PK136, and more easily
sorted for functional studies or adoptive transfers. Yet, if NK1.1
labels practically all NK cells, it does not do so for NKT cells. NKT
cells are heterogeneous in many respects (39), including
CD4/CD8 double-negative surface expression (40) and NK1.1
expression (41). It is thus so far not clear whether NK1.1
positivity defines a distinct lineage as suggested by differences in
V repertoires and CD1d expression, or simply reflects a stage of
maturation or of activability in the life of an NKT cell, as suggested
by the lability of the marker upon in vitro culture contrasting with
the stability of NK1.1 on conventional NK cells (42). In
any event, the practical consequence is that the deletion of
CD3+ NK1.1+ cells does not
ensure total elimination of NKT cells, and, reciprocally, the infusion
of CD3+ NK1.1+ cells may
only partially reflect all the facets of NKT cell physiology. There is
a similar ambiguity with regard to the DX5 marker, which labels only a
fraction of NKT cells. We are presently examining this issue in the
CD4+ NKT subset of
I-A°/° mice (43). Preliminary
data suggest that NK1.1+ cells do more readily
release IFN- following -GC boost than DX5+
or DX5-/PK136- cells
(C.C., personal data).
The finding of augmented resistance to disease in congenic NOD.NK1.1 mice, both homo- and heterozygous for B6 genes, underlines once more the presence of susceptibility genes contributed by the NOD alleles. The distal portion of chromosome 6 has repeatedly emerged as a region of influence upon type 1 diabetes, in several independent outcross- backcrosses or outcross-F2 crosses, with foreign mouse strains (44, 45, 46, 47, 48) or PWK subspecies (49). If all the incriminated intervals encircle the NKC or are compatible with it, within the limits of precision of the method, it does not mean that all these crosses identify the same genes. For instance in the outcrosses with NON and PKW mice, the foreign alleles increase susceptibility rather than afford protection and, as far as PKW is concerned, can modify CY-induced diabetes. Our observations are different, and unless one assumes some complex epistatic effects the simplest explanation is that the B6 genes introgressed in the NOD.NK1.1 congenic strain are not the same as those revealed in the PKW or NON outcross. More relevant to our present data are the two crosses reported by Todd and colleagues (44, 45) and the one by Penha-Gonçalves et al. (47), which attribute disease resistance to the foreign alleles—B10 and B6, respectively—and show maximal linkage scores around the Prp gene cluster (D6 Mit 13), which is a major physical anchor for NKC, at 0.3 cM of Cmv1 and 0.5 cM of the Ly49 cluster (26). Todd et al. were unable at the time of their study to associate Idd6 to putative candidate gene(s) or to a partial phenotype. Penha-Gonçalves, in contrast, associated the locus with thymocyte resistance to steroid apoptosis, a trait that could explain the emergence of autoimmunity by allowing more self-reactive clones to escape negative selection. Again, no candidate gene could be proposed at that time, but now it is clear that the presence 5–10 cM upstream of Tnfr1, coding for the p55 TNFR1, might have been a good candidate. Tnfr1 comaps with D6 Mit 254, our most upstream marker on the congenic NOD.NK1.1. In view of the immense impact of TNF and TNFRs on NOD disease (50, 51, 52), it is obviously an important candidate that will be necessarily considered in our further backcrosses aimed at reducing the B6 genetic interval upstream of the NKC.
As a candidate for Idd6, the NKC is certainly an attractive gene cluster providing a link between innate immunity and type 1 diabetes. The facts that the NKC is at the center of our introgressed region, that both NK and NKT cell responses are modified by the introgression, and that, simultaneously, disease incidence is reduced constitute a good set of evidence in support of this hypothesis, even if time- and labor-consuming breeding will be necessary to further restrict the genetic interval down to the NKC itself.
An inherited defect in the NKC could explain the multiple dysfunctions of innate immunity affecting the NOD strain. We have recently shown that NKT, NK, and B cells constitute a functional network that is rapidly set into motion following the initial activation of NKT cells (53). NKT cells also promptly transactivate dendritic cells (54). Thus a defect originally located on NKT or NK cells could have important consequences upon Ag presentation by dendritic cells or B cells and upon the mobilization of a second line of regulatory cells belonging to cognate immunity (55, 56). The nature of a putative NKC defect is of course not known, but recently reported attempts at cloning NOD allelic variants of NKC genes such as those of the Ly49 family may cast some light upon this issue (57). Genetic approaches including intra-NKC recombinants will also provide useful information, specially if we use as a phenotypic criterion of segregation the modifications in NK and NKT cell performances that have been identified in the present study.
Finally, how relevant are those findings to human type 1 diabetes? Both the clustering of human NK genes in a unique complex (28) and the conservation of an NKT cell subset (58) support a possible generalization from mouse to human. So far, no susceptibility gene has been identified in the syntenic region carrying the NKC, on chromosome 12p (59), but NK defects have been observed and associated to a genetic origin in diabetic patients (60, 61) and NKT cells have been shown to be deficient in identical twins discordant for type 1 diabetes (14, 62). It is thus an area worth exploration with the hope that the identification of NK or NKT cell-related genetic differences among individuals may have an important impact on various medical domains including infectious immunity, antitumor immunity, and autoimmune diseases.
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Acknowledgments |
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-GC, Dr. E. Melanitou for advice on
the microsatellite typing of the region, and Drs. A. Lehuen and
O. Lantz for their critical reading of the manuscript. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. C. Carnaud, Institut National de la Santé et de la Recherche Médicale Unité 25, Hôpital Necker, 161 rue de Sèvres, 75743, Paris Cedex 15, France.
3 Abbreviations used in this paper: NOD, nonobese diabetic; BB, BioBreeding; NKC, NK complex; B6, C57BL/6; BC, backcross; CY, cyclophosphamide; HSA, heat-stable Ag; -GC, -galactosylceramide; LU, lytic unit.
Received for publication September 25, 2000. Accepted for publication December 4, 2000.
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 S. E. Johansson, H. Hall, J. Bjorklund, and P. Hoglund Broadly impaired NK cell function in non-obese diabetic mice is partially restored by NK cell activation in vivo and by IL-12/IL-18 in vitro Int. Immunol., January 1, 2004; 16(1): 1 - 11. [Abstract] [Full Text] [PDF]
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M.-L. Bergman, N. Duarte, S. Campino, M. Lundholm, V. Motta, K. Lejon, C. Penha-Goncalves, and D. Holmberg Diabetes Protection and Restoration of Thymocyte Apoptosis in NOD Idd6 Congenic Strains Diabetes, July 1, 2003; 52(7): 1677 - 1682. [Abstract] [Full Text] [PDF]
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N. Matsuki, A. K. Stanic, M. E. Embers, L. Van Kaer, L. Morel, and S. Joyce Genetic Dissection of V{alpha}14J{alpha}18 Natural T Cell Number and Function in Autoimmune-Prone Mice J. Immunol., June 1, 2003; 170(11): 5429 - 5437. [Abstract] [Full Text] [PDF]
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T. C. Brodnicki, F. Quirk, and G. Morahan A Susceptibility Allele From a Non-Diabetes-Prone Mouse Strain Accelerates Diabetes in NOD Congenic Mice Diabetes, January 1, 2003; 52(1): 218 - 222. [Abstract] [Full Text] [PDF]
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V. Laloux, L. Beaudoin, C. Ronet, and A. Lehuen Phenotypic and Functional Differences Between NKT Cells Colonizing Splanchnic and Peripheral Lymph Nodes J. Immunol., April 1, 2002; 168(7): 3251 - 3258. [Abstract] [Full Text] [PDF]
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K. J. L. Hammond, D. G. Pellicci, L. D. Poulton, O. V. Naidenko, A. A. Scalzo, A. G. Baxter, and D. I. Godfrey CD1d-Restricted NKT Cells: An Interstrain Comparison J. Immunol., August 1, 2001; 167(3): 1164 - 1173. [Abstract] [Full Text] [PDF]
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