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Originally published online as doi:10.1189/jlb.0704399 on November 17, 2004

Published online before print November 17, 2004
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(Journal of Leukocyte Biology. 2005;77:151-158.)
© 2005 by Society for Leukocyte Biology

Reduction in CD1d expression on dendritic cells and macrophages by an acute virus infection

Yinling Lin, Tonya J. Roberts, Philip M. Spence and Randy R. Brutkiewicz1

Department of Microbiology and Immunology, Indiana University School of Medicine, The Walther Oncology Center, and The Walther Cancer Institute, Indianapolis

1 Correspondence: Department of Microbiology and Immunology, Indiana University School of Medicine, Building R2, Room 302, 950 W. Walnut St., Indianapolis, IN 46202-5181. E-mail: rbrutkie{at}iupui.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mice were infected with lymphocytic choriomeningitis virus (LCMV) to determine if changes in CD1d expression occurred during an acute virus infection. It is interesting that a decrease in CD1d expression on splenic dendritic cells (DC) and macrophages (M{Phi}) was observed for at least 3 months post-LCMV infection, and vaccinia virus and vesicular stomatitis virus induced similar changes in CD1d upon infection with those viruses. The reduction of CD1d cell-surface expression on DC and M{Phi} was independent of interferon-{gamma} and interleukin-12 expression but partially recovered in transporter associated with antigen processing-1-deficient mice, suggesting that CD8+ T cells may play a role. Thus, one consequence of the induction of a cellular immune response is a change in CD1d expression, which may constitute a key element in regulating antiviral immunity.

Key Words: innate immunity • spleen • peripheral organs • antigen presenting cells


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The CD1 family of cell-surface glycoproteins is comprised of major histocompatibility complex (MHC) class I-like molecules encoded by genes located on a different chromosome than that on which the MHC locus resides [1 ]. CD1 molecules have been classified into two subgroups: Group 1 includes the human CD1a, CD1b, and CD1c molecules, whereas human CD1d is the representative Group 2 CD1 molecule. CD1e is categorized as "intermediate" [2 ]. The mouse CD1 locus contains a pair of highly homologous genes (>95% homology) encoding the CD1d1 and CD1d2 molecules, which are related to human CD1d.

Group 1 CD1 molecules have been shown to be expressed on hematopoietic cells and are inducible on virtually all circulating monocytes following stimulation with granulocyte macrophage (M{Phi})-colony stimulating factor (GM-CSF) and interleukin (IL)-4 [1 ]. Group 2 CD1 molecules in humans and mice are also mainly restricted to cells of hematopoietic origin [1 ]. However, the Group 2 CD1 molecules have also been reported to be expressed on hepatocytes [3 , 4 ] and gastrointestinal epithelium [3 , 5 ].

We have reported that a major natural ligand of the mouse CD1d1 molecule is a phosphatidylinositol [6 7 8 ]. In addition, CD1d molecules have been shown to be able to specifically stimulate (in an antigen-dependent manner) a unique subpopulation of T cells, natural killer T (NKT) cells, present in mice, humans, and other species [9 , 10 ] via the presentation of glycolipids such as {alpha}-galactosylceramide ({alpha}-GalCer) [11 ] or phospholipids [12 ]. A majority of NKT cells coexpresses many cell-surface markers (e.g., NK1.1) found on NK cells and like NK cells, can lyse susceptible targets in a perforin-dependent manner [13 ]. Canonical NKT cells have a restricted T cell receptor (TCR) repertoire that is made up predominantly of an invariant rearrangement of the V{alpha}14 and J{alpha}18 (formerly J{alpha}281) gene segments associated with Vß8, Vß7, or Vß2 chains [11 ]. In response to TCR ligation, NKT cells promptly produce cytokines such as IL-4 and interferon (IFN)-{gamma} [11 ], which endow it with therapeutic efficacy in various disease models by regulating T helper cell type 1 (Th1)- or Th2-mediated immune responses. The production of IFN-{gamma} enables the immune system to combat a wide variety of infectious diseases, including malaria [14 ] and hepatitis B virus (HBV) [15 16 17 ], as well as prevent tumor metastases. The production of IL-4 allows protection from a number of different autoimmune diseases, such as type 1 diabetes [18 ] and experimental autoimmune encephalomyelitis [19 ]. Moreover, NKT cells have been implicated in controlling a variety of immune responses during inflammatory responses induced by bacterial, protozoan, fungal, and virus infections [8 , 20 , 21 ]. For example, NKT cells can promote a protective immune response against Cryptococcus neoformans [22 ], Pseudomonas aeruginosa [23 ], Trypanosoma cruzi [24 ], Leishmania major [25 ], diabetogenic encephalomyocarditis virus (EMCV) [26 ], HBV [15 ], herpes simplex virus [27 ], and Plasmodium [28 ]. Thus, NKT cells are critical in the control of many key immune responses in a number of different diseases.

It is as yet unknown whether a virus infection can generate antigens capable of stimulating NKT cells. However, following treatment with {alpha}-GalCer, the only known ligand capable of stimulating NKT cells, these cells have been shown to display inhibitory activity against some virus infections such as EMCV and HBV [29 ].

Infection of adult mice with the natural murine pathogen, lymphocytic choriomeningitis virus (LCMV), provides one of the best-characterized, model systems for studying antiviral T cell responses. The virus is cleared within 1 week by CD8+ T cells, which just precedes the peak of the cytotoxic T lymphocyte response [30 ]. The effector phase of the immune response declines sharply, and by 20–30 days postinfection (p.i.), a stable population of memory CD8+ T cells will protect the host from a secondary challenge [31 32 33 ]. In a previous study, we reported that a selective loss of NKT cells from the liver and spleen by day 3 post-LCMV infection occurs [34 ], suggesting that this reduction in NKT cells is a part of normal viral immunopathogenesis. We have recently found a CD1d1 dependence in the control of the magnitude of acute antiviral immune response, as there is more IFN-{gamma} production as well as better virus clearance in CD1d1 knockout (KO; and thus, NKT cell-deficient) mice [35 ].

Following an acute virus infection, virus peptide-loaded MHC class I molecules are increased on the cell surface, resulting in the activation of virus-specific CD8+ T cells [36 ]. Although all CD1 molecules are structurally similar to MHC class I [1 ], any alterations in the expression of CD1 molecules following a virus infection has not been reported. Here, we show that CD1d expression is reduced on dendritic cells (DC) and M{Phi} (but not B cells) p.i., suggesting an important role for this CD1d dynamic during an acute virus infection.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Mice
Male and female C57BL/6 wild-type (WT) and IFN-{gamma}-, IL-12 (p40)-, and transporter associated with antigen processing-1 (TAP-1)-deficient mice were obtained from The Jackson Laboratory (Bar Harbor, ME). CD1d1-deficient mice [37 ], back-crossed 10 times onto the C57BL/6 background, were kindly provided by Dr. Luc Van Kaer (Vanderbilt University, Nashville, TN) and were bred in specific, pathogen-free facilities at the Indiana University School of Medicine (Indianapolis). All mice were age- and sex-matched and were used between 6 and 12 weeks of age. The Indiana University School of Medicine Animal Care and Use Committee approved all animal procedures.

Virus and infection of mice
The Armstrong strain of LCMV was kindly provided by Dr. Raymond M. Welsh (University of Massachusetts Medical Center, Worcester). LCMV stocks were prepared in baby hamster kidney cells and titrated on Vero cells. The Western Reserve strain of vaccinia virus (VV) and the Indiana strain of vesicular stomatitis virus (VSV) were kindly provided by Drs. Jonathan Yewdell and Jack Bennink [Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD]. VV stocks were grown and titrated in 143B human osteosarcoma cells, whereas VSV was propagated and titrated in murine L cell fibroblasts. Mice were infected intraperitoneally with 1–2 x 105 plaque-forming units (pfu) of LCMV or 1 x 106 pfu of VV or VSV.

Organ isolation
Thymi, lymph nodes (LN), peritoneal exudate cells (PEC), and spleens were harvested from uninfected and LCMV-infected mice at the indicated time-points and processed into single-cell suspensions as described previously [34 ]. Peripheral blood mononuclear cells (PBMC) were collected from killed mice via cardiac puncture and treated with 0.5 mM EDTA and stained with the appropriate monoclonal antibodies (mAb) before fluorescein-activated cell sorter (FACS) analysis. Liver mononuclear cells (MNC) were isolated by using 30% percoll gradient, and erythrocytes were lysed in 0.84% NH4Cl and prepared for FACS analysis as described previously [34 ].

Antibodies and cytofluorography
Single-cell suspensions were stained for cytofluorography with the following anti-mouse mAb, all purchased from PharMingen (San Diego, CA): biotinylated or phycoerythrin (PE)-conjugated anti-mouse CD1d, fluorescein isothiocyanate (FITC)-conjugated mAb against H2-Kb, mouse TCRß, B220, and CD11c, and PE-conjugated mAb against NK1.1, I-Ab, CD4, and CD8. PE- and FITC-conjugated rat immunoglobulin G (IgG)2b or PE-conjugated mouse IgG2a mAb were included as isotype controls. The biotinylated mAb were subsequently stained with Streptavidin-allophycocyanin. FITC-conjugated anti-F4/80 mAb was from Serotec, Inc. (Raleigh, NC). FITC-conjugated rat IgG2b (clone A95-1) was used as the isotype control. All mAb were added at 0.5 µg per 1 x 106 cells. Splenocytes were pretreated with supernatant from the anti-mouse CD16 hybridoma, 2.4G2 (anti-mouse Fc receptor for IgG-specific), kindly provided by Drs. J. Yewdell and J. Bennink (NIH). The labeling procedure and the flow cytometric analysis details were performed as described previously [34 , 38 , 39 ]. PE-labeled CD1d/{alpha}-GalCer tetramers were kindly provided by Dr. Chyung-Ru Wang (University of Chicago, IL) and used as described previously [40 ].

Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis
RNA was extracted from splenocytes obtained from uninfected and LCMV-infected mice using Tri-Reagent (Molecular Research Center, Cincinnati, OH). RNA was reverse-transcribed into cDNA with Moloney murine leukemia virus (MMLV) RT (Promega, Madison, WI), according to the manufacturer’s instructions. Amplification of V{alpha}14J{alpha}18-specific and ß-actin control sequences was performed as described previously [34 ]. PCR products were run on a 1% agarose gel, stained with ethidium bromide, and photographed.

Quantitative real-time RT-PCR
Primers and probes for CD1d1 were designed using Primer Express software (Applied Biosystems, Foster City, CA) and purchased from Applied Biosystems. Primers and probe for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were derived from TaqMan® rodent GAPDH control reagents (Applied Biosystems). For CD1d1, the forward and reverse primers were 5'-AAGCTGGTCCCGCACAGA-3' and 5'-GCTGATGGTGGCTGAGTCATT-3', and the TaqMan probe was 6-carboxyfluorescein-AGCGTGGTCTGGC-MGBNFQ. RNA was reverse-transcribed into cDNA with MMLV RT (Promega). The cDNA was amplified using the TaqMan® Universal PCR master mix (Applied Biosystems). The PCR cycle parameters were 50°C for 2 min and 95°C for 10 min, followed by 50 cycles at 95°C for 15 s and 60°C for 1 min. GAPDH PCR reactions were performed in triplicate using separate tubes from those for CD1d1, and the threshold cycle (CT), representing the fractional cycle at which the amount of the amplified target achieves a fixed threshold, was used in subsequent calculations. The relative difference in the level of CD1d1 transcripts among samples from uninfected and infected mice was determined using the CT method as outlined in the Applied Biosystems protocol for real-time PCR. Briefly, a CT value for GAPDH was subtracted from the CT values for CD1d1 for each sample. The amount of CD1d1 transcript was then normalized to GAPDH and given by the formula The data are presented as the relative amount of CD1d1 transcript.

Cell sorting
Different subpopulations of spleen cells were immunomagnetically separated using the magnetic cell sorter (MACS) system (Miltenyi Biotec, Bergish Gladach, Germany) according to the manufacturer’s instructions. Briefly, splenocytes were incubated with 2.4G2 supernatant for 10 min at 4°C. The cells were then stained with FITC-conjugated anti-B220 or anti-TCR mAb for 15 min at 4°C. The cells were then incubated with anti-FITC antibody-coated magnetic beads for 15 min at 4°C and passed through magnetic columns. The flow-through (marker-negative) population was collected, and the positive cells were then harvested by removing the column from the magnet and flushing with MACS buffer (0.5% of bovine serum albumin and 2 mM EDTA in phosphate-buffered saline). Cell purity was determined by FACS.

Statistical analyses
Differences in CD1d expression before and after infection were analyzed by Student’s t-test using the Prism 3.0 program (GraphPad, San Diego, CA). A P value below 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Infection of mice with LCMV causes a down-regulation of CD1d cell-surface expression on DC and M{Phi}
The murine CD1d1 molecule has been shown to be essential for the positive selection of V{alpha}14J{alpha}18 NKT cells, as CD1d1-deficient mice lack NKT cells [37 , 41 , 42 ]. Professional antigen-presenting cells (APC; i.e., DC, M{Phi}, and B cells) express high levels of MHC class II molecules [43 ] and also express the highest levels of CD1d on their cell surface [4 , 44 ], which plays an important role in NKT cell activation [45 , 46 ]. To determine if a LCMV infection has an effect on the cell-surface expression of CD1d, C57BL/6 mice were infected with the Armstrong strain of LCMV, and surface CD1d expression was detected on different spleen cell subpopulations. Following an acute LCMV infection, significant decreases in CD1d levels were detected on splenic DC and M{Phi} on day 10 (Table 1 ). CD1d expression on B cells was unaltered following a LCMV infection. CD1d levels on T cell populations (i.e., CD8+, CD4+, NK, and NKT cells) following infection did not change or were altered only slightly (Table 1) . To further understand the CD1d dynamics during this time p.i., we analyzed CD1d expression on M{Phi} [MHC class II (I-Ab) and F4/80 double-positive] from different organs on days 6 and 10 p.i. This population was then gated for the analysis of CD1d expression. On day 6 p.i., M{Phi} increased in the spleen, LN, liver, PEC, and PBMC with a concomitant elevation in CD1d expression (Table 2 ). However, on day 10 p.i. in all tissues except LN, M{Phi} CD1d levels were lower than those observed on day 0. It is interesting that there was a greater than 30% reduction in the surface level of splenic M{Phi} CD1d as compared with day 0, in spite of the fact that the M{Phi} population had increased approximately threefold by day 10 (Table 2) . In PBMC, although there were almost fivefold more M{Phi} on day 10 p.i. than in control mice, there was still a 30% overall decrease of surface CD1d, where levels in LN M{Phi} on day 10 returned to normal levels, despite a greater than twofold increase in M{Phi} between days 6 and 10 p.i.


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  		Table 1. Comparison of the Relative Cell-Surface CD1d Expression on Different Splenocyte Subpopulations and Cell Number before and after an Acute LCMV Infectiona

 

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  		Table 2. Changes in CD1d Cell-Surface Expression on M{Phi} from Various Tissues Following an Infection with LCMVa

 
To determine how long CD1d levels in splenic DC and M{Phi} from C57BL/6 mice were reduced p.i., these leukocyte populations were stained with mAb specific for CD1d, MHC class II (I-Ab), and CD11c (for DC) or F4/80 (for M{Phi}) and were examined 10, 14, and 30 days or 3 months p.i. and compared with those from uninfected mice. As was observed above (Table 1) , CD1d expression on DC and M{Phi} was substantially reduced on day 10 p.i. (Fig. 1 ). Furthermore, on day 30 (and as late as 3 months) p.i., CD1d levels on DC and M{Phi} were still lower than those found in control mice (Fig. 1) . Therefore, our overall data suggest that CD1d levels on DC and M{Phi} (but not B cells) are reduced following a LCMV infection.



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  		Figure 1. Long-term reduction in CD1d expression on DC and M{Phi} following a LCMV infection. Splenocytes from uninfected and LCMV-infected mice were harvested at the indicated time-points p.i. and stained with mAb against CD11c, F4/80, CD1d, and MHC class II. CD1d levels on the MHC class II+ CD11c+ (DC, {blacksquare}) and MHC class II+ F4/80+ (M{Phi}, {square}) populations were determined and presented as the MFI relative to these populations from uninfected mice on the indicated days p.i. The experiment shown is representative of two performed.

 
Virus-induced down-regulation of CD1d is not restricted to LCMV
To determine if the decrease in CD1d expression on DC and M{Phi} following a LCMV infection was specific for LCMV or is a normal consequence of a virus infection, C57BL/6 mice were infected with LCMV, VV, or VSV, and spleen cells were harvested at various times p.i. CD1d cell-surface levels on DC and M{Phi} were then analyzed by FACS. As was established above, a LCMV infection resulted in reduced cell-surface levels of CD1d in splenic DC and M{Phi} populations (Table 3 ). It is interesting that a VV or VSV infection also caused a decrease in splenic CD1d molecules on DC and M{Phi} by day 6 p.i. VV induced comparable reductions in CD1d as compared with a LCMV infection, whereas the down-regulation of CD1d following a VSV infection was more modest. It is not surprising that as with LCMV, decreases in overall splenocyte CD1d levels were also observed following infection with VV or VSV (data not shown). Therefore, these data suggest that the reduction in splenic CD1d cell-surface expression normally occurs following an acute virus infection.


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  		Table 3. Alterations in CD1d Levels on Splenic DC and M{Phi} following Infection with LCMV, VSV, and VVa

 
The LCMV-induced down-regulation of CD1d cell-surface expression on DC and M{Phi} is IL-12- and IFN-{gamma}-independent but TAP-1-dependent
A LCMV infection is cleared well before day 10 p.i. [30 , 31 ]. However, the cell-surface expression of CD1d on DC and M{Phi} was substantially decreased during this time (Table 1 and Fig. 1 ). Thus, the down-regulation of CD1d surface expression was not caused by a direct effect of the virus infection per se. It was possible that the reduction in CD1d expression occurred indirectly, as a consequence of the immune response to a LCMV infection. In WT C57BL/6 mice, an acute LCMV infection induces a Th1 cytokine secretion pattern [47 ], and the physiological role for IL-12 is in governing Th1 cytokine responses [48 ]. IL-12 is a highly potent inducer of IFN-{gamma} synthesis, and endogenous expression of IL-12 is critical for IFN-{gamma} production during the innate-immune responses to a variety of pathogens [49 ]. Although the clearance of a LCMV infection is not a result of IL-12 [50 , 51 ], it was nonetheless possible that IL-12 (and/or IFN-{gamma}) played a role in the observed down-regulation of CD1d p.i. (Fig. 1) . To determine if the LCMV-induced down-regulation of CD1d expression was a result of IL-12 and/or IFN-{gamma} production, IL-12- and IFN-{gamma}-deficient mice of the C57BL/6 background were infected with LCMV, and 10 days later, splenocytes were analyzed for the cell-surface expression of CD1d on DC and M{Phi} as above. CD1d expression on DC and M{phi} of IL-12- and IFN-{gamma}-deficient mice was substantially reduced on day 10 p.i.; this was comparable with that seen in WT C57BL/6 mice (Fig. 2 ). Therefore, these data suggest that the decrease in CD1d surface expression on DC and M{Phi} following an acute LCMV infection is independent of IL-12 or IFN-{gamma} production.



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  		Figure 2. FACS analysis of CD1d surface expression on DC and M{Phi} from WT and IL-12-, IFN-{gamma}-, and CD1d1-deficient mice following a LCMV infection. WT C57BL/6 mice and CD1d1 (CD1KO)-, IL-12-, and IFN-{gamma}-deficient mice (all of the C57BL/6 background) were uninfected or infected 10 days previously with LCMV. Splenocytes were stained with mAb against CD11c, F4/80, CD1d, and MHC class II. CD1d levels on the MHC class II+ CD11c+ (DC) and MHC class II+ F4/80+ (M{Phi}, open) populations are presented as histograms. The number shown in each histogram indicates the MFI of CD1d-specific staining. The results are representative of two independent experiments.

 
A primary LCMV infection is cleared by CD8+ T cells [52 , 53 ], and the peak of the effector CD8+ T cell response occurs 7–10 days p.i. [54 ]. The tap-1 gene encodes a subunit for a heterodimeric transporter (TAP-1/TAP-2) that is involved in the delivery of endogenously processed peptides into the endoplasmic reticulum for association with MHC class I molecules and ultimate presentation to CD8+ T cells [36 ]. It has been shown previously that TAP-1-deficient mice are defective in MHC class I-mediated antigen presentation and have low levels of cell-surface MHC class I molecules and few CD8+ T cells [55 ]. To determine if the cytolytic T lymphocyte (CTL) response could affect CD1d cell-surface expression on DC or M{Phi}, TAP-1-deficient C57BL/6 mice were infected with LCMV for 10 days, and splenocytes were analyzed for CD1d expression on DC and M{Phi} by FACS and compared with those of uninfected mice. Although the cell-surface expression of CD1d on DC and M{Phi} from TAP-1-deficient mice was also reduced on day 10 p.i., the reduction was less than that seen in WT C57BL/6 mice (DC, WT 61.4±4%; TAP-1KO, 83.0±8.6%; M{Phi}, WT 57.0±6.1%; TAP-1KO, 83.5±7.4%; Fig. 3 ). This difference in CD1d expression between WT and TAP-1KO mice is statistically significant (DC, P<0.01; M{Phi}, P<0.001). Therefore, these results suggest that the LCMV-induced down-regulation of CD1d cell-surface expression on DC and M{Phi} is to some degree TAP-1 (and thus, likely CD8+ T cell-)-dependent.



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  		Figure 3. FACS analysis of CD1d surface expression on DC and M{Phi} from WT and TAP-1-deficient mice following a LCMV infection. WT C57BL/6 and TAP-1-deficient mice were uninfected or infected 10 days previously with LCMV. Splenocytes were stained with mAb against CD11c, F4/80, CD1d, and MHC class II. CD1d levels on the MHC class II+ CD11c+ (DC) and MHC class II+ F4/80+ (M{Phi}) populations were determined and presented as the percentage from LCMV-infected mice relative to uninfected (control) mice. The experiment shown is representative of two performed. **, P < 0.01; ***, P < 0.001.

 
Down-regulation of CD1d surface expression is independent of changes in cd1d1 RNA expression
Following an acute virus infection, MHC class I expression increases as a result of the transcriptional up-regulation of genes encoding these molecules [56 ]. To determine if the decrease in surface CD1d expression on DC and M{Phi} was related to RNA transcription, splenic B and T cells from LCMV-infected WT and TAP-1KO mice were depleted to enrich DC and M{Phi} populations by MACS sorting and then used for CD1d1 detection by quantitative real-time RT-PCR. As Figure 4 shows, cd1d1 mRNA expression in the B and/or T cell-depleted populations from WT and TAP-1KO mice was comparable before or after an acute LCMV infection. Thus, changes in cd1d1 mRNA expression following an acute virus infection did not account for the down-regulation of CD1d surface expression on DC and M{Phi}.



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  		Figure 4. Transcription of cd1d1 in B and T cell-depleted splenocytes following a LCMV infection in WT and TAP-1KO mice. WT C57BL/6 or TAP-1KO mice were uninfected or infected with LCMV for 10 days. Splenocytes from two mice were pooled per group, and B and T cell subpopulations were removed by MACS sorting. The DC- and M{Phi}-enriched cells were used for RNA extraction and RT and were analyzed for cd1d1 expression by real-time PCR. Levels of GAPDH mRNA were used as a control to normalize the amount of the CD1d1 transcript. The data are shown as the relative levels of the CD1d1 transcript in B and T cell-depleted splenocytes from uninfected and LCMV-infected mice as indicated.

 
Infection of mice with VV and VSV also causes a reduction in NKT cells
We have previously shown that following an acute LCMV infection, there is a selective loss of NKT cells as detected by FACS analysis as well as by semiquantitative RT-PCR amplification of the V{alpha}14J{alpha}18 TCR rearrangement [34 , 57 ]. As Figure 5A shows and as we have previously reported [34 ], a substantial reduction in the intensity of a V{alpha}14J{alpha}18-specific band was observed in LCMV-infected mice on day 8 p.i. Similarly, a decrease in the NKT cell population also occurred in mice infected with VSV or VV infection (Fig. 5B) . Therefore, concomitant with the down-regulation of CD1d expression on DC and M{Phi}, there is also a virus-induced loss of splenic V{alpha}14J{alpha}18+ NKT cells that remains for several months thereafter.



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  		Figure 5. Molecular analysis of the LCMV-induced, long-term reduction in NKT cells. (A) Splenocytes from uninfected C57BL/6 mice or those infected with LCMV for the indicated amount of time (8 and 90 days) were harvested for RNA extraction. The NKT cell population was detected by semiquantitative RT-PCR using primer pairs for the V{alpha}14J{alpha}18 TCR rearrangement. Actin was used as a control. (B) Splenocytes from uninfected C57BL/6 mice or those infected with LCMV (day 8), VSV, or VV (day 6) were harvested for the detection of NKT cells by semiquantitative RT-PCR as in A.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The expression of MHC class I and Group 1 CD1 molecules can be affected by various cytokines, such as type I and type II IFN and GM-CSF + IL-4, respectively [58 59 60 ], and GM-CSF + IL-4 is also capable of up-regulating CD1d [61 ]. In contrast, the basal cell-surface expression of CD1d may be at a more maximal level on the individual cell types. Whereas it is well-known that IFN-{alpha}/ß or IFN-{gamma} will increase MHC class I expression [58 59 60 , 62 ], they have no apparent effect on CD1d expression (data not shown). This observation is consistent with our finding that the virus-induced CD1d down-regulation on DC and M{Phi} is independent of changes in IFN-{gamma} production (Fig. 2) . The reduction in cell-surface CD1d expression on DC and M{Phi} was neither a result of a direct effect of virus replication (as the reduction in CD1d occurred and was maintained well after viral clearance) nor of Th1 cytokines such as IL-12 (Fig. 2) . Furthermore, other viruses such as VV or VSV could also cause a decrease in the cell-surface levels of CD1d on DC and M{Phi} (Table 3) . There was no dramatic reduction in CD1d expression on DC and M{Phi} in TAP-1-deficient mice on day 10 p.i., suggesting the involvement of CD8+ T cells (Fig. 3) . Because a similar down-regulation in cd1d1 mRNA transcription was found in WT and TAP-1KO mice after an acute LCMV infection, this suggests that the decrease in CD1d on DC and M{Phi} is independent of cd1d1 gene expression. CTL can trigger DC maturation [63 ], as DC may have various levels of CD1d on the surface during differentiation. Thus, the proliferation and activation of CTL p.i. may affect CD1d expression on DC and M{Phi} by killing them directly or by enhancing their maturation.

Compared with the high proportion of NKT cells in the thymus (10–20% of mature T cells), bone marrow, and liver (20–30% of T cells), the percentage of NKT cells in the spleen is very low (0.5–2.0%) [11 , 64 ]. Nonetheless, CD1d-mediated NKT cell activation can rapidly release IFN-{gamma} and IL-4; these cytokines can bias the immune response toward a Th1 or Th2 cytokine profile, respectively [11 , 64 , 65 ], although the NKT cells themselves are resistant to polarization [66 , 67 ]. Moreover, the spleen is the major site of LCMV-Armstrong replication, where the proliferation, activation, and apoptosis-mediated contraction of LCMV-specific T cells are easily detected [31 ].

Our results confirmed previous reports demonstrating that CD1d is highly expressed on B cells, DC, and M{Phi} [44 , 68 , 69 ]. The importance of CD1d expression on marginal zone B cells has been pointed out in other models [44 , 69 , 70 ], and we found that the expression of CD1d on B cells did not change following infection (Table 1) . Conversely, CD1d expression on splenic DC and M{Phi} was decreased dramatically by day 10 p.i. and continued for months thereafter. It is interesting that on day 6 p.i., the CD1d level on M{Phi} in all organs analyzed was increased. However, as the size of this population was reduced by day 10 p.i. in the liver, PEC, and PBMC, the remaining M{Phi} in these tissues expressed lower surface CD1d levels than in the uninfected control. It is possible that different subpopulations of M{Phi} or their differentiation status vary in the levels of functional CD1d expressed on the cell surface.

It has been reported that Group 1 CD1 molecules (e.g., CD1b) are decreased in GM-CSF + IL-4-stimulated, human PBMC upon infection with the bacterium Mycobacterium tuberculosis [71 ]. Here, we found that the virus-induced decrease in CD1d on the DC and M{Phi} populations was not restricted to LCMV, as an infection with VV or VSV could do the same (Table 3) . This suggests that the down-regulation of CD1d on DC and M{Phi} is a normal occurrence following an acute virus infection. CD1d is critical for NKT cell development and proliferation [64 ], so the reduction in CD1d on DC and M{Phi} may have an effect on NKT cell function. We have found that splenic APC from LCMV-infected mice can increase the activation of NKT cells, and this loss is by activation-induced cell death (Y. Lin et al., manuscript submitted). In the current report, we found that the NKT cell population loss observed by day 3 p.i. [34 ] does not return to control levels even after 3 months, correlating with the decrease in CD1d levels on DC and M{Phi} (Fig. 5) . This is consistent with our data showing that the NKT cell population was still reduced 10 days following a LCMV infection (Table 1) . In addition, the loss of the NKT cell population was also observed in mice infected with VSV or VV. Thus, it is possible that following an acute virus infection, the decrease in CD1d cell-surface expression on splenic DC and/or M{Phi} hinders the recovery of the NKT cell population. Conversely, the lower level of CD1d on DC and M{Phi} p.i. could prevent the remaining NKT cells from over-reacting, as activated NKT cells can cause tissue injury [72 , 73 ]. Recently, we reported that there are elevated levels of IFN-{gamma} and IL-2 production and a more rapid clearance of virus in LCMV-infected CD1KO mice, suggesting that CD1d molecules (and/or NKT cells) may control the magnitude of the acute antiviral immune response [35 ]. Thus, maintaining a lower level of CD1d on DC and M{Phi} (and a reduced NKT cell population) is an important part of the generation of antiviral immunity.


   ACKNOWLEDGEMENTS
 
This work was supported by a grant to R. R. B. from NIH (RO1 AI46455). T. J. R. was the recipient of a Predoctoral Fellowship for Under-represented Minorities from NIH. The expert technical assistance of D. Jay and C. Willard is also gratefully acknowledged. R. R. B. is a Scholar of the Leukemia and Lymphoma Society. The authors thank L. Van Kaer for the CD1d1-deficient C57BL/6 mice, J. Yewdell and J. Bennink for 2.4G2, VV, and VSV, Chyung-Ru Wang for the CD1d1 tetramers, as well as R. Welsh for the Armstrong strain of LCMV.

Received July 14, 2004; accepted October 26, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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