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* Immunomodulation Research Center, University of Ulsan, Ulsan, Korea;
Department of Ophthalmology and Louisiana State University Eye Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112;
Department of Microbiology and Immunology and Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN 46202;
Department of Microbiology and Immunology, Chosun University Dental School, Kwangzu, Korea;
¶ Department of Medicine, University of North California, Chapel Hill, NC 27559; and
|| Department of General Surgery, University of Michigan Medical School, Ann Arbor, MI 48109
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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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The 4-1BB, which is an inducible T cell Ag present on
CD4+, CD8+, and NK
1.1 cells, provides CD28-independent costimulation of T cell activation
(2, 4). Murine 4-1BB is a 30-kDa glycoprotein that belongs
to the TNFR/nerve growth factor receptor superfamily (5).
This molecule contains repeats of a cysteine-rich extracellular motif,
a transmembrane domain, and a cytoplasmic tail (6). We
isolated and characterized 4-1BB genomic clones and found that the
4-1BB gene contains two different 5' untranslated regions (UTRs), which
are used alternately to form 4-1BB mRNA. The two 5' UTRs
are encoded in the same chromosome and are separated from one
another by an intron of 2.5 kb. The entire gene spans 
13 kb of
mouse chromosome 4. The 4-1BB gene consists of 10 exons
and nine introns, among which are two exons for 5' UTRs and
eight exons for coding regions (6).
The 4-1BB-mediated signaling has been shown to
play a critical role in preventing activation-induced cell death,
promoting the rejection of cardiac allografts and skin transplants,
enhancing integrin-mediated cell adherence, and increasing the T cell
cytolytic potential (reviewed in Refs. 2 and
3), as well as eradicating established tumors
(7). Recently, mice deficient in 4-1BBL have been
generated (8). These gene-deficient mice had normal
humoral responses against vesicular stomatitis virus (VSV), decreased
CTL responses to influenza virus, and decreased IFN-
expression
under the influence of lymphocytic choriomeningitis virus
(8, 9, 10). This latter observation supports the finding that
4-1BB-mediated costimulation is critical for CD8+
T cell responses (11). Another interesting feature of the
4-1BB/4-1BBL interaction lies in its ability to provide bidirectional
signals to interacting APCs. For example, stimulation through 4-1BBL by
4-1BB-bearing cells costimulates B cells (12), whereas the
triggering of 4-1BBL on monocytes by 4-1BB Fc plus anti-Fc leads to
the secretion of proinflammatory cytokines (13). The
molecular mechanisms involved in 4-1BB-mediated signaling are now
beginning to be appreciated. Data to date reveal that 4-1BB mediates
signals through the TNFR-associated factor/NF-
B-inducing kinase
pathway and activates NF-B (14, 15, 16).
To evaluate further the role of 4-1BB in mediating immune responses, mice deficient in 4-1BB expression were generated using homologous recombination in embryonic stem (ES) cells. The 4-1BB-deficient mice developed normally and were fully fertile. These mice were also characterized by dysregulated cell proliferation in response to mitogens, the ability to mount normal in vivo Ag-specific responses, and a capacity to display increased turnover of myeloid progenitors. The 4-1BB-deficient mice showed attenuated graft-vs-host diseases in two marrow graft rejection models (17). The results demonstrate an important role for 4-1BB in regulating some facets of cellular immunity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To clone mouse strain 129/SV genomic DNA containing exons of
4-1BB genes, 129/SV genomic DNA was digested with various restriction
enzymes and subjected to Southern blot analysis using the 5' half of
4-1BB cDNA as a probe. BglII restriction enzyme produced a
single 7-kb fragment that hybridized to the 4-1BB probe. To clone this
fragment, 129/SV genomic DNA (100 µg) was first completely
digested with BglII and fractionated on 1% agarose gel at
20 V for 16 h. A zone of DNA resolved around the 7-kb fragment was
purified by Gene-Clean (Bio 101) and ligated with a
BglII-cleaved dephosphorylated pBluescript
SK+ vector. The ligation mixture was
electroporated into Electro-Max (Life Technologies, Rockville,
MD) competent cells. Approximately 2 x
105 colonies were screened from the genomic
sublibraries with the 4-1BB probe. One colony that was hybridized
contained a 7-kb insert. Analysis of the clone revealed that the
genomic fragment contained the type I 5' UTR (exon 1) and exons 2–8 of
the 4-1BB gene. The 7-kb BglII fragment was transferred to
the BamHI site of the pGem 7 vector.
The 4-1BB gene fragment contained a unique NcoI site at its initiation codon. The gene was cut at NcoI, treated with S1 nuclease, and blunt ended to eliminate the potential for recreation of the ATG codon. A neomycin gene with a thymidine kinase promoter and polyadenylation signal (Stratagene, La Jolla, CA) was inserted into the NcoI site. The HSV thymidine kinase gene with a polyoma virus enhancer, PYF 411 (a gift from M. Capecchi, University of Utah, Salt Lake City, UT), was inserted at the 3' end of the BglII fragment of the 4-1BB gene. ES cell line E13TG2a was transfected with the linearized plasmid DNA and selected for G418 and ganciclovir resistance, as previously described (18). Genomic DNA from individual selected clones was digested with SacI and hybridized with a 1.2-kb SacI/XbaI fragment external to the targeting vector to screen for homologous recombination, as previously described (19). A DNA restriction fragment of 5.5 kb corresponded to the wild-type allele, whereas a new 6.7-kb fragment resulted from the targeted allele. Four targeted clones were obtained from the 50 G418 and ganciclovir-resistant ES cell colonies. The targeted ES cells were microinjected into 3- to 5-day-old C57BL/6 blastocysts and transferred to the uterine horn of pseudopregnant C57BL/6 mice. Eight male and seven female chimeras were obtained. We tested for transmission of the mutated allele by mating the chimeras with (C57BL/6 x DBA/2)F1 mice. Two males and one female showed germline transmission of the targeted allele. Homozygous 4-1BB-deficient mice (4-1BB-/-) were bred with C57BL/6 or BALB/c mice for at least seven generations to obtain 4-1BB-/- mice on the C57BL/6 or BALB/c background. The genotypes of the offspring were determined by Southern blot analysis of DNA obtained from tail biopsies.
Flow cytometry and Abs
Unless otherwise indicated, all of the following Abs are directed against murine Ags. The hybridomas 145-2C11 (anti-CD3) and HO-13-4 (anti-Thy-1.2) were obtained from the American Type Culture Collection (Manassas, VA). The hybridoma 1AH2 produces an agonistic anti-4-1BB mAb and was generated in our laboratory, as reported previously (20). The hybridoma 37.51 (anti-CD28) was a gift from J. P. Allison (University of California, Berkeley, CA). Anti-CD3, anti-4-1BB, anti-Thy-1.2, and anti-CD28 were purified from ascites fluids through protein G columns (Amersham Pharmacia Biotech, Piscataway, NJ). Purified anti-CD8, PE anti-CD4, PE anti-CD8, PE rat IgG2a, PE rat IgG2b, purified rat IgG1 FITC-conjugated anti-B220, biotin-conjugated anti-hamster IgG mAbs, and biotin-conjugated anti-rat IgG1 were obtained from BD PharMingen (San Diego, CA). Goat anti-mouse IgM isotype-specific Ab was purchased from Southern Biotechnology Associates (Birmingham, AL). PE-conjugated streptavidin was obtained from Caltag Laboratories (San Francisco, CA). Goat anti-hamster IgG and BSA were obtained from Sigma-Aldrich (St. Louis, MO). Single-cell suspensions of lymphocytes from lymph nodes, spleen, and bone marrow were obtained and were subsequently stained and analyzed on a FACScan (BD Biosciences, San Jose, CA).
Cell culture and cytokine analysis
Splenocytes from wild-type and mutant mice were prepared in
balanced salt solution (pH 7.2). The RBCs were lysed using hemolytic
Gey’s solution. CD4+ and
CD8+ T cells from wild-type and mutant mouse
spleens were prepared using commercial kits from CELLECT (Biotex
Laboratories, Alberta, Canada), according to the manufacturer’s
instructions. Cells were cultured (2 x
106/well) in 24-well plates in 1 ml RPMI/10%
FBS. Culture supernatants collected after 48 h were processed for
the estimation of IL-2, IL-4, and IFN- by commercial ELISA kits
(Endogen, Cambridge, MA).
Generation of 4-1BB-expressing cells and activation of 4-1BB-/- cells
The sf-21 cells were infected with wild-type or 4-1BB-expressing recombinant (sf-4-1BB) baculovirus. The cells were washed twice in PBS, fixed in 1% formaldehyde for 15 min at room temperature, then washed three times in PBS. The fixed sf-21 cells (5 x 104) were incubated in 96-well plates with 1 x 105 splenocytes from 7-wk-old female 4-1BB -/- mice and littermate wild-type (4-1BB+/+) controls. Where indicated, the cultures also received graded concentrations of anti-CD3. Seventy-two hours later, the cells were pulsed with 1 µCi/well [3H]thymidine. Eight hours later, the cultures were harvested and the incorporated radioactivity was measured in a liquid scintillation counter.
Immunization of mice
Eight- to 10-wk-old mice were immunized i.p. with 250 µg keyhole limpet hemocyanin (KLH; Sigma-Aldrich) without adjuvant and boosted 21 days later. Mice were bled before and 5 days after each injection. Isotypes of Abs to KLH were measured by ELISA using HRP-conjugated affinity-purified goat anti-mouse IgM, IgG, IgG2a, IgG2b, IgG3, and IgE (Southern Biotechnology Associates). Mean titers were calculated from three independent experiments. To assess specific Ab production in response to a T-independent Ag, mice were immunized with 50 µg trinitrophenol (TNP)-LPS (Sigma-Aldrich) in saline and bled 7 and 14 days later for determination of anti-TNP Ab level.
Plaque reduction neutralization assay
Groups of wild-type and mutant mice were infected with 1 x 106 PFU VSV by the i.v. route. The mice were bled 4, 8, 12, and 20 days postimmunization. The sera were diluted 40-fold in DMEM/FBS and heat inactivated for 30 min at 56°C. The diluted samples were subjected to further serial 2-fold dilution, the resulting samples were mixed with equal volumes of 500 PFU/ml VSV, and the mixtures were incubated for 90 min at 37°C with 5% CO2. Aliquots of 100 µl serum-virus mix were overlaid on Vero cell cultures, followed by incubation for 60 min at 37°C. At the end of the incubation period, the serum-virus mix was aspirated from the cultures and 0.5% agarose containing DMEM/FBS was added. On the following day, the agarose layer was overlaid with 5% neutral red containing 0.5% agarose-DMEM. The extent of plaque reduction was assessed visually under a light microscope.
VSV-specific CTL responses
The 4-1BB+/+ and 4-1BB-/- littermates on C57BL/6 background were infected with 1 x 106 PFU VSV i.v. Lymph node T cells were harvested 7 days later and tested directly for CTL activity, using the H-2b-restricted, VSV-derived peptide (SDLRGYVYQGLKSG)-pulsed EL-4 cells as target cells (21). 51Cr-labeled EL-4 target cells (104 cells/well) were added to effectors at ratios from 1:1 to 1:100. After 4 h, a 51Cr release assay was performed, as previously described (22).
Colony assay
Cells from blood, femur, and spleen of 4-1BB+/+, 4-1BB+/-, and 4-1BB-/- mice were plated at 1 x 105, 5 x 104, and 5 x 105, respectively, in 35-mm tissue culture dishes (Corning, Corning, NY) in 1% methylcellulose culture medium. The culture medium also contained 30% FBS, 1 U/ml Epo (Amgen Biologicals, Thousand Oaks, CA), 10% v/v PWM mouse spleen cell-conditioned medium, a source of multiple growth-stimulating factors, and 0.1 mM hemin, as described elsewhere (23, 24, 25). Colonies derived from granulocyte-macrophage, erythroid, and multipotential progenitor cells were scored after 7 days of incubation in a humidified environment in an N2-O2-CO2 incubator (model BNP-210; Taboi ESPEC, South Plainfield, NJ) at 5% CO2 and lowered (5%) O2. Absolute numbers of progenitor cells per organ were calculated based on the number of viable, unseparated nucleated cells per femur or spleen, and the number of viable low density (<1.077 gm/cm3) peripheral blood cells retrieved after density cut separation using Ficoll-Hypaque (Amersham Pharmacia Biotech). The percentage of progenitor cells in S phase of the cell cycle was estimated by the high sp. act. [3H]TdR kill assay (23, 24).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The 4-1BB gene (Fig. 1
A)
was disrupted by inserting a neomycin-resistant gene cassette (Fig. 1B) into the initiation codon of the 4-1BB gene (Fig. 1C). Homologous recombination events in ES cells were
screened by Southern blot analysis (Fig. 1D). Of the 50
colonies that were G418 and ganciclovir resistant, four contained the
desired mutation. Chimeric mice were obtained by injecting mutant ES
cells into C57BL/6 blastocytes. Transmission of the mutated allele was
tested for by mating the chimeric mice with (C57BL/6 x
DBA/2)F1 mice. Heterozygous offspring were
crossed to generate mice homozygous for the targeted mutation of the
4-1BB gene. To verify inactivation of the 4-1BB molecule, we stained
the Con A- or PMA plus ionomycin-stimulated T cell surface with
biotin-labeled 1AH2 (anti-4-1BB mAb) and used PE-streptavidin for
detection of 4-1BB. The stimulated splenic T cells from homozygous
targeted mice did not express 4-1BB, indicating that the 4-1BB locus
was disrupted in 4-1BB-/- mice. The stimulated
T cells from heterozygous (4-1BB+/-) mice had
approximately one-half the level of 4-1BB expression of normal
(4-1BB+/+) mice (Fig. 1E). Deletion of
the 4-1BB molecule was further confirmed by stimulating
4-1BB+/- and 4-1BB-/-
cells with a combination of anti-CD3, anti-4-1BB, and
anti-CD28 mAbs. The results indicated a significantly
reduced proliferation in 4-1BB-/- cells, but
not in 4-1BB+/- cells or
anti-CD28-stimulated cells (Fig. 1F).
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Mice homozygous for the 4-1BB-targeted mutation (4-1BB-/- mice) were detected at the expected Mendelian frequency. No abnormalities were observed in the organs of heterozygous or homozygous animals upon gross necropsy or histopathologic examination. The mutant mice were of normal size and weight, and both sexes were fully fertile. To address the issue of 4-1BB deletion on T cell development in primary and secondary lymphoid organs, various lymphoid cell populations were assessed. Flow cytometric analyses of thymocytes, splenocytes, and lymph node cells from 4-wk-old BALB/c wild-type, heterozygous, and homozygous mice revealed no abnormalities in expression of CD4+, CD8+, B220+, or IgM+ cells (data not shown). Hence, 4-1BB does not appear to be required for normal T cell maturation or seeding of mature T cells to peripheral lymphoid organs.
B cell responses in 4-1BB-/- mice
To evaluate Ag-specific B cell responses in
4-1BB-/- mice, the mice were immunized with
KLH, and serum Ig production in 4-1BB+/- and
4-1BB-/- littermates was compared. A 2- to
3-fold decrease in IgG2a and IgG3 isotypes was seen in the
4-1BB-/- mice, compared with the heterozygous
littermates (Fig. 2). Decreased
production of IFN- in 4-1BB-/- mice may
explain the decrease in IgG2a because IFN- is known to drive IgG2a
switching (26). Significant differences between the two
genotypes were not seen for any of the other isotypes.
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). Thus, despite a slight
decrease in the IgG2a and IgG3 responses, overall neutralizing IgG
levels were not different, indicating that 4-1BB may not be important
in the Ig switching process.
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T cell function in 4-1BB-/- mice
The 4-1BB was identified on the basis of its ability to enhance T
cell activation (2). Therefore, mitogen-induced cytokine
production and T cell proliferation were assessed in the mutant and
wild-type mice. The results showed that cellular proliferation was
significantly increased in the 4-1BB-/- mice
over a wide range of plate-immobilized anti-CD3 or soluble Con A
concentrations and durations of exposure, in contrast to the normal
proliferation responses to these mitogens seen in the wild-type mice
(Fig. 4).
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). Because 4-1BBL is also induced on T
cells, the 4-1BB/4-1BBL system must have a self-regulating
mechanism.
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in the mutant mice,
whereas IL-4 levels were significantly decreased (Fig. 6). When purified
CD4+ and CD8+ T cells from
the mutant mice were stimulated with anti-4-1BB mAb, the levels of
IL-2, IL-4, and IFN- were also significantly decreased (Fig. 7). These experiments indicate that
although 4-1BB-/- T cells show enhanced
proliferation, their capacity for cytokine production is decreased.
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. The
4-1BB-/- mice showed significantly decreased
CTL activity to VSV, compared with wild-type littermates.
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To further explore a potential role for 4-1BB in the
observed dysregulated cellular proliferation, myeloid progenitor cells
were examined in bone marrow, spleen, and blood. We found that the
absolute numbers of granulocyte-macrophage, erythroid, and
multipotential progenitor cells in bone marrow, blood, and spleen were
significantly higher in the 4-1BB-/- mice,
compared with wild-type mice (Fig. 9, A–C). These progenitors were undergoing rapid turnover in
the mutant 4-1BB-/- mice, as determined by the
percentage of cells in the S phase of the cell cycle (Fig. 9D). In the heterozygous 4-1BB+/-
mice, the absolute numbers of myeloid progenitor cells and their
cycling status were intermediate between those of the mutant
4-1BB-/- mice and the wild-type
4-1BB+/+ mice (Fig. 9D). However,
there were no apparent differences in nucleated cellularity in bone
marrow, blood, and spleen among the three groups of mice. Our finding
of dysregulated production of progenitor cells suggests that the
4-1BB/4-1BBL system may also be involved in progenitor cell
proliferation, in that the absence of 4-1BB resulted in enhanced
cellular proliferation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast to the dysregulated T cell proliferation in the 4-1BB-/- mice, the T cell immune responses, such as cytokine production and CTL activity, were diminished, suggesting that the proliferative response of 4-1BB-/- T cells is independent of T cell function. When 4-1BB and CD28 are both deficient, the hyperproliferation of T cells seen in the 4-1BB-/- mice disappears (manuscript in preparation). Thus, 4-1BB-/- T cells appear to receive the proliferative signal mainly through CD28, and the absence of 4-1BB-mediated signals leads to T cell hyperproliferation.
Another interesting finding concerned the role of 4-1BB in the regulation of precursor cell turnover in primary and secondary lymphoid organs. The study of myeloid progenitor cells indicated growth enhancement in the numbers and cycling status of these cells in 4-1BB-/- mice, suggesting that 4-1BB plays a previously unrecognized role in myelopoiesis. The exact mechanisms associated with enhanced myeloid progenitor cell proliferation in 4-1BB-/- mice are not known, but may reflect the absence of 4-1BB-mediated signals or indirect mechanisms associated with lymphocyte interactions and cytokine productions, as many lymphocyte products are known to be involved in the regulation of blood cell production (25). In this context, we have demonstrated that 4-1BB and 4-1BBL are expressed in a wide variety of tissues and cell types, which has not been recognized previously (30). Detection of surface expression is difficult, but 4-1BB and 4-1BBL can be detected easily by intracellular staining (manuscript in preparation). The mechanism of control for 4-1BB and 4-1BBL surface expression remains to be determined.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Byoung S. Kwon, Immunomodulation Research Center, University of Ulsan, Ulsan, Korea. E-mail address: bskwon{at}uou.ulsan.ac.kr
3 Abbreviations used in this paper: 4-1BBL, 4-1BB ligand; ES, embryonic stem; KLH, keyhole limpet hemocyanin; TNP, trinitrophenol; UTR, untranslated region; VSV, vesicular stomatitis virus.
Received for publication June 18, 2001. Accepted for publication March 21, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B. Mol. Cell. Biol. 18:558. regulates the isotypes of Ig secreted during in vivo humoral immune responses. J. Immunol. 140:1022.[Abstract]
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S. K. Seo, H. Y. Park, J. H. Choi, W. Y. Kim, Y. H. Kim, H. W. Jung, B. Kwon, H. W. Lee, and B. S. Kwon Blocking 4-1BB/4-1BB Ligand Interactions Prevents Herpetic Stromal Keratitis J. Immunol., July 15, 2003; 171(2): 576 - 583. [Abstract] [Full Text] [PDF]
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 Q. Li, A. Carr, F. Ito, S. Teitz-Tennenbaum, and A. E. Chang Polarization Effects of 4-1BB during CD28 Costimulation in Generating Tumor-reactive T Cells for Cancer Immunotherapy Cancer Res., May 15, 2003; 63(10): 2546 - 2552. [Abstract] [Full Text] [PDF]
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 L. Myers, C. Takahashi, R. S. Mittler, R. J. Rossi, and A. T. Vella Effector CD8 T cells possess suppressor function after 4-1BB and Toll-like receptor triggering PNAS, April 29, 2003; 100(9): 5348 - 5353. [Abstract] [Full Text] [PDF]
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Z.-Q. Wu, A. Q. Khan, Y. Shen, K. M. Wolcott, W. Dawicki, T. H. Watts, R. S. Mittler, and C. M. Snapper 4-1BB (CD137) Differentially Regulates Murine In Vivo Protein- and Polysaccharide-Specific Immunoglobulin Isotype Responses to Streptococcus pneumoniae Infect. Immun., January 1, 2003; 71(1): 196 - 204. [Abstract] [Full Text] [PDF]
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