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* Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114;
Massachusetts Eye and Ear Infirmary/National Eye Institute Training Program in the Molecular Bases of Eye Diseases, Massachusetts Eye and Ear Infirmary, Boston, MA 02114; and
Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Abstract |
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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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, IL-4, and IL-10, very quickly
(8, 9, 10). Chemokines are well known for their roles in coordinating leukocyte migration during conventional immunity and inflammation; however, their roles in regulating immune cell movement during tolerance induction are not well understood. Chemokines belong to a family of low molecular mass cytokines (8–10 kDa) that direct the migration of leukocytes during immune and inflammatory responses (11, 12, 13, 14). Categorized according to the positions of cysteines in their N termini, the chemokine families are subdivided into four groups including CC, CXC, CX3C, and C. Among the best studied chemokines are RANTES, a member of the CC family, and IL-8, the prototypic chemokine belonging to the CXC family (15). During the past decade, chemokines were found not only to control cellular migration but also to modulate the expression of cytoskeletal associated genes, activate intracellular signal transduction events such as Ca2+ flux, and induce cytokine production (11, 12, 16).
The chemokines responsible for directing leukocyte migration during immune homeostasis and inflammation are well characterized (11, 12, 17, 18), but there is a general lack of information regarding the role of chemokines and cell trafficking during the induction of peripheral tolerance. Previously, we showed that during the induction of tolerance to Ags injected into the eye, eye-derived APCs selectively increased expression of macrophage-inflammatory protein (MIP)3-2 during their preferential migration to the splenic marginal zones (MZ) and that MIP-2 was responsible for recruiting NKT cells to the spleen (19). Additionally, we observed that the number of F4/80+ APCs increased in the MZ where they formed discrete clusters with the NKT cells and CD8+ T cells in the splenic MZ where they remained at for least 7 days (19). This is in contrast to cellular interactions during immune inflammatory responses in which the interacting cells migrate from the MZ to the T cell areas within 4–6 h of entrance into the spleen (20). These data also suggest that there must be migration and retention signals involved in the cell cluster formation in the MZ.
In our efforts to understand cell trafficking and interactions during tolerance induction, we proposed that CD1d/TCR ligation of NKT cells stimulated them to release chemokines that orchestrate the colocalization of additional cells needed for the generation of Tr cells and tolerogenic immune responses. Furthermore, disruption of colocalization of crucial cell types is implied if interference with chemokine signaling prevents generation of Tr cells and tolerance. A useful model for elucidating mechanisms involved in tolerance induction is anterior chamber-associated immune deviation (ACAID). ACAID is demonstrated experimentally by the inability of anterior chamber (a.c.)-inoculated mice to display Ag-specific delayed-type hypersensitivity (DTH) responses in the periphery (21). ACAID requires both the eye and spleen to remain intact for the first 3 days after a.c. injection, after which only the spleen is required (22). Once eye-derived APCs arrive in the spleen, they engage newly recruited NKT cells and stimulate their production of the immunosuppressive cytokine IL-10 (3) that contributes to the generation of Ag-specific CD8+ T-regulatory (Tr) cells that actively suppress the expression phase of DTH (21, 23).
Here we present data to show that stimulation of NKT cells by CD1d-bearing, tolerogenic APCs (both in vitro and in vivo) leads to their production of RANTES and the subsequent recruitment of the additional APCs needed for tolerance. Although many cell types are reported to make RANTES during inflammatory conditions, we report that the NKT cell-derived RANTES is critical for the generation of CD8+ Tr cells during tolerance induction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 mice used in these experiments were obtained from the Schepens Eye Research Institute Vivarium (Boston, MA) or Taconic Farms (Taconic, NY). Mice were housed on a 12/12-h light/dark cycle and provided food and water ad libitum. All animals were treated humanely and in accordance with the guidelines set forth by the Schepens Eye Research Institute Animal Care and Use Committee and the National Institute of Health guidelines.
Cell culture and cell enrichment
DN32.D3 NKT cells were maintained in RPMI, 10% FCS (Life
Technologies, Gaithersburg, MD). Parental L cells and L cells
transfected with murine CD1d (1) were maintained in DMEM,
10% FCS (Life Technologies). For all experiments described here, cells
were cultured in serum-free medium (SFM) consisting of RPMI 1640, 10 mM
HEPES, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 100 U/ml
penicillin, and 100 µg/ml streptomycin (all from Life Technologies),
supplemented with 0.1% BSA and ITS+ culture
supplement (1 µg/ml iron-free transferrin, 10 ng/ml linoleic acid,
0.3 ng/ml Na2Se, and 0.2 µg/ml
Fe(NO3)3; Collaborative
Biomedical, Medford, MA). The peritoneal exudate cells (PECs) used in
the in vitro coculture systems were cultured overnight in SMF ±
OVA (5 mg/ml) ± TGF-
2 (5 ng/ml). PECs were then washed with
HBSS to remove excess OVA and TGF-. Enriched T and NKT cells were
isolated using IMMULAN goat anti-mouse IgG-coated beads (Biotecx
Laboratories, Houston, TX). Enriched T and NKT cells (2.0 x
106 cells/ml) were cocultured with the PECs in
six-well plates for either 30 min or 1 h. NKT cells were depleted
from IMMULAN-enriched cells by incubation with anti-NK1.1 mAb
(clone PK136), followed by incubation with baby rabbit complement
(Pel-Freez, Brown Deer, WI).
Isolation and analysis of chemokine mRNA
Total cellular RNA was isolated from DN32.D3 NKT cells,
IMMULAN-enriched T cells, and FACS-sorted NKT cells using TriZol
reagent (Life Technologies). RNA isolation was performed according to
the manufacturer’s protocol. Chemokine mRNA was analyzed with the
RiboQuant multiprobe RNase protection assay (RPA) and the mCK-5 mouse
chemokine riboprobe template set (BD PharMingen, San Diego, CA)
encoding lymphotoxin (Ltn), RANTES, eotaxin, MIP-1
and -1, MIP-2,
inflammatory protein-10 (IP-10), monocyte chemoattractant protein-1
(MCP-1), T cell activation (TCA3), L32, and GAPDH. Total RNA (5
µg) was used for the RPA, followed by electrophoresis on
polyacrylamide sequencing gels. The gels were dried at 80°C for
1 h, and the mRNA bands were detected by phosphorimaging with a
Bio-Rad Molecular FX Imaging system (Bio-Rad, Hercules, CA). Chemokine
mRNA quantification was completed with QuantiOne Molecular Imaging
Software (Bio-Rad). To compensate for loading imperfections and for
quantitative purposes, chemokine mRNA bands were normalized to GAPDH
bands. Scanning densitometry results are expressed as relative OD units
(ODx/ODGAPDH, where "x"
is the OD of the chemokine band of interest).
RT-PCR
Total cellular RNA was isolated from FACS-sorted NKT cells using
TRIzol, and 100 ng of total RNA were reverse transcribed and amplified
using the Access RT-PCR system (Promega, Madison, WI) according to the
manufacturer’s specifications. RT-PCR products were resolved by
electrophoresis in a 1.5% agarose gel containing GelStar nucleic acid
stain (FMC BioProducts, Rockland, ME). The bands were visualized and
gels were photographed using a Bio-Rad Molecular FX Imaging station and
GelDoc (Bio-Rad Laboratories). The primers used were: murine RANTES,
sense 5'-GTG CCC ACG TCA AGG AGT AT-3', antisense 5'-GGG AAG CGT ATA
CAG GGT CA-3'; murine -actin, sense 5'-GTG GGC CGC TCT AGG CAC
CAA-3', antisense 5'-CTC TTT GAT TGC ACG CAC GAT TTC-3'.
Analysis of RANTES protein
Supernatants from L-CD1d/DN32.D3 cocultures that had been stored at -20°C were thawed at room temperature and assayed for RANTES protein using a murine RANTES Quantikine-M sandwich ELISA (R&D Systems, Minneapolis, MN). All samples were assayed undiluted and were measured in duplicate. The ELISA was performed according to the manufacturer’s instructions.
Antibodies
The Abs used for flow cytometry were as follows: FITC-conjugated
NK1.1 (PK136), FITC-conjugated CD3
(BD PharMingen); and
PE-conjugated F4/80 (Caltag Laboratories, Burlingame, CA). The Abs used
for in vivo assays were: rat anti-mouse RANTES (R&D Systems); rat
anti-mouse CD1d (purified from hybridoma clone 3C11; gift of Dr. S.
Balk, Beth Israel Deaconess Medical Center, Boston, MA); rat IgM (BD
PharMingen), and rat IgG (Sigma-Aldrich, St. Louis, MO). Abs delivered
in vivo were suspended in 100 µl sterile PBS and injected
i.v.
Intracellular cytokine immunostaining for detection of RANTES
Erythrocyte-free, total splenocyte suspensions were
immunostained for cell surface markers Cy5-TCR- chain and FITC-NK1.1
as previously described (19). The cells were then fixed
and permeabilized with PermeaFix (Ortho Diagnostics, Raritan, NJ)
according to the manufacturer’s protocol and incubated with
biotinylated anti-RANTES mAb (R&D Systems) followed by
R-PE-conjugated streptavidin (Jackson ImmunoResearch Laboratories, West
Grove, PA). To prevent background staining due to endogenous biotin,
the cells were treated with the DAKO Biotin Blocking System (DAKO,
Carpinteria, CA) before incubation with the biotinylated
anti-RANTES mAb. The percent of RANTES-positive NKT cells was
determined by flow cytometric analyses of PE-positive cells within the
NKT (FITC+Cy5+)
population.
Anterior chamber inoculation of Ag
Ags were administered into the anterior chambers of mice
anesthetized with ketamine-xylazine as previously described
(19). Briefly, the cornea was punctured with a 30-gauge
needle, and the aqueous humor was drained (
2 µl). The anterior
segment of the eye was reinflated with 2 µl of air. Using finely
drawn glass needles, 50 µg of OVA (2 µl of a 25-mg/ml solution in
HBSS) were instilled into the anterior chamber, displacing the air. The
OVA solutions used in all studies were passed through DetoxiGel
AffinityPak polymyxin B columns (Pierce, Rockford, IL) to remove
contaminating endotoxin-LPS (98% efficiency of endotoxin removal of
concentrations up to 2 mg/ml).
Local adoptive transfer assay (LAT)
LAT was used to test for the presence or absence of regulatory CD8+ T cells as previously described (3, 19). Briefly, OVA-primed effector T cells were generated by immunizing C57BL/6 mice with OVA in CFA (Sigma-Aldrich). Seven days later, the spleens were collected and enriched for T cells by passage over IMMULAN columns (Biotecx). Tr cells were enriched from the spleens of mice that received anti-RANTES mAb or control IgG (i.p.) 7 days post-OVA or HBSS (a.c.). Stimulator cells were obtained by culturing thioglycolate-elicited PECs with OVA (5 ng/ml) overnight. Stimulator, effector, and regulatory cells (5 x 105 each) were resuspended in 10 µl HBSS and injected intradermally into the ear pinnae of naive mice. The change in ear thickness was measured at 24 and 48 h after ear challenge using an engineer’s micrometer (Mitutoyo; MTI, Paramus, NJ).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD1d stimulation of the invariant TCR on NKT cells induces their
expression of immunomodulatory cytokines including IL-4, IL-10, and
IFN- (1, 2, 3). To determine whether CD1d stimulation
induced the expression of chemokines in NKT cells, we cocultured
CD1d-transfected fibroblasts (or untransfected control cells)
(24) with NKT hybridoma (DN32.D3) cells. After 30 min or
1, 2, 4, or 8 h of coculture, total cellular RNA was isolated from
the DN32.D3 NKT cells and examined for chemokine mRNA expression with a
MultiProbe RPA. NKT cells that were cocultured with untransfected
fibroblasts constitutively expressed low levels of RANTES mRNA
throughout the time course (Fig. 1
A). In contrast, NKT cells
cocultured with CD1d transfectants increased their expression of RANTES
mRNA over time, beginning with 30 min, peaking at 4 h, and
returning to baseline after 8 h (Fig. 1, A and
B). Although the RPA template contained probes for several
chemokines (Ltn, eotaxin, RANTES, MIP-1 and -1, MCP-1,
IP-10, and TCA3), only RANTES was expressed after CD1d stimulation of
DN32.D3 NKT cells. A very minor level of eotaxin expression was also
noted among CD1d-stimulated NKT cells (band located directly beneath
the RANTES band in Fig. 1); however, the level of expression does not
likely represent a biologically relevant change in mRNA.
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C). As expected, CD1d-stimulated NKT cells
began to secrete RANTES protein after 1 h of stimulation. RANTES
protein production was greatest in samples collected after 4 h of
coculture. Moreover, the RANTES protein production was CD1d dependent
because DN32.D3 NKT cells cocultured with untransfected fibroblasts
secreted only baseline levels of RANTES. Because the transfected
fibroblasts do not express activation receptors other than CD1d, we
concluded that stimulation by CD1d appears to be sufficient for the
production of RANTES by NKT cells. Stimulation of ex vivo NKT cells by tolerogenic APCs leads to the rapid production of chemokines
Because DN32.D3 NKT cells hybridoma cells do not necessarily
express all of the characteristics of freshly isolated NKT cells, we
examined the production of chemokines by ex vivo NKT cells after
culturing with resting, tolerogenic, or immunogenic APCs in vitro. In
brief, IMMULAN-enriched T and NKT cells were prepared from the spleens
of B6 mice as previously described (7) and cocultured (30
min or 1 h) with unstimulated, OVA-pulsed immunogenic, or OVA +
TGF--treated tolerogenic APCs. At the end of the coculture period,
nonadherent T and NKT cells were aspirated and examined for chemokine
mRNA expression by RPA. Compared with IMMULAN-enriched cells cocultured
with either resting or immunogenic APCs, cells cocultured with
tolerogenic APCs increased their expression of RANTES mRNA 3- to 4-fold
after 30 min of coculture (Fig. 2). In
similar experiments that examined the kinetics of chemokine expression
by IMMULAN-enriched cells stimulated by tolerogenic APCs, we observed
that RANTES expression peaked at 30 min and gradually decreased over
the course of 8 h (data not shown). Additionally, we observed that
RANTES expression was unique to cocultures of IMMULAN-enriched cells
and tolerogenic (OVA plus TGF--treated) APCs and did not occur when
cells were cocultured with APCs treated with either OVA or TGF-
alone. To determine the contribution of NKT cells to the chemokine
profile, parallel groups of IMMULAN-enriched cells were depleted of NKT
cells by pretreatment with anti-NK1.1 mAb and baby rabbit
complement. IMMULAN-enriched cells that were depleted of NKT cells by
Ab and complement before coculture with tolerogenic APCs did not have
increased expression of RANTES mRNA at this time (Fig. 2). Thus, we
concluded that tolerogenic APCs were able to induce the rapid
expression of RANTES by NKT cells. In addition to RANTES, we also
observed that tolerogenic APCs induced a modest increase in the
expression of MIP-1 and MIP-1 that disappeared when IMMULAN
fractions were depleted of NKT cells. The potential roles of MIP-1
and MIP-1 were not pursued in this study.
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To test the postulate that NKT cells that accumulate in the spleen
during tolerance induction increase their expression of RANTES mRNA,
total cellular RNA was isolated from splenic NKT cells (collected by
FACS sorting) 3 and 7 days after a.c. inoculation of B6 mice with OVA
(Fig. 3A). RANTES mRNA was
detected in the samples by RT-PCR with mouse RANTES-specific primers.
NKT cells isolated 7 days after inoculation of OVA (a.c.) expressed 2-
to 3-fold higher levels of RANTES mRNA than NKT cells from naive mice
or mice that received OVA 3 days before (Fig. 3, B and
C). Production of RANTES protein by NKT cells was confirmed
by intracellular cytokine staining and flow cytometry of spleen cells
that were collected 7 days after intraocular inoculation of OVA (or
HBSS as a control). Inoculation of OVA led to a 2-fold increase in the
number of splenic RANTES-positive NKT cells (Fig. 4). RANTES production was exclusive to
the NKT cell population, because neither conventional T cells nor NK
cells increased their production of the RANTES protein, regardless of
whether the mice were given OVA (a.c.) or vehicle (data not shown).
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A) and RANTES mRNA
expression was assessed by RT-PCR. NKT cells from a.c.-inoculated mice
that received control IgM expressed higher levels of RANTES mRNA than
NKT cells from naive mice (Fig. 5B). In contrast, RANTES
mRNA expression was not increased in NKT cells harvested from
a.c.-inoculated mice that received anti-CD1d mAb (i.v.) (Fig. 5B). Thus, the increased expression of RANTES mRNA in
NKT cells that accumulate in the spleen during tolerance must be
dependent on interaction with CD1d, presumably expressed on the
APC.
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Our previous reports showed cell clusters in the spleen that contained F4/80+ APCs (dendritic cells) and NKT cells (19). Confocal microscopy of immunostained spleen sections from a.c.-inoculated mice showed a substantial increase in the number of F4/80+ cells localizing in the marginal zones, indeed far more than could have migrated from the iris and ciliary body of one mouse eye. Because RANTES is a potent macrophage and DC chemoattractant, we wondered whether the NKT-derived RANTES recruited the additional F4/80+ APCs to the spleen during tolerance induction.
B6 mice were given inoculations of OVA or HBSS (a.c.) in conjunction
with rat IgG or a neutralizing anti-RANTES mAb (i.v.). Four days
later, all mice received a second injection of Abs; 3 days after that,
the number of F4/80+ cells in the spleen was
calculated by flow cytometry analyses of cells immunostained with
PE-conjugated anti-F4/80 mAb. Naive B6 mice had an average
of 4.9 x 106 F4/80+
cells per spleen, whereas after anterior chamber inoculation with OVA
the number of F4/80+ cells increased to an
average of 8.7 x 106 per spleen (Fig. 6). The differences between naive and
a.c.-inoculated were statistically significant
(p < 0.05). In contrast, when mice received
OVA (a.c.) in conjunction with systemic anti-RANTES neutralizing
mAb, the number of splenic F4/80+ APCs did not
increase (Fig. 6).
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). Moreover, if the supernatants from
CD1d-stimulated NKT cells were treated with anti-RANTES mAb for 30
min before being used in Boyden chemotaxis assays, the supernatants
failed to induce CD8+ chemotaxis. Thus, through
their production of RANTES, NKT cells can recruit additional
F4/80+ APCs and CD8+ T
cells that are needed for tolerance.
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Because colocalization of the APCs, NKT cells, and
CD8+ T cells is presumably required for
tolerance, we postulated that in the absence of RANTES,
CD8+ Tr cell would not be generated, presumably
because the required cells would associate with one another. To block
the effects of RANTES during tolerance in vivo, mice were inoculated
(a.c.) with OVA and given either anti-RANTES mAb or control rat IgG
(i.v, Days 0 and 4). Seven days after a.c. inoculation, splenic T cells
were collected and examined for their ability to suppress DTH responses
in a local adoptive transfer (LAT) assay. While T cells from
a.c.-inoculated mice that received control rat IgG suppressed the
subsequent DTH response, T cells from mice that received a.c.
inoculation of OVA in conjunction with systemic anti-RANTES mAb did
not (Fig. 8). T cells from naive mice
treated with rat IgG did not interfere with the generation of the local
DTH response (Fig. 7). In conclusion, RANTES contributes to the process
of tolerance induction by recruiting F4/80+ APCs
and potential CD8+ Tr cells to the
microenvironment that nurtures the differentiation of
CD8+ Tr cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous reports from our laboratory showed that during tolerance induction, CD1d stimulation of NKT cells was required for CD8+ Tr cell formation and that CD8+ Tr differentiation was linked directly to the ability of NKT cells to produce IL-10 (3, 7). The data presented here support the concept that CD1d stimulation of NKT cells not only influences the cytokine milieu that supports differentiation of Tr cells but also initiates production of chemokines that can recruit lymphocytes and additional APCs into the tolerogenic microenvironment. We further propose that the initial eye-derived APCs travel to the marginal zone to recruit NKT cells, where together, the two cell types initiate an amplification cascade that recruits additional F4/80+ APCs needed for maintenance of the tolerogenic microenvironment that supports differentiation of CD8+ T lymphocytes into regulatory cells. Because F4/80 is a marker for multiple populations of macrophages and dendritic cells, it remains to be shown whether the F4/80+ cells recruited by RANTES are dendritic cells or macrophages. Confocal microscopic evaluation of the recruited F4/80 cells shows that they exhibit a typical dendritic morphology (19).
In our in vitro coculture experiments, we observed a lack of increased RANTES mRNA expression when NK1.1+ cells were depleted with specific Ab. Although anti-NK1.1 mAb depleted both NK and NKT cells, we observed in our ex vivo intracellular cytokine staining experiments that during tolerance induction, RANTES protein was produced only by NKT and not conventional T or NK cells. Moreover, RANTES expression among splenic NKT cells was CD1d dependent, and if the chemokine was neutralized the generation of CD8+ Tr cells failed. Together, with our previous reports showing CD1d dependency for Tr cell generation, these findings support the concept of a direct effect of NKT cell-derived RANTES in the generation of CD8+ Tr cells.
Like conventional T lymphocytes, NKT cells need to be stimulated to increase their RANTES production. Unlike conventional lymphocytes that require 3–5 days after stimulation by Ag and MHC to begin to express RANTES (25, 26), NKT cells produce RANTES mRNA in minutes and RANTES protein within hours of CD1d stimulation of their invariant TCR. The kinetics and magnitude of RANTES production by NKT cells are similar to their production of other cytokines.
The mechanisms used by tolerogenic but apparently not immunogenic APCs
to induce RANTES in NKT cells require further study. All APCs express
CD1d; however, APCs treated simultaneously with Ag and TGF- express
significantly higher levels of CD1d on their cell surface than APCs
treated with either Ag alone or TGF- alone (Ref. 27 and
our unpublished observations). Although the magnitude of CD1d
expression clearly differs between subsets of APCs and CD1d is
sufficient for stimulation, it is unlikely that levels of CD1d alone
are responsible for the induction of RANTES in NKT cells associated
with tolerance. Besides expressing high levels of CD1d, tolerogenic
APCs exhibit low B7.1 and B7.2, low CD40, and low MHC II
(28). Moreover, the tolerogenic APCs secrete TGF- and
IL-10, two cytokines known to influence lymphocyte function and
phenotype. Thus, the ability of tolerogenic (but not immunogenic) APCs
to induce rapid RANTES production by NKT cells may result from a
combination of CD1 stimulation of the NKT cells and signals within the
tolerogenic microenvironment, although this remains to be proved.
Several cell types including T cells, monocytes, and dendritic cells produce RANTES; however, our studies show that during tolerance only NKT cells produce the chemokine, implying the importance of NKT-derived RANTES in the promotion of tolerogenic cell clusters. Although our experiments here did not directly address the impact of RANTES on colocalization and clustering of cells in the splenic MZ, we show that disruption of either CD1d stimulation of NKT cells or RANTES signaling prevents the end result of the tolerogenic cluster formation, implying their disruption as well.
The data reported here expand the current knowledge of RANTES beyond its role in Th1-like immune responses to include tolerance and the generation of Tr cells. Our data raise the possibility that defective chemokine production may contribute to flaws in cell trafficking events that are needed for the generation of self-tolerance, thus allowing the clinical appearance of certain autoimmune diseases. Additionally, our findings suggest that therapeutic targeting of RANTES signaling pathways, as is being done for treatment of HIV infection, may interfere with the generation or maintenance of tolerance to self-Ags. Understanding the precise mechanisms involved in tolerance induction will enable the development of more effective treatment strategies for circumstances where tolerance to self (for prevention of autoimmune disease) or foreign Ags (prevention of organ transplant rejection) is preferred.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joan Stein-Streilein, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114. E-mail address: jstein{at}vision.eri.harvard.edu
3 Abbreviations used in this paper: MIP, macrophage inflammatory protein; a.c., anterior chamber; MZ, marginal zone; ACAID, a.c.-associated immune deviation; DTH, delayed-type hypersensitivity; Tr cell, T-regulatory cell; SFM, serum-free medium; PEC, peritoneal exudate cell; IP-10, inflammatory protein-10; MCP-1, monocyte chemoattractant protein-1; Ltn, lymphotoxin; RPA, RNase protection assay; LAT, local adoptive transfer assay.
Received for publication January 28, 2002. Accepted for publication April 23, 2002.
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M. Nowak, F. Kopp, K. Roelofs-Haarhuis, X. Wu, and E. Gleichmann Oral nickel tolerance: fas ligand-expressing invariant NK T cells promote tolerance induction by eliciting apoptotic death of antigen-carrying, effete B cells. J. Immunol., April 15, 2006; 176(8): 4581 - 4589. [Abstract] [Full Text] [PDF]
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 S. C. Yue, A. Shaulov, R. Wang, S. P. Balk, and M. A. Exley CD1d ligation on human monocytes directly signals rapid NF-{kappa}B activation and production of bioactive IL-12 PNAS, August 16, 2005; 102(33): 11811 - 11816. [Abstract] [Full Text] [PDF]
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T. Nakamura, A. Terajewicz, and J. Stein-Streilein Mechanisms of Peripheral Tolerance following Intracameral Inoculation Are Independent of IL-13 or STAT6 J. Immunol., August 15, 2005; 175(4): 2643 - 2646. [Abstract] [Full Text] [PDF]
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N. Kitaichi, K. Namba, and A. W. Taylor Inducible immune regulation following autoimmune disease in the immune-privileged eye J. Leukoc. Biol., April 1, 2005; 77(4): 496 - 502. [Abstract] [Full Text] [PDF]
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K. Oh, S. Kim, S.-H. Park, H. Gu, D. Roopenian, D. H. Chung, Y. S. Kim, and D.-S. Lee Direct Regulatory Role of NKT Cells in Allogeneic Graft Survival Is Dependent on the Quantitative Strength of Antigenicity J. Immunol., February 15, 2005; 174(4): 2030 - 2036. [Abstract] [Full Text] [PDF]
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M. S. Duthie, M. Kahn, M. White, R. P. Kapur, and S. J. Kahn Critical Proinflammatory and Anti-Inflammatory Functions of Different Subsets of CD1d-Restricted Natural Killer T Cells during Trypanosoma cruzi Infection Infect. Immun., January 1, 2005; 73(1): 181 - 192. [Abstract] [Full Text] [PDF]
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O. Shibolet, Y. Kalish, A. Klein, R. Alper, L. Zolotarov, B. Thalenfeld, D. Engelhardt, E. Rabbani, and Y. Ilan Adoptive transfer of ex vivo immune-programmed NKT lymphocytes alleviates immune-mediated colitis J. Leukoc. Biol., January 1, 2004; 75(1): 76 - 86. [Abstract] [Full Text] [PDF]
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A. Teige, I. Teige, S. Lavasani, R. Bockermann, E. Mondoc, R. Holmdahl, and S. Issazadeh-Navikas CD1-Dependent Regulation of Chronic Central Nervous System Inflammation in Experimental Autoimmune Encephalomyelitis J. Immunol., January 1, 2004; 172(1): 186 - 194. [Abstract] [Full Text] [PDF]
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K.-H. Sonoda, Y. Sasa, H. Qiao, C. Tsutsumi, T. Hisatomi, S. Komiyama, T. Kubota, T. Sakamoto, Y.-I. Kawano, and T. Ishibashi Immunoregulatory Role of Ocular Macrophages: The Macrophages Produce RANTES to Suppress Experimental Autoimmune Uveitis J. Immunol., September 1, 2003; 171(5): 2652 - 2659. [Abstract] [Full Text] [PDF]
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