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Cutting Edge |
* Department of Immunology, Mayo Clinic, Rochester, MN 55905;
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and
Carlos and Marguerite Mason Transplantation Biology Research Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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CD137 (4-1BB) is a TNFR superfamily member expressed by activated T lymphocytes (12, 13). The ligand for CD137 could be detected in DCs, activated macrophages, B cells, and activated T cells (12). In vitro studies have demonstrated that agonistic mAb to both CD137 and its ligand (CD137L) costimulate proliferation and cytokine secretion in both CD4+ and CD8+ T cells (14, 15, 16, 17, 18). However, studies performed in vivo suggest that CD137 plays a more prominent role in the generation of a CD8+ CTL response than a Th cell response (17, 19, 20, 21). The systemic administration of mAbs against CD137 or gene transfer of CD137L into tumor cells induces potent cell-mediated immune responses against tumors (19, 22, 23, 24, 25). Injection of anti-CD137 mAb in tumor-bearing mice leads to regression of well-established tumors in various mouse models (19) and prevents the death of T cells responding to superantigen stimulation (26). The studies using CD137 as well as CD137L-deficient mice revealed the importance of CD137 costimulation in graft-vs-host disease and antiviral CTL responses (27, 28, 29, 30). Thus, the accumulating reports suggest a crucial role for CD137 costimulation in CD8+ T cell responses.
We report in this work that mouse DCs express CD137. More importantly, engagement of DC-associated CD137 by agonistic mAb or CD137L delivers a stimulatory signal to DCs leading to secretion of cytokines and an improved ability to stimulate T cell responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Female C57BL/6 (B6) and BALB/c mice were purchased from the National Cancer Institute (Frederick, MD). Age-matched mice (6–10 wk old) were used for all experiments. Female C57BL/6 RAG-1 knockout mice were purchased from The Jackson Laboratory (Bar Harbor, ME). OT-1 mice, a TCR-transgenic mouse strain specific for an epitope derived from chicken OVA, were a gift from Dr. E. Celis (Mayo Clinic, Rochester, MN). P815 cells transfected to express mouse CD137L were previously described (31).
SMART cDNA preparation and virtual Northern blot analysis
Switch mechanisms at the 5' end of RNA transcript (SMART) can be used to generate high yields of full-length double-stranded cDNA from as little as 50 ng total RNA. The method uses the addition of cytosines by reverse transcriptase at the end of its first strand synthesis run to extend the first strand. This extension primer together with oligo(dT) provides the opportunity to amplify cDNA using short rounds of PCR (Clontech Laboratories, Palo Alto, CA). For virtual Northern blot analysis, 4- to 6-wk-old female BALB/c mice were used for tissue RNA preparation. Total RNA were extracted with TRIzol (Life Technologies, Rockville, MD) and SMART cDNA (Clontech Laboratories) synthesis from tissues; sorted DCs and activated macrophages were performed according to the manufacturer’s protocol. SMART PCR cDNAs were purified by PCR purification kit (Qiagen, Valencia, CA). A total of 0.5 mg/lane purified DNAs were run on a 1% agarose gel and transferred on a Nytran nylon membrane (Schleicher & Schuell, Keene, NH). Preparation of radioactive probes by PCR using primer sets (5'-GTAACGGCCGCCAGTGTGCTG-3' and 5'-CGCCAGTGTGATGGATATCTGCA-3'), radiolabeling of probes, hybridization, washing, and autoradiography were done as previously described (32)
Abs and other reagents
2A is a rat IgG2a mAb specific for mouse CD137 (33). The mAb to mouse CD137L (clone 14B3) was generated in a similar fashion. Another mAb to mouse CD137 (clone 3H3) was described previously (18). The mAb was purified from the culture supernatant HiTrap Protein G-Sepharose column (Amersham Pharmacia Biotech, Piscataway, NJ) and was endotoxin-free, as determined by the Limulus Amebocyte Lysate assay (Associates of Cape Cod, Falmouth, MA). The rat IgG control Ab was purchased from Sigma-Aldrich (St. Louis, MO). Both anti-CD3 and anti-CD28 Abs were purchased from BD PharMingen (San Diego, CA).
The PE-labeled CD137 mAb was purchased from eBioscience (San Diego, CA). FITC-labeled or biotinylated Abs against mouse B7-1, B7-2, CD40, I-Ab, OX40 ligand, and streptavidin-PE were purchased from BD PharMingen. Rat IgG and 2A were biotinylated using EZ-Link NHS-LC-LC Biotin according to the manufacturer’s instructions (Pierce, Rockford, IL). FITC- and PE-labeled rat IgG and hamster IgG isotype control Abs were purchased from BD PharMingen.
The chicken OVA257–264 peptide (SIINFEKL) representing the H-2Kb-restricted epitope recognized by OT-1 T cells was synthesized by the Mayo Clinic Molecular Biology Core Facility.
Generation of DC
The method to generate bone marrow (BM)-derived DC was previously described (34). Briefly, BM-DCs were cultured in complete medium (RPMI 1640 supplemented with 10% FBS, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin) supplemented with 10 ng/ml murine GM-CSF obtained from J558L-GM-CSF supernatant (35) and 2 ng/ml recombinant murine (rm)IL-4 (R&D Systems, Minneapolis, MN). Nonadherent cells were removed and fresh medium was added on days 2 and 4. Nonadherent BM-DCs were harvested on day 6 for FACS analysis. Mature BM-DCs were generated by the inclusion of 10 µg/ml LPS (Sigma-Aldrich) for the last 48 h of culture.
The method to generate DCs from spleens (sDC) of B6 or
B6-RAG-1-/- mice was previously described
(36). Briefly, spleens were dissected into small pieces
(
1 mm3) and incubated at 37°C in complete
RPMI 1640 supplemented with 2 mg/ml collagenase (Sigma-Aldrich), 100
mg/ml DNase (Sigma-Aldrich), and 10 µg/ml polymyxin B (Sigma-Aldrich)
for 30–45 min. Cell suspension was obtained by vigorous pipetting and
was passed through a nylon mesh filter and washed with complete RPMI
1640. After lysis of RBCs with ACK lysis buffer,
CD11c+ sDC were isolated using CD11c
microbeads according to the manufacturer’s instructions (Miltenyi
Biotec, Auburn, CA). The cells isolated were 90%
CD11c+CD11b+ and 10%
CD11c+CD11b-.
T cell stimulation
Twenty-four-well plates were coated overnight with 10 µg/ml anti-CD3 and 1 µg/ml anti-CD28 mAb. Both CD4+ and CD8+ T cells were purified from the spleens and lymph nodes of B6 mice with CD4 or CD8 microbeads, according to the manufacturer’s instructions (Miltenyi Biotec). Freshly isolated T cells, as well as T cells that had been activated with anti-CD3/anti-CD28 for 48 h, were stained for CD137 expression.
FACS analysis
DCs were isolated and stained at 4°C for 30 min with 1 µg of the Abs indicated and 10 µg of anti-CD16 and anti-CD32 (American Type Culture Collection, Manassas, VA) in 50 ml PBS supplemented with 3% FBS and 0.02% azide. DCs were washed and stained an additional 30 min at 4°C with 1 µg of the appropriate secondary Ab before washing and FACS analysis. For CD137 staining, either biotinylated mAb 2A and streptavidin-PE or PE-conjugated anti-CD137 (eBioscience) was used. Fluorescence was analyzed by a FACScan (BD Biosciences, Mountain View, CA).
In vitro proliferation assays
sDC were isolated from B6 or B6-RAG-1-/- mice that had received 100 µg mAb 2A or rat IgG i.p 24 and 72 h previously. For the MLR, sDC were cocultured with 4 x 105 BALB/c lymph node cells in a flat-bottom 96-well plate at the responder:stimulator ratios indicated. For OT-1 stimulation experiments, CD8+ T cells were purified from OT-1 mice using CD8 microbeads according to the manufacturer’s instructions (Miltenyi Biotec). A total of 1 x 104 purified OT-1 cells were cocultured with 4 x 104 sDC in a 96-well, U-bottom plate in the presence (1 ng/ml) or absence of OVA peptide. T cell proliferation was assessed by the addition of 1 µCi/well [3H]TdR during the last 15 h of a 2- or 3-day culture. [3H]TdR incorporation was measured in a MicroBeta TriLux liquid scintillation counter (Wallac, Turku, Finland).
ELISA
For detection of soluble CD137, supernatants were collected from BM-DCs cultured for 48 h in the presence or absence of LPS. Similarly, sDC were cultured in complete RPMI 1640 supplemented with rmGM-CSF and rmIL-4, and supernatants were collected 24 and 48 h later. A 96-well ELISA plate (Dynatech, Chantilly, VA) was coated with 50 µl of the capture mAb 3H3 (1 µg/ml) at 4°C overnight. Biotinylated mAb 2A was used to detect soluble CD137 in DC supernatants and CD137Ig fusion protein in a standard curve. IL-6 and IL-12 were detected in cell-free supernatants by sandwich ELISA according to the manufacturer’s instructions (BD PharMingen).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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(broad
expression) (Fig. 1
A). In
addition to a dominant 2.1- to 2.5-kb cDNA, which may encode
full-length CD137, there was an additional 1-kb band found in some
cell lines. However, it is unknown whether this additional species of
cDNA represents the alternative splice form of CD137 (see Fig. 1D). The data thus suggest that DCs express CD137. To
confirm this finding, we examined the surface expression of CD137 by
BM-DC and sDC using CD137-specific mAb 2A. BM-DCs were generated in
vitro in the presence of GM-CSF and IL-4. These BM-DCs had a typical DC
morphology and expressed DC markers, including CD11c, CD11b, and high
levels of I-Ab (data not shown). Both immature
and mature BM-DCs that had been cultured in the presence of LPS for
48 h were stained for CD137. As shown in Fig. 1B, both
the immature and mature BM-DC expressed CD137. Like B7-1 and B7-2,
CD137 was up-regulated on LPS-matured DC. However, it should be noted
that the level of expression of CD137 on the surface of immature BM-DC
was variable among different DC preparations, albeit detectable
(R. A. Wilcox and L. Chen, unpublished data). As shown in
Fig. 1C, both CD4+ and
CD8+ T cells express CD137 following activation
by anti-CD3 mAb, although expression levels were greater for
CD8+ T cells. The levels of CD137 expression
observed in the mature BM-DC were comparable to those observed on
CD4+ T cells.
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D). Soluble CD137 likely represents an alternative splice
form, as multiple RNA transcripts representing both cell-associated and
soluble CD137 have been identified in T cells (37).
However, the possibility that CD137 is cleaved by proteases from the
cell surface of the DCs cannot be excluded. The significance of soluble
CD137 is not yet clear, but it is possible that soluble CD137 plays a
role in the down-regulation of a T cell response by blocking its
endogenous ligand (data not shown).
We next examined the expression of CD137 on the surface of freshly
isolated sDCs. The freshly isolated sDCs were largely
CD11c+CD11b+, although
10% of them were
CD11c+CD11b- and may
represent the recently characterized murine equivalent of the human
plasmacytoid DC (38). Importantly, the purified sDCs did
not contain any CD14+ cells, suggesting that
contamination with monocytes or macrophages was negligible in our
preparation. Furthermore, these sDCs expressed high levels of
I-Ab (data not shown) and both B7-1 and B7-2
(Fig. 1B). As was observed with the BM-DC, freshly isolated
sDCs also express CD137, albeit to a greater extent than immature BM-DC
(Fig. 1B), suggesting that immature DCs may constitutively
express CD137 in vivo. Although CD137 transcripts could not be detected
in the spleen or lymph node by Northern blot analysis (Fig. 1A), this technique may not be sufficiently sensitive to
detect CD137 transcripts in DCs and activated T cells present in
secondary lymphoid organs. No significant change in CD137 expression
was observed upon stimulation with LPS, although the in vitro culture
of sDC in medium increased expression levels of B7-1, B7-2, and CD137,
compared with freshly isolated sDC (33). Similarly, we
also detected low levels (<5 ng/ml) of soluble CD137 in sDC
supernatants during the first 24 h of culture and extended in
vitro incubation for an additional 24 h increased the levels of
soluble CD137 significantly (Fig. 1D).
To determine whether ligation of DC-associated CD137 stimulates DCs, we
cocultured BM-DC with CD137L/P815 cells. As shown in Fig. 2A, BM-DCs stimulated with
irradiated CD137L/P815 secreted high levels of IL-6. IL-12 was also
detected in the CD137L/P815-stimulated BM-DCs that were cultured with a
low dose of LPS (Fig. 2B). These cytokines were not
detectable in the mock/P815 cocultures. In addition, the stimulatory
effect of CD137L/P815 could be neutralized completely by
anti-CD137L mAb. Our results indicate that CD137 ligation delivers
an activation signal to DCs.
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A), as demonstrated by
the >30% increase in thymidine incorporation. Similarly, OVA
peptide-pulsed sDCs from 2A-treated mice were better stimulators of
OT-1 transgenic T cells than those sDCs isolated from control
IgG-treated mice (Fig. 3B).
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C) and
OVA-specific OT-1 cells (Fig. 3D). Our results support the
notion that anti-CD137 mAb directly stimulates DC-associated CD137,
resulting in a significant enhancement of their capacity to stimulate
naive T cells. The mechanism involved in the regulation of DC function upon CD137 ligation is unknown. It was reported that binding of CD137 on T cells by its ligand recruited TNFR-associated factor-2 and led to activation of p38 MAPK, apoptosis signal-regulating kinase-1, and c-Jun N-terminal/stress-activated protein kinases (39, 40, 41). These signaling events presumably increase secretion of cytokines and expression of additional cell surface molecules. Our results suggest that cytokines such as IL-6, and particularly IL-12, may play a critical role in this process. However, we were unable to find any significant changes upon CD137 ligation in the expression of CD80, CD86, 4-1BBL, OX40 ligand, CD40, B7-H1, B7-H2, B7-H3, and B7-DC on the cell surface (data not shown). Therefore, CD137 signaling may enhance DC function through a yet unknown mechanism.
We reported previously that the systemic administration of mAb against CD137 could eradicate established tumors in mice by the vigorous amplification of tumor-specific CD8+ CTL activity (19). A combination of anti-CD137 mAb and IL-12 (22) or a peptide vaccine (33) can further increase immunity against tumors that are resistant to anti-CD137 mAb. Our findings in this study suggest that, in addition to directly triggering CD137 on primed tumor-specific T cells, administration of agonistic CD137 mAb may also stimulate DCs directly and enhance their ability to stimulate the vigorous T cell response observed in tumor-bearing mice treated with anti-CD137 mAb. CD137 signaling on the DC may thus explain, at least in part, the potent effect of anti-CD137 mAb in the activation of tumor-specific CTL. In addition, CD137 is also expressed on activated mouse NK cells (31) and human monocytes (42). Interestingly, CD137 signaling on human monocytes induced cell contact-dependent apoptosis of B cells (42). Taken together with the observation that CD137L is also found on activated T cells, B cells, macrophages, and even some tumor cells (43), our results suggest that CD137 and its ligand may play a role in the cross-talk among these cells during the generation of an immune response. The work presented here may have profound implications for both our understanding of DC immunobiology and our mechanistic understanding of CD137-based immunotherapy.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Lieping Chen, Department of Immunology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail address: chen.lieping{at}mayo.edu
3 Abbreviations used in this paper: DC, dendritic cell; sDC, spleen DC; BM, bone marrow; CD137L, CD137 ligand; SMART, switch mechanisms at the 5' end of RNA transcript; rm, recombinant murine.
Received for publication January 18, 2002. Accepted for publication February 26, 2002.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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