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Th1 Cytokine-Conditioned Bone Marrow-Derived Dendritic Cells Can Bypass the Requirement for Th Functions During the Generation of CD8⁺ CTL¹

Marimo Sato^*, Kenji Chamoto^*, Takemasa Tsuji^*, Yoichiro Iwakura, Yuji Togashi^*, Toshiaki Koda^* and Takashi Nishimura^2,*

^* Division of Immunoregulation, Institute for Genetic Medicine Hokkaido University, Sapporo, Japan; and Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Bone marrow-derived dendritic cell (BMDC) subsets have distinct immunoregulatory functions. Th1 cytokine-induced BMDC (BMDC1), compared with Th2 cytokine-induced BMDC2, have superior activities for the differentiation and expansion of CTL. To evaluate the cellular interactions between dendritic cells and CD8⁺ T cells for the induction of CTL, BALB/c-derived BMDC subsets were cocultured with purified CD8⁺ T cells from C57BL/6 mice. Our results demonstrate that BMDC1 support the generation of allogeneic CD8⁺ CTL in the absence of CD4⁺ Th cells. In contrast, BMDC0 (GM-CSF- plus IL-3-induced BMDC) and BMDC2 failed to promote the differentiation of CD8⁺ CTL. Using Ab-blocking experiments and studies with gene knockout mice, IL-2 and LFA-1 are demonstrated to be critical for BMDC1-induced CTL differentiation. Unexpectedly, BMDC1 were able to induce CTL from CD8⁺ T cells isolated from IFN-^-/- and IFN- receptor^-/- mice. However, BMDC1 produced higher levels of IFN- than other BMDC subsets, and anti-IFN- mAb blocked BMDC1-dependent CTL generation. These results indicated an indispensable role of IFN-, but not IFN-, during BMDC1-induced CTL differentiation. We conclude that Th1-cytokine-conditioned BMDC1 can bypass Th cell function for the differentiation of naive CD8⁺ T cells into CTL.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Dendritic cells (DC)³ play a central role in bridging innate and acquired immunity via direct cell-cell interactions and/or cytokine production (1, 2). These interactions influence the activation status of immunoregulatory cells such as NKT cells, as well as conventional CD4⁺ T cells and CD8⁺ CTL (3, 4, 5, 6). Recent work has demonstrated functional heterogeneity among DC subsets (7, 8, 9, 10, 11). For example, in mice, two distinct DC subsets have been identified. Murine lymphoid DC subsets, termed DC1, are involved in the activation of Th1 immunity, whereas CD11c⁺CD8^-CD11b⁺ myeloid DC, termed DC2, play a critical role in the development of Th2 immunity (7, 8). However, different results have been obtained in humans (9, 10). Some investigators reported that human myeloid DC act as DC1, and lymphoid DC exhibit DC2 function, but other groups proposed that DC subsets could derive from common myeloid progenitors in vivo (10). Moreover, we have proposed that both DC1 and DC2 can be induced from myeloid type bone marrow (BM) cells under Th1-biasing (GM-CSF, IL-3, IL-12 plus IFN-) and Th2-biasing (GM-CSF, IL-3 plus IL-4) conditions, respectively (11, 12). Thus, there are a number of unresolved issues in DC biology. However, a thorough understanding of the role of DC subsets in immunoregulation will be required to use these cells to manipulate adaptive immune responses in vivo.

In the present paper we have investigated the mechanism by which BM-derived DC (BMDC) can induce CTL differentiation from isolated CD8⁺ T cells in the absence of CD4⁺ Th cells. Our results demonstrate 1) BMDC1, but not BMDC2, support the generation of CTL from isolated CD8⁺ T cells in the absence of Th cells; 2) IL-2 and LFA-1 molecules play an important role during BMDC1-induced CTL generation; 3) BMDC1 produce higher amounts of IFN- compared with other BMDC subsets; and 4) IFN-, but not IFN-, plays a critical role during BMDC1-induced CTL generation. Collectively, these findings reveal that BMDC1 can bypass the requirement for Th cells during the generation of CTL. Implications of these results for the development of DC-based tumor vaccines are discussed.

	Materials and Methods

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Animals

Female BALB/c and C57BL/6 mice were purchased from Charles River Japan (Yokohama, Japan). IFN-^-/- C57BL/6 mice and IFN-R^-/- C57BL/6 mice were provided by Dr. Y. Iwakura (Institute of Medical Science, University of Tokyo, Tokyo, Japan) (13). All animals used in this study were 5–8 wk of age and maintained in specific pathogen-free conditions.

Induction of DC from BM cells

BM cells obtained from BALB/c mouse femora were cultured under three distinct culture conditions in 12-well plates (Costar, New York, NY) for 5 days. BMDC0 were induced by culture of BM cells (5 x 10⁶ cells/well) in the presence of GM-CSF (20 ng/ml) and IL-3 (20 ng/ml). BMDC1 were induced by culture of BM cells in the presence of IFN- (20 ng/ml) and IL-12 (20 U/ml) in addition to GM-CSF plus IL-3. BMDC2 were induced by culture of BM cells in the presence of IL-4 (20 ng/ml) in addition to GM-CSF plus IL-3. Three days after the initiation of culture, nonadherent lymphoid cells contaminating the BM cells were removed from the culture and replaced with fresh medium containing cytokine mixtures. DC harvested from 5-day-old cultures of BM cells were used as BMDC subsets (11, 12). As described previously (10, 11), most (>95%) of BMDC subsets expressed CD11c, which is a marker for mouse DC. In some experiments we used FACS-sorted pure CD11c⁺ BMDC1 to exclude the contamination of other cell types. rIL-12 was donated by Genetics Institute (Cambridge, MA). rIL-3, IL-4, IFN-, and GM-CSF were purchased from PeproTech EC (London, U.K.). Cultured cells were detached from the plates by vigorous pipetting after treatment with 0.25% trypsin in the presence of 0.5 mM EDTA solution.

Isolation of lymphoid cell subsets by FACS

Spleen cells were incubated on nylon wool columns for 45 min, and the nonadherent cells were stained with FITC-conjugated anti-CD4 mAb and PE-conjugated anti-CD8 mAb. These cells were used for isolation of CD4⁺ T cells or CD8⁺ T cells by cell sorting using a FACSVantage (BD Biosciences, San Jose, CA). CD11c⁺ BMDC subsets were isolated after staining with PE-conjugated anti-CD11cmAb. All mAb used in these experiments were purchased from BD PharMingen (San Diego, CA). The purity of the sorted cells was >99%. Detailed procedures of the staining and sorting have been described previously (14).

Generation of CTL in MLC

Whole spleen cells (10⁶ cells) obtained from C57BL/6 mice were cocultured with BMDC0, BMDC1, or BMDC2 (10⁵ cells), which were inactivated by pretreatment with mitomycin C (60 µg/ml; Kyowa Hakko, Tokyo, Japan). These cells were cocultured for 5 days in round-bottom 5-ml tubes (Falcon; BD Biosciences). After culture, the cells were harvested and used in cytotoxicity assays. To investigate the mechanism underlying BMDC-induced CTL generation, isolated CD8⁺ T cells (10⁶ cells) obtained from wild-type C57BL/6, IFN-^-/- C57BL/6, or IFN- receptor-deficient (IFN-R^-/-) C57BL/6 mice were used as responder cells for MLC. In some experiments rat-IgG, anti-IL-2, anti-CD40, anti-CD40 ligand (anti-CD40L), anti-LFA-1, anti-IFN-, anti-IFN-, or anti-IFN- mAb (20 µg/ml) was added to MLC to clarify their role in the generation of CTL in these cultures. Anti-IL-2, anti-CD40, anti-CD40L, anti-LFA-1, and anti-IFN- mAb were purchased from BD PharMingen (San Diego, CA). Anti-IFN- mAb was purchased from Cosmobio, Tokyo, Japan. Anti-IFN- mAb was donated by Dr. F. Okano (Toray Industries, Nagoya, Japan).

Cytotoxicity assay

The cytotoxicity mediated by CTL generated in MLC was measured by 4-h ⁵¹Cr release assays as described previously (15). H-2^d-specific cytotoxicity was determined using BALB/c-derived P815 mastocytoma cells (H-2^d) as target cells. As a control C57BL/6-derived MBL-2 T lymphoma cells (H-2^b) were used. The percent cytotoxicity was calculated as described previously (15).

RT-PCR

Total RNA from primary cultured dendritic cell (BMDC) subsets was isolated with the Isogen kit (NipponGene, Toyama, Japan) according to the manufacturer’s recommendation. Expression of IFN- and IFN- mRNA in BMDC subsets was determined by RT-PCR. As an internal control we also measured mRNA levels of -actin. The cDNA mixture was synthesized from 1 µg of total RNA by the RT reaction using poly(dT)₁₈ primer and Moloney murine leukemia virus reverse transcriptase (PerkinElmer, Norwalk, CT) in a total reaction volume of 20 µl. PCR was performed using 1.0 µl of the cDNA mixture, 1 µl of each primer set, and AmpliTaq Gold (PerkinElmer) in a total reaction volume of 25 µl. Nucleotide sequences of the forward (-F) and reverse (-R) primers are as follows: IFN--F, 5'-AATGACCTCCACCAGCAGCT-3'; IFN--R, 5'-TCTCAGGTACACAGTGATCCG-3'; IFN--F, 5'-GAAAAGCAAGAGGAAAGATT-3'; IFN--R, 5'-AAGTCTTCGAATGATGAGAA-3'; -actin-F, 5'-GTGGGGCGCCCCAGGCACCA-3'; and -actin-R, 5'-CTCCTTAATGTCACGCACGATTTC-3'. The amplification protocol consisted of denaturation for 30 s at 95°C, annealing for 30 s at 55 or 60°C, and extension for 30 s at 72°C for a total of 20–35 cycles, using a GeneAmp PCR system model 2400 (PerkinElmer). The PCR products were visualized with ethidium bromide staining under UV light following electrophoresis on 4% agarose (1% SeaKem GTG agarose and 3% NuSieve GTG agarose; BioWhittaker Molecular Applications, Rockland, ME) gels.

Measurement of IFN- activity

IFN- activity was assayed by its ability to inhibit virus-induced cell death, using vesicular stomatitis virus and mouse L cells, as previously described (16). Titers were expressed in terms of international reference units calibrated with international standards of murine IFN-.

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Three distinct DC subsets, designated BMDC0, BMDC1, and BMDC2, were induced from BALB/c mouse BM cells by culture with neutral or Th1- or Th2-biasing cytokines, respectively (11, 12). As described previously (11), BMDC1 expanded under Th1-biasing conditions (GM-CSF, IL-3, IL-12, and IFN-) promote the differentiation of Th1 cells from naive Th cells. Moreover, BMDC1 have superior activities for induction of allogeneic CTL in MLC compared with other BMDC subsets (12). However, those MLC were performed with unfractionated spleen responder cells and BMDC1 stimulator cells. Therefore, the precise mechanisms underlying BMDC1-induced CTL generation remain unclear. For this purpose, we developed an MLC system that contains isolated CD8⁺ T cells from C57BL/6 mice and BALB/c-derived BMDC subsets. As shown in Fig. 1A, BMDC1 permit the generation of CTL from isolated CD8⁺ T cells as well as from unfractionated spleen cells. Such strong CTL responses are absent in MLC from isolated CD4⁺ T cells and BMDC1. Thus, these findings clearly demonstrate that Th1 cytokine-conditioned BMDC1 support the differentiation of CTL from isolated CD8⁺ T cells in the absence of CD4⁺ Th cells. Neither BMDC0 nor BMDC2 support the generation of CTL from isolated CD8⁺ T cells (Fig. 1B), indicating that this property is specific to BMDC1 cells. Over 95% of BMDC subsets expressed CD11c, which is a marker for DC, and isolated CD11c⁺ BMDC1 also exhibited the same supporting effect on CTL generation (data not shown). As previously demonstrated (11, 12), BMDC1 expressed higher levels of MHC class I, class II, and CD40 molecules compared with BMDC2. Therefore, judging from MHC expression levels, BMDC1 appeared to be defined as mature DC. However, BMDC2 also expressed higher levels of MHC and CD40 molecules compared with freshly isolated DC from spleen (data not shown). Moreover, both BMDC1 and BMDC2 showed the same level of ability to capture dextran-FITC, and they could process OVA Ag and primed OVA-specific T cells at the same levels (data not shown). Thus, in terms of Ag capture ability, both BMDC1 and BMDC2 are defined as immature DC. It might be difficult to define our BMDC subsets as immature or mature DC by previously accepted definition (1) based on MHC expression levels and Ag capture ability.

View larger version (29K): [in this window] [in a new window]   FIGURE 1. BMDC1 can bypass the requirement for Th function during the generation of CTL from isolated CD8+ T cells. BMDC0, BMDC1, and BMDC2 were induced from BALB/c (H-2d) BM cells as described in Materials and Methods. A, Aliquots (106 cells) of unfractionated spleen cells (), sorted CD8+ T cells (•), or sorted CD4+ T cells () prepared from C57BL/6 mice (H-2b) were cocultured with mitomycin C-treated BMDC1 cells for 4 days in round-bottom 5 ml Falcon tubes to induce CTL. After culture, cytotoxicity of these cells against allogeneic H-2d-expressing P815 mastocytoma (a) or syngeneic H-2b-expressing MBL-2 lymphoma cells (b) was measured by a 4-h 51Cr release assay at an E:T cell ratio of 20:1. B, Sorted CD8+ T cells (106 cells) were cocultured with BMDC1, BMDC2, or BMDC0 for 4 days. After culture, cytotoxicity of these cells against P815 target cells was determined by a 4-h 51Cr release assay at an E:T cell ratio of 20:1. The bars represent the mean ± SE of triplicate samples. Similar results were obtained in three different experiments.

View larger version (41K): [in this window] [in a new window]   FIGURE 2. Critical molecules involved in BMDC1-induced CTL generation from isolated CD8+ T cells. MLC consisting of isolated CD8+ T cells and BMDC1 were conducted as described in Fig. 1. To investigate critical molecules involved in BMDC1-induced CTL generation, various mAbs were added to MLC to determine their ability to block CTL generation. After 4 days of culture, CTL activity against P815 was measured at an E:T cell ratio of 20:1. Rat IgG was used as a control Ab. The bars represent the mean ± SE of triplicate samples. Similar results were obtained in three different experiments.

View larger version (23K): [in this window] [in a new window]   FIGURE 3. IFN- is dispensable for BMDC1-dependent CTL generation. CD8+ T cells isolated from wild-type, IFN-R-/-, or IFN--/- C57BL/6 mouse spleen cells were cocultured with BALB/c BM-derived BMDC1 for 4 days. After culture, CTL activity against P815 cells was determined by 51Cr release assay at an E:T cell ratio of 20:1. The bars represents the mean ± SE of triplicate samples. Similar results were obtained in three different experiments.

View larger version (32K): [in this window] [in a new window]   FIGURE 4. Critical role of IFN- for BMDC1-induced CTL generation. A, Expression of IFN- and IFN- mRNA in BMDC0, BMDC1, and BMDC2. BMDC0, BMDC1, and BMDC2 subsets were induced from BALB/c mouse BM cells as described in Fig. 1. IFN- and IFN- mRNA expression levels were determined by RT-PCR before or after stimulation with LPS (20 µg/ml) for 24 h. B, LPS-stimulated BMDC1, but not BMDC0 or BMDC2, produce higher levels of IFN-. IFN- activity was measured by bioassay, described in Materials and Methods. C, Isolated CD8+ T cells were cocultured with BMDC1 cells with (• and ) or without () mAb against IFN- (•) or IFN- (). FACS-sorted pure CD11c+ BMDC subsets were used for all the experiments shown here. The bars represents the mean ± SE of triplicate samples. Similar results were obtained in three different experiments.

DC plays a critical role in the activation of effector cells involved in both innate and acquired immunity (1, 2, 3, 4, 5, 6). Emerging evidence indicates that DC subsets have functional heterogeneity that differentially promote the differentiation of functional Th cells and CTL (4, 5, 6). However, a number of issues concerning the definition and function of distinct DC subsets remain unresolved. In the human system it has been reported that myeloid DC function as DC2 to promote the differentiation of Th2 cells (9). However, we have demonstrated that both BMDC1 and BMDC2 can be induced from mouse bone marrow cells expressing the myeloid cell marker CD11b in addition to the DC marker CD11c (11, 12). Our result is consistent with recent finding that CD8⁺ DC were induced from common myeloid progenitor (10). Here, we further demonstrated that BMDC1 induced from BM cells under Th1-cytokine conditions can bypass the requirement of Th cell function for the generation of CTL. Moreover, our present data indicate that IFN- is a critical cytokine for BMDC1-induced CTL differentiation. Surprisingly, IFN-, which is considered as essential for the generation of CTL (19, 20), is not required for this activation. Our findings are consistent with prior studies indicating that IFN- produced by DC links innate and adaptive immunity (24) and that IFN- is an important cytokine for CTL generation (26).

Our present results suggest a novel pathway for activation of naive CD8⁺ T cells by BMDC1 without CD4⁺ T cell help. Recently, a number of clinical trials employing DC-based tumor vaccines have been initiated (27, 28). In most the studies DC were induced in the presence of GM-CSF plus IL-4. Our studies in mice have demonstrated that vaccination on Th1-conditioned BMDC1 have superior antitumor activities in vivo, whereas Th2 cytokine-conditioned BMDC2 lack antitumor activity in vivo (data not shown). Therefore, BMDC1 should be a powerful tool for inducing immunodeviation during therapy of tumors and immune-mediated diseases.

	Acknowledgments

 
We thank Dr. Luc Van Kaer (Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, TN) for reviewing this paper, Dr. J. Tanabe (Toray Industries, Kanagawa, Japan) for his help with the IFN- and IFN- assays, and Dr. Michiko Kobayashi (Genetics Institute, Cambridge, MA) and Takuko Sawada (Shionogi Pharmaceutical Institute Co., Osaka, Japan) for their kind donations of IL-12 and IL-2, respectively.

	Footnotes

 
¹ This work was supported in part by a grant-in-aid for Science Research on Priority Areas, Scientific Research (B) and Millennium Project from the Ministry of Education, Culture, Sports, Science, and Technology and by the Long-Range Research Initiative Project of Japan Chemical Industry Association.

² Address correspondence and reprint requests to Dr. Takashi Nishimura, Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine Hokkaido University, Sapporo 060-0815, Hokkaido, Japan. E-mail address: tak24{at}imm.hokudai.ac.jp

³ Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; BMDC, bone marrow-derived dendritic cell; BMDC1, Th1 cytokine-induced BMDC; BMDC2, Th2 cytokine-induced BMDC; BMDC0, BMDC induced by GM-CSF plus IL-3; CD40L, CD40 ligand; -F, forward; IFN-R^-/-, IFN- receptor-deficient; -R, reverse.

Received for publication May 22, 2001. Accepted for publication July 20, 2001.

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