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CUTTING EDGE |

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Department of Microbiology, Oregon State University, Corvallis OR 97331; and
Department of Immunology and Inflammation, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08540
| Abstract |
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| Introduction |
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In many cases, the use of adjuvants are thought to be the difference between the induction of tolerance vs immunity. Specifically, it has been proposed that a "danger" signal can impede tolerance induction and promote long-term immunity (9). Recently, it has been shown that LPS can block superantigen (SAg)3-induced deletion consistent with the danger theory (10). These data suggest that proinflammatory factors promote long-term survival of Ag-activated T cells in vivo. Additionally, it is clear that IL-2 and IL-4 therapy can inhibit deletion of activated T cells (11, 12). Therefore, Ag-activated T cells may die in vivo by failing to acquire growth factors.
To examine how T cells avoid death in vivo after exposure to SAg, we examined the possibility that other costimulatory molecules may function differently than CD28. 4-1BB is a member of the TNF receptor family and its ligand 4-1BB ligand is a member of the TNF family (13, 14). 4-1BB has been shown to be a potent costimulatory molecule for CD8 T cells by enhancing cytokine production, and proliferative and cytolytic activity (15, 16, 17). Functionally, this receptor/ligand pair can facilitate anti-tumor activity (18). Thus, 4-1BB is a costimulatory molecule that heightens CD8 T cell function.
We report that 4-1BB expression on SAg-activated T cells is rapid and differential between CD4 and CD8 subpopulations. After ligation of 4-1BB on SAg-activated CD8 T cells in vivo, using an agonist mAb, peripheral deletion is almost entirely inhibited. This occurs in the absence of an adjuvant or cytokine treatments. Thus, 4-1BB ligation can inhibit activation-induced cell death in vivo possibly by providing a long-term survival signal to activated T cells.
| Materials and Methods |
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Female B10.A mice were purchased from the National Cancer Institute (Frederick, MD) and maintained in our animal facility under specific pathogen-free conditions.
Reagents, protocols, and Abs
Staphylococcal enterotoxin A (SEA) was purchased from Toxin Technology (Madison, WI) and administered to mice as i.p. injections of 0.30 µg. The agonist anti-4-1BB mAb 3H3 and biotinylated anti-4-1BB mAb 1D8 were used as a receptor agonist or staining reagent, respectively (17). As a control, rat IgG (Sigma, St. Louis, MO) was injected in doses equal to mAb 3H3.
Anti-TCR Vß3 was purified from hybridoma supernatants over protein G columns (Pharmacia, Piscataway, NJ) (19). The Ab was FITC-conjugated by us. FITC-conjugated anti-Vß14, PE-conjugated anti-CD4, PE-conjugated streptavidin, and biotinylated anti-TCR Vß3 were purchased from PharMingen (San Diego, CA). Red 613-conjugated anti-CD4 and Red 613-conjugated anti-CD8 were purchased from Life Technologies (Grand Island, NY).
Injection of SEA was at time 0 h, and all other injections were done in relation to SEA. In all experiments, 3H3 mAb was coinjected with SEA, and doses are described in the figure legends. Rat IgG was given to a control group at the same time as 3H3 mAb was given to an experimental group.
Cell processing and flow cytometry
Spleens were removed and teased through nylon mesh (Falcon, Becton Dickinson, Franklin Lakes, NJ) and subjected to ammonium chloride to lyse RBCs. Peripheral lymph nodes (LN) were teased into single-cell suspensions and washed with BSS. T cells from spleen or LN populations were purified on nylon wool columns as previously described (20).
For staining, cells were incubated on ice with a primary mAb in the
presence of 5% normal mouse serum, culture supernatant containing
anti-mouse Fc receptor mAb (24.G2), and 10 mg/ml human
-globulin
(Sigma) to block nonspecific binding. After a 30 min incubation on ice
in staining buffer (BSS, 3% FBS, 0.1% sodium azide), the cells were
washed and analyzed by flow cytometry, or if a second step was
necessary, the incubation and wash procedures were repeated. Analysis
was conducted on an EPICS XL flow cytometer (Coulter Electronics,
Miami, FL).
Cell viability counts were completed by trypan blue exclusion. Equal volumes of cells and trypan blue (PBS, 0.4% trypan blue, 0.2% NaN3) were mixed, and viable cells were counted.
| Results and Discussion |
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At 0, 0.5, 1.5, 3, 12, 24, and 48 h after SEA injection, LN T
cells were purified and stained for CD4 or CD8, Vß3, and 4-1BB
expression (Fig. 1
). Flow cytometric
analysis determined that 3-h activated CD4 Vß3 T cells do not express
detectable levels of 4-1BB compared with the equivalent cell
populations from noninjected mice. At 12 h, there is a profound
increase in 4-1BB expression, and by 24 and 48 h levels of 4-1BB
decrease. In contrast, SEA-activated CD8 Vß3 T cells began to express
4-1BB by 90 min and further at 3 h (Fig. 1
). Peak expression
occurred at 12 h followed by a decline to background levels by
48 h. Additionally, at 12 h the amount of 4-1BB appears to be
higher on the CD8 over the CD4 T cells. However, it is also possible
that the kinetics of peak expression is different between the two
populations. We conclude that 4-1BB is rapidly expressed on both CD4
and CD8 SAg-stimulated T cells in vivo and that CD8 T cells express
this molecule faster after stimulation than CD4 T cells.
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It is unclear why CD4 T cells were not rescued to the same degree from deletion as CD8 T cells. One possibility is that CD4 T cells are less responsive to 4-1BB ligation compared with CD8 T cells. There is at least one study that supports this notion (17).
These in vivo data demonstrate the effectiveness of 4-1BB ligation in
preventing death of SAg-activated CD8 T cells; however, this model does
not afford practical mechanistic studies due to the complication of in
vivo analyses. To remedy this problem, an ex vivo model was employed.
At the peak of SEA-induced clonal expansion, LN T cells were purified
and cultured in vitro with no added stimuli. The cells were monitored
for survival by counting the remaining number of viable CD8 Vß3 T
cells at 0, 8, 12, and 16 h in culture. As a control, Vß14 T
cells were stained, and the data show that these cells were unaltered
regardless of the treatment (data not shown). On the other hand, CD8
Vß3 T cells from SEA/control IgG-treated mice preferentially died in
vitro compared with equivalent cells from normal animals (Fig. 4
). In contrast, CD8 Vß3 T cells from
SEA/anti-4-1BB-treated mice preferentially survived compared with
all other cell populations tested. This was not the case for
SEA/control IgG cells, which decreased by greater than fourfold in
absolute numbers over the 16-h incubation. In a separate experiment, we
tested the idea that the rescued T cells were surviving due to IL-2
production. Our data indicate that IL-2 was not keeping these cells
alive because a neutralizing IL-2 mAb did not block survival but was
able to block IL-2-driven proliferation (data not shown). Nevertheless,
it is possible that other survival factors were produced by the rescued
cells.
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The potency of the rescuing effect may have practical application, such as the design of CD8 T cell-based vaccines. Collectively, these data suggest that 4-1BB may be an integral component of CD8 T cell memory acquisition and may be a link between a putative danger signal and long-term immunity.
| Footnotes |
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2 Address correspondence and reprint requests to Dr. Anthony T. Vella, Department of Microbiology, 220 Nash Hall, Oregon State University, Corvallis, OR 97331. E-mail address: ![]()
3 Abbreviations used in this paper: SAg, superantigen; SEA, staphylococcal enterotoxin A; LN, lymph node. ![]()
Received for publication December 16, 1998. Accepted for publication February 9, 1999.
| References |
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G. Demirci, W. Gao, X. X. Zheng, T. R. Malek, T. B. Strom, and X. C. Li On CD28/CD40 Ligand Costimulation, Common {gamma}-Chain Signals, and the Alloimmune Response J. Immunol., May 1, 2002; 168(9): 4382 - 4390. [Abstract] [Full Text] [PDF] |
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G. J. D. van Mierlo, A. Th. den Boer, J. P. Medema, E. I. H. van der Voort, M. F. Fransen, R. Offringa, C. J. M. Melief, and R. E. M. Toes CD40 stimulation leads to effective therapy of CD40- tumors through induction of strong systemic cytotoxic T lymphocyte immunity PNAS, April 16, 2002; 99(8): 5561 - 5566. [Abstract] [Full Text] [PDF] |
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L. Diehl, G. J. D. van Mierlo, A. T. den Boer, E. van der Voort, M. Fransen, L. van Bostelen, P. Krimpenfort, C. J. M. Melief, R. Mittler, R. E. M. Toes, et al. In Vivo Triggering Through 4-1BB Enables Th-Independent Priming of CTL in the Presence of an Intact CD28 Costimulatory Pathway J. Immunol., April 15, 2002; 168(8): 3755 - 3762. [Abstract] [Full Text] [PDF] |
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E. M. Bertram, P. Lau, and T. H. Watts Temporal Segregation of 4-1BB Versus CD28-Mediated Costimulation: 4-1BB Ligand Influences T Cell Numbers Late in the Primary Response and Regulates the Size of the T Cell Memory Response Following Influenza Infection J. Immunol., April 15, 2002; 168(8): 3777 - 3785. [Abstract] [Full Text] [PDF] |
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A. Yamada, A. D. Salama, and M. H. Sayegh The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation J. Am. Soc. Nephrol., February 1, 2002; 13(2): 559 - 575. [Full Text] [PDF] |
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Y. Sun, X. Lin, H. M. Chen, Q. Wu, S. K. Subudhi, L. Chen, and Y.-X. Fu Administration of Agonistic Anti-4-1BB Monoclonal Antibody Leads to the Amelioration of Experimental Autoimmune Encephalomyelitis J. Immunol., February 1, 2002; 168(3): 1457 - 1465. [Abstract] [Full Text] [PDF] |
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K. Nozawa, J. Ohata, J. Sakurai, H. Hashimoto, H. Miyajima, H. Yagita, K. Okumura, and M. Azuma Preferential Blockade of CD8+ T Cell Responses by Administration of Anti-CD137 Ligand Monoclonal Antibody Results in Differential Effect on Development of Murine Acute and Chronic Graft-Versus-Host Diseases J. Immunol., November 1, 2001; 167(9): 4981 - 4986. [Abstract] [Full Text] [PDF] |
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G. Zhu, D. B. Flies, K. Tamada, Y. Sun, M. Rodriguez, Y.-X. Fu, and L. Chen Progressive Depletion of Peripheral B Lymphocytes in 4-1BB (CD137) Ligand/I-E{alpha}-Transgenic Mice J. Immunol., September 1, 2001; 167(5): 2671 - 2676. [Abstract] [Full Text] [PDF] |
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J. L. Cannons, P. Lau, B. Ghumman, M. A. DeBenedette, H. Yagita, K. Okumura, and T. H. Watts 4-1BB Ligand Induces Cell Division, Sustains Survival, and Enhances Effector Function of CD4 and CD8 T Cells with Similar Efficacy J. Immunol., August 1, 2001; 167(3): 1313 - 1324. [Abstract] [Full Text] [PDF] |
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J. A. Kim, B. J. Averbook, K. Chambers, K. Rothchild, J. Kjaergaard, R. Papay, and S. Shu Divergent Effects of 4-1BB Antibodies on Antitumor Immunity and on Tumor-reactive T-Cell Generation Cancer Res., March 1, 2001; 61(5): 2031 - 2037. [Abstract] [Full Text] |
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B. R. Blazar, B. S. Kwon, A. Panoskaltsis-Mortari, K. B. Kwak, J. J. Peschon, and P. A. Taylor Ligation of 4-1BB (CDw137) Regulates Graft-Versus-Host Disease, Graft-Versus-Leukemia, and Graft Rejection in Allogeneic Bone Marrow Transplant Recipients J. Immunol., March 1, 2001; 166(5): 3174 - 3183. [Abstract] [Full Text] [PDF] |
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J. L. Cannons, Y. Choi, and T. H. Watts Role of TNF Receptor-Associated Factor 2 and p38 Mitogen-Activated Protein Kinase Activation During 4-1BB-Dependent Immune Response J. Immunol., December 1, 2000; 165(11): 6193 - 6204. [Abstract] [Full Text] [PDF] |
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I. Gramaglia, A. Jember, S. D. Pippig, A. D. Weinberg, N. Killeen, and M. Croft The OX40 Costimulatory Receptor Determines the Development of CD4 Memory by Regulating Primary Clonal Expansion J. Immunol., September 15, 2000; 165(6): 3043 - 3050. [Abstract] [Full Text] [PDF] |
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R. S. Kornbluth The emerging role of CD40 ligand in HIV infection J. Leukoc. Biol., September 1, 2000; 68(3): 373 - 382. [Abstract] [Full Text] [PDF] |
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H. R. Salih, S. G. Kosowski, V. F. Haluska, G. C. Starling, D. T. Loo, F. Lee, A. A. Aruffo, P. A. Trail, and P. A. Kiener Constitutive Expression of Functional 4-1BB (CD137) Ligand on Carcinoma Cells J. Immunol., September 1, 2000; 165(5): 2903 - 2910. [Abstract] [Full Text] [PDF] |
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J. T. Tan, J. K. Whitmire, K. Murali-Krishna, R. Ahmed, J. D. Altman, R. S. Mittler, A. Sette, T. C. Pearson, and C. P. Larsen 4-1BB Costimulation Is Required for Protective Anti-Viral Immunity After Peptide Vaccination J. Immunol., March 1, 2000; 164(5): 2320 - 2325. [Abstract] [Full Text] [PDF] |
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I. Suzuki and P. J. Fink The dual functions of Fas ligand in the regulation of peripheral CD8+ and CD4+ T cells PNAS, February 15, 2000; 97(4): 1707 - 1712. [Abstract] [Full Text] [PDF] |
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S. D. Pippig, C. Pena-Rossi, J. Long, W. R. Godfrey, D. J. Fowell, S. L. Reiner, M. L. Birkeland, R. M. Locksley, A. N. Barclay, and N. Killeen Robust B Cell Immunity but Impaired T Cell Proliferation in the Absence of CD134 (OX40) J. Immunol., December 15, 1999; 163(12): 6520 - 6529. [Abstract] [Full Text] [PDF] |
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R. S. Mittler, T. S. Bailey, K. Klussman, M. D. Trailsmith, and M. K. Hoffmann Anti-4-1bb Monoclonal Antibodies Abrogate T Cell-Dependent Humoral Immune Responses in Vivo through the Induction of Helper T Cell Anergy J. Exp. Med., November 15, 1999; 190(10): 1535 - 1540. [Abstract] [Full Text] [PDF] |
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G. J. D. van Mierlo, A. Th. den Boer, J. P. Medema, E. I. H. van der Voort, M. F. Fransen, R. Offringa, C. J. M. Melief, and R. E. M. Toes CD40 stimulation leads to effective therapy of CD40- tumors through induction of strong systemic cytotoxic T lymphocyte immunity PNAS, April 16, 2002; 99(8): 5561 - 5566. [Abstract] [Full Text] [PDF] |
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N. Arbour, D. Naniche, D. Homann, R. J. Davis, R. A. Flavell, and M. B.A. Oldstone c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Signaling Pathways Have Divergent Roles in CD8+ T Cell-mediated Antiviral Immunity J. Exp. Med., March 25, 2002; 195(7): 801 - 810. [Abstract] [Full Text] [PDF] |
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