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*
The Carlos and Marguerite Mason Transplantation Biology Research Center and Department of Surgery, and
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; and
Epimmune, San Diego, CA 92121
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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staining, and IFN- enzyme-linked immunospot
assay (ELISPOT) indicated that CD8 T cell responses were reduced 3- to
10-fold in the absence of 4-1BB costimulation. Moreover, when agonistic
anti-4-1BB Ab was given, CD8 T cell responses in
4-1BBL-/- mice were augmented to levels similar to those
in 4-1BBL+/+ mice. Two months after immunization,
4-1BBL+/+ mice still had epitope-specific cells and were
protected against viral challenge, demonstrating that peptide
vaccination can induce long-term protection. In fact, 70% of CD8 T
cells were specific for the immunizing peptide after viral challenge,
demonstrating that strong, epitope-specific CD8 T cell responses are
generated after peptide vaccination. In contrast, peptide-immunized
4-1BBL-/- mice had fewer epitope-specific cells and were
impaired in their ability to resolve the infection. These results show
that immunization with a single LCMV peptide provides long term
protection against LCMV infection and point to costimulatory molecules
such as 4-1BB as important components for generating protective
immunity after vaccination. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To confer protection against viral infection, peptide vaccines must activate significant numbers of CD8 T cells. Signals through costimulatory receptors are important components to the generation of an effective T cell response. In many different experimental systems, the costimulatory molecules CD28 and CD40 are critical for generating strong T cell responses (12, 13, 14, 15). In the absence of either one of these costimulatory signals, the ability to generate T cell responses is diminished. The CD28 and CD40 pathways are also important for the induction of T cell responses by several different vaccines. For example, B7- and CD40-dependent responses promote immunity induced by tumor vaccination or DNA vaccines (16, 17, 18, 19, 20).
4-1BB is a costimulatory molecule that is expressed on activated T cells (21, 22), and its ligand, 4-1BBL, is expressed on activated B cells, macrophages, and dendritic cells (23, 24, 25, 26). Several studies have shown that signals through 4-1BB induce T cell activation and CD8 T cell survival (23, 26, 27, 28, 29, 30, 31, 32, 33). In addition, 4-1BB costimulation has also been shown to facilitate CTL development to induce clearance of tumors from mice (34, 35, 36).
We have previously examined the role of 4-1BB costimulation on the generation of primary T cell responses in the LCMV system (37). Although 4-1BBL-/- mice generated effective primary anti-viral CD8 T cell responses and were able to eliminate the infection, quantitation of these responses showed that 4-1BBL-/- mice generated 2- to 3-fold fewer numbers of LCMV-specific cells compared with 4-1BBL+/+ mice. In this study the role of 4-1BB costimulation in T cell responses following peptide vaccination was examined by comparing the responses of 4-1BBL-/- and 4-1BBL+/+ mice after immunization with a lipidated MHC class I-restricted LCMV peptide, NP396–404, covalently linked to an OVA Th epitope. In the absence of 4-1BB costimulation, CTL generation was reduced 10-fold and the number of Ag-specific CD8 T cells generated was 3- to 10-fold fewer than that in 4-1BBL+/+ mice. In addition, agonistic anti-4-1BB Abs restored peptide-specific CD8 T cell responses to numbers comparable to those in 4-1BBL+/+ mice, showing that 4-1BB costimulation plays an important role in inducing CD8 T cell responses. Memory CD8 T cell responses were also lower than those in 4-1BBL+/+ mice. A high percentage of Ag-specific cells was generated after LCMV challenge of immunized 4-1BBL+/+ mice, whereas immunized 4-1BBL-/- mice generated lower percentages of Ag-specific cells and were impaired in their ability to eliminate the infection. Together, these studies demonstrate that 4-1BB costimulation is important in the generation of CD8 T cell responses after peptide immunization, and that vaccination with a single peptide epitope along with 4-1BB costimulation can induce long term immunity that is protective against viral challenge.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(B6 x 129)F2 (H-2b) or C57BL/6 (H-2b) were purchased from The Jackson Laboratory (Bar Harbor, ME). (C57BL/6 x 129)F2 4-1BBL-/- mice were provided by Jacques Pechon, Immunex (Seattle, WA) (32). The 3E1 clone of the agonistic anti-4-1BB Ab has been previously described (30). Rat IgG was obtained from Jackson ImmunoResearch Laboratories (West Grove, PA). 4-1BBL-/- mice were treated with 200 µg of anti-4-1BB Ab or rat IgG on days 0, 2, 4, and 6 after immunization.
NP396–404 peptide synthesis and immunization
The lipidated MHC class I-restricted LCMV peptide NP396–404 consisted of the NP396–404 peptide covalently attached to a chicken OVA Th epitope and a lipid moiety (9, 11). The NP396–404 peptide binds strongly to the MHC class I molecule Db and is a dominant LCMV CD8 T cell epitope. Mice, 6–10 wk old, were immunized s.c. at the base of the tail with 10 µg of lipidated NP396–404 peptide as previously described (11).
Virus
Seventy days after NP396–404 peptide immunization, mice were challenged with 2 x 106 PFU of the clone 13 variant of LCMV i.v. (38, 39, 40, 41). Infectious LCMV in serum was quantitated by plaque assay on Vero cell monolayers as described previously (40).
Tetramer staining
Tetramers of H-2Db bound to LCMV peptide NP396–404 or GP33–41 were prepared and used as described previously (42). Spleen cells were stained with allophycocyanin-conjugated H-2Db NP396–404 or GP33–41 tetramers and FITC-conjugated monoclonal anti-mouse CD8 purchased from PharMingen (La Jolla, CA) and analyzed by flow cytometry.
Intracellular staining for IFN-
The method for intracellular IFN- staining has been described
previously (42). Spleen cells were stimulated in vitro
with medium, NP396–404, or
GP33–41 for 5 h in vitro with brefeldin A
(Golgiplug, PharMingen). They were then stained with
allophycocyanin-conjugated monoclonal anti-CD8 (clone 53-6.7,
PharMingen) and stained for intracellular IFN- using the
Cytofix/Cytoperm staining kit (PharMingen) according to the
manufacturer’s recommended protocol. FITC-conjugated monoclonal rat
anti-mouse IFN- (clone XMG1.2) and its control isotype Ab (rat
IgG1) from PharMingen were used for intracellular IFN- staining.
Quantitation of peptide-specific IFN--secreting CD8 T cells by
ELISPOT assay
Peptide-specific CD8 T cell responses were measured by IFN-
ELISPOT assay as described previously (42, 43). Spleen
cells were stimulated with 0.1 µg/ml of purified
NP396–404 peptide. Unimmunized spleen cells had
a frequency of 
2 IFN--producing cells/106
spleen cells with or without stimulation.
CTL assay
Splenocytes that were not treated with NH4Cl were cultured in vitro in 24-well plates at 4 x 106 effector cells/well. The cells were stimulated in the presence of LCMV-infected splenocytes from congenitally infected C57BL/6 mice at 1 x 106 cells/well. After 5 days, the cells were harvested, and CTL activity was measured in a 51Cr release assay as described previously (40). The target cells used in the CTL assay were either uncoated or coated with NP396–404 peptide (0.1 µg/ml).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine the role of 4-1BB costimulation in the development of T
cell responses after peptide immunization,
4-1BBL+/+ and 4-1BBL-/-
mice were immunized s.c. with the lipidated LCMV MHC class I-restricted
peptide NP396–404 covalently linked to an OVA Th
epitope. Seven or eight days following immunization, spleen cells were
harvested and cultured in vitro for 5 days with LCMV. The presence of
peptide-specific CTL was determined in a cytolytic T cell assay using
51Cr-labeled
NP396–404-coated target cells. As shown in Fig. 1
, CTL responses in
4-1BBL-/- mice were 10-fold lower than those in
4-1BBL+/+ mice (10-fold more effector cells from
4-1BBL-/- mice were required to achieve the
same percentage of specific lysis in 4-1BBL+/+
mice).
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staining. The percentage of
NP396–404-specific CD8 T cells in
4-1BBL+/+ peptide-immunized mice was 1%, whereas
it was only 0.2% in peptide-immunized
4-1BBL-/- mice (Fig. 2A). The percentage observed
was not due to any background staining, because <0.01% of CD8 T cells
were Ag specific in the absence of peptide stimulation in both
4-1BBL+/+ and 4-1BBL-/-
mice. 4-1BBL-/- mice generated 3-fold fewer
epitope-specific cells compared with 4-1BBL+/+
mice as measured by intracellular IFN- staining.
4-1BBL-/- mice had 1.7 x
104 NP396–404-specific
cells in the spleen compared with 5.6 x 104
cells in 4-1BBL+/+ mice (Fig. 2B). The
frequencies of IFN--secreting
NP396–404-specific cells in the draining
inguinal lymph nodes as measured by IFN- ELISPOT were 1/6522 in
4-1BBL-/- mice and 1/877 in
4-1BBL+/+ mice.
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ELISPOT analysis of spleen cells indicated that
4-1BBL-/- mice generated 3- to 10-fold fewer
NP396–404-specific cells compared with
4-1BBL+/+ mice (Table I). Wild-type mice had 2–6 x
104 NP396–404 cells
compared with 0.2–2 x 104 cells in
4-1BBL-/- mice. To determine whether signaling
through 4-1BB could rescue the defective CD8 T cell response and
increase the number of Ag-specific cells generated in these mice,
4-1BBL-/- mice were immunized with
NP396–404 peptide and treated with an agonistic
anti-4-1BB Ab. Table I shows that anti-4-1BB Ab treatment of
4-1BBL-/- mice increased the number of
NP396–404-specific cells 2- to 30-fold, so that
these mice now generated 3–7 x 104
NP396–404-specific cells. These numbers are
comparable to the response generated by
4-1BBL+/+ mice.
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To examine whether 4-1BB costimulation affects T cell memory
following peptide immunization, 4-1BBL+/+ and
4-1BBL-/- mice were analyzed 2 mo
postimmunization. The percentage and total numbers of Ag-specific
memory CD8 T cells were measured by intracellular IFN- staining.
Some 0.3% of CD8 T cells were NP396–404
specific in 4-1BBL+/+ mice. In
4-1BBL-/- mice, the percentage of
NP396–404-specific cells was <0.01% or below
the level of detection (Fig. 3A). These numbers
corresponded to 1.4 x 104
NP396–404 specific cells in
4-1BBL+/+ mice and <7 x
103 in 4-1BBL-/- mice
(Fig. 3B).
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). Among the unimmunized mice,
4-1BBL+/+ and 4-1BBL-/-
mice had comparable viral titers, showing that the initial viral burden
was similar in both groups of mice, and that the impaired viral
clearance observed in immunized 4-1BBL-/- mice
was due to a weaker memory CD8 T cell response. By 23 days after
challenge, all immunized 4-1BBL+/+ mice had
cleared the infection. In contrast, only two of four immunized
4-1BBL-/- mice cleared LCMV by this time point,
and these mice still had 8.3 x 103 to
1.4 x 105 PFU/ml in the serum (data not
shown).
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A). Eight days after clone 13
challenge, there was a strong skewing toward the
NP396–404 epitope in
4-1BBL+/+ mice (70% of CD8 T cells were
NP396–404 specific) that was 6-fold greater than
that found in 4-1BBL+/+ unimmunized mice (13% of
CD8 T cells were NP396–404 specific). In
contrast, the skewing toward the NP396–404
epitope was less pronounced in 4-1BBL-/- mice,
where 39% of CD8 T cells were NP396–404
specific. This corresponded to a 4-fold increase compared with
unimmunized 4-1BBL-/- mice (10% of CD8 T cell
were Ag specific). Similar results were observed when Ag-specific cells
were quantitated by intracellular IFN- staining (Fig. 6). In immunized
4-1BBL+/+ mice, 47% of CD8 T cells were Ag
specific, a 7-fold increase compared with that in unimmunized
4-1BBL+/+ mice. In contrast, 26% of CD8 T cells
in 4-1BBL-/- mice were Ag specific, a 4-fold
increase compared with that in unimmunized
4-1BBL-/- mice.
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B). Eight
days following clone 13 infection, about 10% of CD8 T cells
were GP33–41 specific in unimmunized mice.
Interestingly, the percentage of CD8 T cells that were
GP33–41 specific in
4-1BBL+/+ mice after
NP396–404 peptide immunization was reduced to
3% and reflected the strong skewing toward the
NP396–404 epitope. In
4-1BBL-/- mice, the percentage of
GP33–41-specific cells was 10% (comparable to
that in unimmunized mice). The higher percentage of
GP33–41-specific cells in
NP396–404 peptide-immunized
4-1BBL-/- mice reflected the weaker skewing
toward the NP396–404 epitope. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Peptide immunization induced weaker CD8 T cell responses than infection with LCMV. One percent of Ag-specific CD8 T cells were generated following peptide immunization compared with 20% after LCMV infection (42, 44). The percentages correspond to about 5 x 104 cells in the spleen after immunization, whereas the number was about 1.2 x 107 cells 8 days after LCMV infection. The reasons why the lipidated NP396–404 peptide is a weaker stimulator of CD8 T cell responses compared with LCMV infection may be that there is a fixed amount of the peptide, the immunogen does not replicate, and the Ag is not systemically distributed. In contrast, much more Ag is present after systemic viral infections, where high amounts of Ag are produced, so that the total number of cells expressing the epitope and the amount of the epitope expressed by each of these cells are much greater than those after peptide immunization.
In our previous studies when T cell responses were measured after acute LCMV infection, we observed that expansion of CD8 T cells was 2- to 3-fold lower in 4-1BBL-/- mice than in 4-1BBL+/+ mice, whereas CTL generation in 4-1BBL-/- mice was comparable to that in 4-1BBL+/+ mice (37). In this study responses to a nonreplicating Ag were 3- to 10-fold weaker in 4-1BBL-/- mice. These results show that 4-1BB costimulation clearly plays a more important role in CD8 T cell activation in cases of limiting Ag, such as peptide immunization, than in cases where there is a lot of Ag, such as after systemic viral infection. A reason for this may be that LCMV infection provides a sufficiently strong stimulus for TCR so that some CD8 T cell responses do not require 4-1BB costimulation. Previous studies have shown that when no costimulation was provided, many more TCRs needed to be engaged for effective T cell activation, whereas fewer TCRs needed to be engaged when CD28 costimulation was provided (45). Therefore, during peptide immunization, where lower amounts of Ag are presented, the optimal number of TCRs required for T cell activation may not be available. Consequently, costimulatory molecules such as 4-1BB may be required for optimal T cell responses. Previous studies using agonistic anti-4-1BB Abs have shown that 4-1BB costimulation is important for promoting tumor-specific CTL generation, proliferation of CD8 T cells, induction of T cell activation markers, and enhancing CD8 T cell survival (30, 31, 34).
Alternatively, the reduced CD8 T cell expansion observed in the absence of 4-1BBL-dependent signals may not be due to a direct interaction of 4-1BB on the CD8 T cell with its ligand, but could be due to a lack of CD4 T cell help. The immunizing NP396–404 peptide contains an OVA Th epitope for generating CD4 T cell responses. Because peptide immunization provides a limiting, nonreplicating stimulus, CD8 T cell responses may be CD4 Th dependent. 4-1BB costimulation may be required for inducing CD4 T cell responses to provide help for developing CD8 T cell responses. Although previous work has shown that 4-1BB costimulation is not required for anti-viral CD4 T cell expansion (37), it cannot be ruled out that 4-1BB could be important for the induction of peptide-specific CD4 Th responses that facilitate the generation of CD8 T cell responses.
Our results confirm previous studies showing that the lipidated
NP396–404 peptide is an effective vaccine and
extend these studies by showing that peptide vaccination can induce
protective immunity against a viral challenge 2 mo after immunization.
Previous work has shown that peptide immunization can induce protective
immunity against viral infection 
2 wk after peptide immunization
(10, 11). We show in this study that memory T cells could
be detected 2 mo or more after immunization, and immunized mice were
able to mount strong epitope-specific secondary responses and quickly
control a viral challenge.
Previous studies have shown that in chronically infected mice, cells responsive to NP396–404 are deleted at later time points after infection (<1% of CD8 T cells were NP396–404 specific by 45 days postinfection (46). In contrast, peptide-immunized mice did not delete the NP396–404 epitope at later time points following clone 13 challenge (50 and 30% of CD8 T cells were NP396–404 specific on days 23 and 45 postchallenge, respectively; data not shown). The skewing toward the NP396–404 epitope of NP396–404 peptide-immunized mice was so strong that 70% of CD8 T cells in NP396–404-immunized mice were NP396–404 specific 8 days after clone 13 infection. Interestingly, this strong skewing toward the NP396–404 epitope was reflected in the low percentages of GP33–41-specific CD8 T cells. These results suggest that the number of NP396–404-specific cells generated was so high in NP396–404 peptide-immunized mice after clone 13 challenge that the viral infection was quickly eliminated and the deletion of the NP396–404-responsive cells was prevented. In addition, these results show that most of the CD8 T cell response after viral challenge is specific to the immunizing peptide. The strong recall response induced by peptide vaccination is Ag specific and not due to nonspecific bystander effects.
Together, these results demonstrate that immunization with a single epitope confers protective immunity and illustrates the importance of costimulation for the effectiveness of vaccines. This study shows that the costimulatory molecule, 4-1BB, is important for establishing a strong memory CD8 T cell response following peptide immunization to induce protective immunity against a viral challenge. Our study therefore points to 4-1BB costimulation as an important therapeutic target for the development of vaccine strategies to boost immune responses against pathogenic agents.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Drs. Christian P. Larsen and Thomas C. Pearson, Department of Surgery, Emory University School of Medicine, Room 5105, 1639 Pierce Drive, Atlanta, GA 30322. E-mail address:
3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; 4-1BBL, 4-1BB ligand; ELISPOT, enzyme-linked immunospot assay.
Received for publication October 1, 1999. Accepted for publication December 14, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R. A. Wilcox, K. Tamada, S. E. Strome, and L. Chen Signaling Through NK Cell-Associated CD137 Promotes Both Helper Function for CD8+ Cytolytic T Cells and Responsiveness to IL-2 But Not Cytolytic Activity J. Immunol., October 15, 2002; 169(8): 4230 - 4236. [Abstract] [Full Text] [PDF]
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D. Laderach, M. Movassagh, A. Johnson, R. S. Mittler, and A. Galy 4-1BB co-stimulation enhances human CD8+ T cell priming by augmenting the proliferation and survival of effector CD8+ T cells Int. Immunol., October 1, 2002; 14(10): 1155 - 1167. [Abstract] [Full Text] [PDF]
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J. L. Cannons, E. M. Bertram, and T. H. Watts Cutting Edge: Profound Defect in T Cell Responses in TNF Receptor-Associated Factor 2 Dominant Negative Mice J. Immunol., September 15, 2002; 169(6): 2828 - 2831. [Abstract] [Full Text] [PDF]
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S. Wirths, J. Reichert, F. Grunebach, and P. Brossart Activated CD8+ T Lymphocytes Induce Differentiation of Monocytes to Dendritic Cells and Restore the Stimulatory Capacity of Interleukin 10-treated Antigen-presenting Cells Cancer Res., September 1, 2002; 62(17): 5065 - 5068. [Abstract] [Full Text] [PDF]
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R. A. Wilcox, D. B. Flies, H. Wang, K. Tamada, A. J. Johnson, L. R. Pease, M. Rodriguez, Y. Guo, and L. Chen Impaired Infiltration of Tumor-specific Cytolytic T Cells in the Absence of Interferon-{gamma} despite Their Normal Maturation in Lymphoid Organs during CD137 Monoclonal Antibody Therapy Cancer Res., August 1, 2002; 62(15): 4413 - 4418. [Abstract] [Full Text] [PDF]
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K. F. May Jr., L. Chen, P. Zheng, and Y. Liu Anti-4-1BB Monoclonal Antibody Enhances Rejection of Large Tumor Burden by Promoting Survival but not Clonal Expansion of Tumor-specific CD8+ T Cells Cancer Res., June 1, 2002; 62(12): 3459 - 3465. [Abstract] [Full Text] [PDF]
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B. S. Kwon, J. C. Hurtado, Z. H. Lee, K. B. Kwack, S. K. Seo, B. K. Choi, B. H. Koller, G. Wolisi, H. E. Broxmeyer, and D. S. Vinay Immune Responses in 4-1BB (CD137)-Deficient Mice J. Immunol., June 1, 2002; 168(11): 5483 - 5490. [Abstract] [Full Text] [PDF]
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T. Wen, J. Bukczynski, and T. H. Watts 4-1BB Ligand-Mediated Costimulation of Human T Cells Induces CD4 and CD8 T Cell Expansion, Cytokine Production, and the Development of Cytolytic Effector Function J. Immunol., May 15, 2002; 168(10): 4897 - 4906. [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. Tawab, J. Fields, E. Chao, and R. J. Kurlander Recombinant lemA without adjuvant induces extensive expansion of H2-M3-restricted CD8 effectors, which can suppress primary listeriosis in mice Int. Immunol., February 1, 2002; 14(2): 225 - 232. [Abstract] [Full Text] [PDF]
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M. Prlic, B. R. Blazar, A. Khoruts, T. Zell, and S. C. Jameson Homeostatic Expansion Occurs Independently of Costimulatory Signals J. Immunol., November 15, 2001; 167(10): 5664 - 5668. [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. 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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J. M. M. den Haan and M. J. Bevan A novel helper role for CD4 T cells PNAS, November 21, 2000; 97(24): 12950 - 12952. [Full Text] [PDF]
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