| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
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
4 M.A. DeBenedette, T. Wen, M.F. Bochmann, P.S. Ohashi, B.H. Barber, K.L. Stocking, J.J. Pechon, and T.R. Watts. Submitted for publication.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and kill
virus-infected cells to eliminate the virus (14, 15, 16, 17).
Virus-specific CD4 T cell responses are also generated
(18), and they contribute to viral clearance by driving
CD8 T cell proliferation and secreting IFN- to activate macrophages.
CD4 T cells are also responsible for helping B cells to generate
neutralizing Abs, which are important for reducing the viral load by
inhibiting infection of cells and by opsonizing virus-infected cells.
These Abs also play an important role in protecting against
reinfection. For an effective T cell response to eliminate infection, T cells must receive signals through the TCR and costimulatory molecules. First, Ag-specific T cells receive a TCR signal after binding of the TCR to APCs expressing peptide-bound MHC molecules. These T cells then receive a second set of signals upon binding of their costimulatory molecules to the corresponding molecular pairs on the APC, and the T cells become activated. The importance of costimulation has been best documented by studies examining the requirement of B7-CD28 interaction for CD4 T cell responses. These studies have shown that CD4 T cell activation is impaired in the absence of B7-CD28 interaction (19). Other studies have shown that B7-dependent signals also play an important role in the generation of CD8 CTL responses, such as after immunization with exogenous Ag or infection with vesicular stomatitis virus, some subtypes of influenza virus, or recombinant vaccinia virus (19, 20, 21).
4-1BB is a costimulatory molecule that belongs to the TNFR superfamily (22). It is expressed on CD4 and CD8 T cell lines (23) and activated primary CD4 T cells and CD8 T cells (unpublished results). The ligand for 4-1BB, 4-1BBL, is a member of the TNF superfamily (24, 25). 4-1BBL is expressed on activated B cells, macrophages, and dendritic cells (24, 25, 26, 27). Several studies show that signals through 4-1BB induce T cell activation. 4-1BBL-expressing cell lines or soluble 4-1BBL induce mitogen-activated, CD3-cross-linked, or alloreactive T cells to proliferate (25) and secrete IL-2 in vitro (27, 28, 29, 30). In addition, 4-1BB fusion proteins block T cell proliferation and IL-2 secretion induced by 4-1BBL (25, 27, 28, 29, 30). Furthermore, agonistic anti-4-1BB mAbs activate T cell proliferation (23, 31) and augment T cell responses in vivo in a tumor immunity model (32).
In this study, we examined the role of 4-1BB costimulation in immune responses in vivo using mice that contained a targeted disruption of the 4-1BBL gene. 4-1BBL-/- mice developed normally and had normal lymphocyte profiles. 4-1BBL-/- mice were infected with LCMV to examine the role of 4-1BB costimulation on the generation of primary CD8 T cell, CD4 T cell, and B cell responses to acute viral infection. Although 4-1BBL-/- mice generated relatively strong CD8 T cell responses, they were consistently 2- to 3-fold lower than +/+ mice. In addition, 4-1BB signals were not required to generate normal levels of epitope-specific CD4 T cell responses or Th-dependent Ab responses. In contrast, CD40L-/- mice generated normal CD8 T cell responses, but generated CD4 T cell responses that were lower than +/+ mice. Furthermore, we investigated whether the absence of both 4-1BBL- and B7-dependent signals would further lower LCMV-specific T cell responses. Treatment of 4-1BBL-/- mice with CTLA4Ig reduced the number of epitope-specific CD8 T cells 5- to 6-fold compared with +/+ mice. CTL responses were also significantly reduced and viral clearance was impaired in the absence of 4-1BBL- and B7-dependent signals. Our results indicate that 4-1BB costimulation is not required for normal mouse development and of immune system organogenesis, but identifies an important costimulatory interaction, along with B7-dependent signals, that can be targeted to improve CD8 T cell responses during vaccination.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
(B6129F1/J+p+Try-c+Mgf-SlJ)F2 (H-2b), C57BL/6 (H-2b), and CD40L-/- mice (33) were purchased from The Jackson Laboratory (Bar Harbor, ME). The derivation of C57BL/6 x 129 4-1BBL-/- mice is described elsewhere.4 4-1BBL-/- mice were maintained in the (C57BL/6 x 129) background at the F2 generation. (B6 x 129)F2 mice were used as the primary controls for 4-1BBL-/- mice.
Virus
Mice 6–10 wk old were infected i.p. with 2 x 105 PFU of the Armstrong CA 1371 strain of LCMV (34). Infectious LCMV in serum and tissues was quantitated by plaque assay on Vero cell monolayers, as described previously (34).
Tetramer staining
Tetramers of H-2Db bound to LCMV peptide NP396–404 were prepared as described previously (35). Spleen cells were stained with allophycocyanin-conjugated H-2Db NP396–404 tetramers and FITC-conjugated 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 (35). Spleen cells were stimulated in vitro
with medium or with GP61–80 (for CD4 T cells) or NP396–404, GP33–41,
GP276–286, or NP205–212 (for CD8 T cells) for 5 h in vitro with
Brefeldin A (GolgiPlug, PharMingen, La Jolla, CA). They were then
stained with APC-conjugated monoclonal anti-CD4 (clone RM4-5;
PharMingen) or APC-conjugated monoclonal anti-CD8 (clone 53-6.7;
PharMingen) and stained for intracellular IFN- using
Cytofix/Cytoperm staining kit (PharMingen), per manufacturer’s
recommended protocol. FITC-conjugated monoclonal rat anti-mouse
IFN- (clone XMG1.2) and its control isotype Ab (rat IgG1;
PharMingen) were used for intracellular IFN- staining.
CTL assay
MHC class I-restricted LCMV-specific CTL activity was determined ex vivo by 51Cr release assay, as described (34). Target cells used were either infected with LCMV or coated with NP396–404 peptide (0.1 µg/ml). One lytic unit is the number of effector cells that gives 30% lysis in a CTL assay.
Flow cytometry
Characterization of lymphocyte populations in +/+ and 4-1BBL-/- was determined by staining thymus and spleen cells for the T cell markers CD4 and CD8, and the B cell markers B220 and Ig heavy and light chain (H & L), followed by FACS analysis, as previously described (17). T cell activation was determined by staining uninfected and day 8-infected mice for the T cell markers CD4 or CD8 and for the activation marker CD44, followed by FACS analysis. PE-conjugated anti-mouse CD8, PE-conjugated anti-mouse CD4, FITC-conjugated anti-mouse CD4, APC-conjugated anti-mouse B220, and FITC-conjugated anti-mouse CD44 were purchased from PharMingen. FITC-conjugated anti-mouse Ig(H & L) was purchased from Caltag (Burlingame, CA).
ELISA
LCMV-specific Ab titer was determined by solid-phase ELISA, as described previously (34, 36).
Fusion protein
CTLA4Ig fusion protein was a kind gift from Peter Linsley (Bristol Myers Squibb, Seattle, WA) (37). Mice were treated i.p. with 500 µg of CTLA4Ig at days 0, 2, 4, and 6 after infection (38). In some experiments, human IgG (Rockland, Gilbertsville, PA) was used as a control. Mice were treated with 500 µg of human IgG on days 0, 2, 4, and 6 after infection. There were no differences between the results obtained from human IgG-treated and untreated mice.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Histological analysis and gross inspection revealed
that the size and tissue architecture of the thymus, spleen, and lymph
node was normal in 4- to 8-wk-old 4-1BBL-/-
mice (data not shown). To phenotypically characterize lymphocyte
populations in 4-1BBL-/- mice, thymus and
spleen cells were stained with anti-CD4 and anti-CD8 or
anti-B220 and anti-Ig(H & L) in the thymus and spleen and
analyzed by flow cytometry. Fig. 1
A shows that the thymus of
both +/+ and 4-1BBL-/- mice contained 
15%
CD4+CD8- cells, 4%
CD4-CD8+ cells, and
80% CD4+CD8+ cells. The
spleens of both +/+ and 4-1BBL-/- mice had
32% CD4+CD8- cells,
17% CD4-CD8+ cells,
and 2% CD4+CD8+ cells.
Similarly, normal percentages of B cells were observed in the thymus
and spleen of 4-1BBL-/- mice. Both +/+ and
4-1BBL-/- mice had 3%
B220+ Ig(H & L)+ cells in
the thymus. In the spleen, +/+ mice had 50%
B220+ Ig(H & L)+ cells and
4-1BBL-/- mice had 43%
B220+ Ig(H & L)+ cells
(Fig. 1B). 4-1BBL-/- mice therefore
had no demonstrable differences in T cell and B cell profiles compared
with +/+ mice.
|
To examine the role of 4-1BB costimulation in the development of
primary CD8 T cell responses to a viral pathogen, we studied CD8 T cell
responses of +/+ and 4-1BBL-/- mice following
infection with LCMV. Previous studies have shown that the expansion of
virus-specific cells is maximal at day 8 after infection
(35). Therefore, as an initial measure of the response of
CD8 T cells to LCMV, we used flow cytometry to determine the ratio of
CD44high to CD44low T cells
and absolute number of activated (CD44high) T
cells in the spleens of +/+ and 4-1BBL-/- mice
8 days after infection. Fig. 2A shows that +/+ mice
generated a vigorous CD8 T cell response, as evidenced by a dramatic
increase in both the ratio of
CD44high:CD44low and
absolute number of CD44highCD8 T cells in the
spleen of infected +/+ mice. The ratio of
CD44high:CD44lowCD8 T cells
changed from 0.6:1 at day 0 to 11:1 at day 8 in +/+ mice. In
4-1BBL-/- mice, less activation was observed as
the ratio changed from 0.6:1 at day 0 to 2.8:1 at day 8 (Fig. 2A). The total number of activated CD8 T cells in the spleen
of 4-1BBL-/- mice was also lower than +/+ mice.
Activated CD8 T cells expanded 8-fold in +/+ mice, but there was only a
3-fold expansion in 4-1BBL-/- mice (Fig. 2B). The total number of nonactivated CD8 T cells
(CD8+CD44low) remained
unchanged in both +/+ and 4-1BBL-/- mice on day
0 and day 8 (Fig. 2B).
|
staining (Fig. 3A). The percentage of
NP396–404-specific CD8 T cells was 21% in both +/+ and
4-1BBL-/- mice. The percentage of CD8 T cells
specific to GP33–41 was 17% in +/+ and 12% in
4-1BBL-/- mice. The percentage of
GP276–286-specific cells was 7% in +/+ and 5% in
4-1BBL-/-, and that of NP205–212 was 2% in +/+ and 1% in
4-1BBL-/- mice. Although the percentage of
epitope-specific CD8 T cells was similar in +/+ and
4-1BBL-/- mice, the overall expansion was lower
in 4-1BBL-/- mice, resulting in 2-fold fewer
CD8 T cells specific to the dominant epitopes NP396–404 and GP33–41.
The number of CD8 T cells specific to NP396–404 was 1 x
107 in +/+ and 5.2 x
106 in 4-1BBL-/- mice,
and the number specific to GP33–41 was 1 x
107 in +/+ and 4.6 x
106 in 4-1BBL-/- mice
(Fig. 3B). A similar trend was found for CD8 T cells
responding to the subdominant epitopes. The number of CD8 T cells
specific to GP276–286 was 2.5 x 106 in +/+
and 1 x 106 in
4-1BBL-/- mice, and there were 1.4 x
106 NP205–212-specific cells in +/+ and 4
x 105 in 4-1BBL-/- mice
(Fig. 3B). Therefore, CD8 T cell expansion in response to
subdominant epitopes was 2.5- to 3.5-fold lower in
4-1BBL-/- than in +/+ mice. Similar results
were found using the IFN- ELISPOT assay (data not shown).
|
shows that
4-1BBL-/- mice had levels of CTL activity
comparable with that observed in +/+ mice. However, the number of LU
per spleen was 2-fold lower in 4-1BBL-/- mice
than +/+ mice (see Fig. 9B), indicating that the CTL
response is in part dependent upon 4-1BB costimulation. Nevertheless,
both +/+ and 4-1BBL-/- were able to clear the
virus by day 8 postinfection because all the mice had <2.3
log10 PFU/g of virus in the liver and <1.7
log10 PFU/ml in the serum.
|
|
Primary CD4 T cell responses to LCMV do not require 4-1BB signals
CD4 T cell activation after infection was measured by flow
cytometry. Both +/+ and 4-1BBL-/- mice
generated strong CD4 T cell responses. In +/+ mice, the ratio of
CD44high to CD44lowCD4 T
cells increased from a baseline of 0.3:1 at day 0 to 1.8:1 at day 8.
The increase in the ratio of
CD44high:CD44lowCD4 T cells
was comparable in 4-1BBL-/- mice with an
increase from 0.3:1 to 1.2:1 on days 0 and 8, respectively (Fig. 4A). Likewise, an increase in
the absolute number of activated CD4 T cells in
4-1BBL-/- and +/+ mice was similar. By day 8
postinfection, the number of activated CD4 T cells expanded 2-fold in
both groups from 5 x 106 to 10
x 106 (Fig. 4B). The number of
nonactivated CD4 T cells remained unchanged in +/+ and
4-1BBL-/- mice on day 0 and day 8 (Fig. 4B).
|
staining of CD4 T cells responding to the MHC
class II-restricted LCMV peptide (GP61–80). The percentage of
GP61–80-specific CD4 T cells was 8% in +/+ and 5% in
4-1BBL-/- mice (Fig. 5A). The number of
GP61–80-specific CD4 T cells in +/+ and
4-1BBL-/- mice was also similar (1.2 x
106 in +/+ vs 0.9 x
106 in 4-1BBL-/- mice) in
Fig. 5B. Similar results were found using the IFN-
ELISPOT assay (data not shown). In addition, the number of
LCMV-specific IL-2-secreting CD4 T cells in the spleen was similar
between +/+ and 4-1BBL-/- mice, as determined
by IL-2 ELISPOT. These data indicate that in contrast to CD8 T cell
responses, CD4 T cell priming was minimally affected by the absence of
4-1BB signals.
|
shows that while CD8 T cell responses
were reduced 2-fold in 4-1BBL-/- mice compared
with +/+ mice, CD8 T cell responses in CD40L-/-
mice were similar to +/+ mice. Interestingly, when CD4 T cell responses
were analyzed in the same mice, it was found that while
4-1BBL-/- mice generated CD4 T cell responses
similar to +/+ mice, CD40L-/- mice had a
10-fold lower CD4 T cell response. These results indicate that CD8 and
CD4 T cells have distinct costimulatory requirements in which optimal
CD8 responses to LCMV require 4-1BB costimulation and CD4 responses
require CD40-CD40L costimulation.
|
Ig class switching from IgM to IgG is a Th-dependent process. To
examine the role of 4-1BB costimulation in the generation of
Th-dependent B cell responses, serum was taken from mice at day 8
postinfection, and the amount of LCMV-specific IgG was measured by
ELISA. Fig. 6 shows that both +/+ and
4-1BBL-/- mice generated high levels of
LCMV-specific Abs, because both mice had a titer of 15
log2. Furthermore, the subclasses of
anti-LCMV IgG were indistinguishable between +/+ and
4-1BBL-/- mice. As shown in the legend of Fig. 6, both +/+ and 4-1BBL-/- mice had similar
percentages of IgG1, IgG2a, IgG2b, and IgG3.
4-1BBL-/- mice therefore have no defect in
their ability to generate Th-dependent B cell responses.
|
Although some have shown that costimulation of CD28 or 4-1BB alone was sufficient to induce immunity for some tumors (32, 39, 40, 41), both 4-1BBL and B7 need to be expressed on the poorly immunogenic tumor AG104A to induce CTL generation and clearance of this tumor (42). In addition, soluble 4-1BBL and 4-1BBL-expressing cell lines induce IL-2 secretion from T cells in the absence of CD28 (27, 30). We therefore examined the role of both 4-1BBL- and B7-dependent signals on T cell responses to LCMV. For these studies, we examined four groups of mice 8 days after LCMV infection. The first group of mice was untreated +/+ mice. The second group was untreated 4-1BBL-/- mice. To block B7-dependent signals, the third group consisted of +/+ mice treated with the fusion protein CTLA4Ig (500 µg on days 0, 2, 4, and 6). Finally, to block both 4-1BBL- and B7-dependent signals, the fourth group consisted of CTLA4Ig-treated 4-1BBL-/- mice.
The number of virus-specific T cells generated was visualized directly
by MHC tetramer staining for NP396–404-specific T cells and
intracellular IFN- staining. The percentage of
tetramer+ CD8 T cells in +/+ mice increased from
a basal level of <1% in uninfected mice to 24% 8 days after
infection (Fig. 7A and data
not shown). Interruption of 4-1BB signaling
(4-1BBL-/- mice) or B7-dependent signaling
(CTLA4Ig treatment) resulted in percentages of
tetramer+ CD8 T cells of 19% and 17%,
respectively. The percentage in the absence of both B7- and
4-1BBL-dependent signals was 15%. The number of NP396–404-specific T
cells in the spleen was also analyzed (Fig. 7B). The number
of tetramer+ CD8 T cells was 13.6 x
106 in +/+ mice, 9.7 x
106 in 4-1BBL-/- mice,
and 9 x 106 cells in CTLA4Ig-treated +/+
mice. The greatest reduction was seen in CTLA4Ig-treated
4-1BBL-/- mice, which generated 3.8 x
106 tetramer+ CD8 T
cells.
|
A shows that the number
of NP396–404-specific CD8 T cells generated, as measured by
intracellular IFN- staining, in +/+ mice was 1 x
107. This number was lowered to 4.6 x
106 cells in CTLA4Ig-treated +/+ mice, indicating
that part of this response is B7 dependent. The number of CD8 T cells
responding to NP396–404 in 4-1BBL-/- mice was
5.2 x 106 and was 2.2 x
106 in CTLA4Ig 4-1BBL-/-
mice. Therefore, combined blockade of 4-1BB-4-1BBL- and B7-dependent
interactions resulted in a 5-fold reduction in the numbers of
epitope-specific CD8 T cells compared with +/+ mice. This same trend
was also found for CD8 T cells specific to GP33–41, GP276–286, and
NP205–212 (Fig. 8A). Similar results were found using the
IFN- ELISPOT assay (data not shown).
|
1 x 106 epitope-specific CD4 T
cells after infection (Fig. 8
B). However, expansion of CD4 T
cells specific to GP61–80 was reduced 10-fold in both +/+ and
4-1BBL-/- mice treated with CTLA4Ig (Fig. 8B). This result shows that B7-dependent signals are
critical for the generation of CD4 T cell responses.
Finally, we compared the ability of the four groups of mice to generate
CTL and clear the virus. CTL responses in
4-1BBL-/- or CTLA4Ig-treated +/+ mice were
indistinguishable from untreated +/+ mice. In contrast, treatment of
4-1BBL-/- mice with CTLA4Ig significantly
reduced CTL development, resulting in an 8-fold lower CTL than
untreated +/+, untreated 4-1BBL-/-, or
CTLA4Ig-treated +/+ mice (Fig. 9A). Untreated
4-1BBL-/- mice generated 2-fold fewer LU/spleen
than untreated +/+ mice, again indicating that part of the CTL response
is dependent upon 4-1BB signals (Fig. 9B). Part of the CTL
response was also dependent upon B7 interactions, because treatment of
+/+ mice with CTLA4Ig reduced the number of LU/spleen by 2-fold. When
both 4-1BB-4-1BBL- and B7-dependent interactions were blocked, the
number of LU/spleen was diminished to lower than detectable levels
(<30) (Fig. 9B). Analysis of viral clearance in the four
groups mirrored CTL function. +/+, 4-1BBL-/-,
and CTLA4Ig-treated +/+ mice had all cleared LCMV from the liver by day
8 postinfection. In contrast, CTLA4Ig-treated
4-1BBL-/- mice had not completely cleared LCMV
by day 8 postinfection (Fig. 9C). Furthermore, these results
demonstrate that the absence of both 4-1BBL- and B7-dependent signals
reduces LCMV-specific CTL responses and impairs clearance of LCMV
infection by day 8 postinfection.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Previous studies using 4-1BB fusion protein, soluble 4-1BBL protein, or 4-1BBL-expressing cell lines indicated that 4-1BB costimulation stimulates anti-CD3 cross-linked T cells (23, 25, 27, 28, 29, 30). Additional reports using agonistic Abs to 4-1BB have also indicated that 4-1BB costimulates T cells (31) and that it induces T cell responses to eliminate tumors from mice (32). This study shows that 4-1BB signals were not required to clear LCMV, as 4-1BBL-/- mice generated a strong CTL response. However, 4-1BB signals did appear to exert some costimulatory effects on CD8 T cell responses to LCMV, because the number of virus-specific CD8 T cells generated in 4-1BBL-/- mice was 1.1 x 107 cells compared with 2.4 x 107 in +/+ mice at day 8 postinfection.
An interesting dichotomy in the requirement of 4-1BB costimulation for
T cell responses was identified. Virus-specific CD8 T cell numbers were
reduced 2- to 3-fold in 4-1BBL-/- mice, whereas
virus-specific CD4 T cell numbers were minimally affected. This result
contrasts with what is seen after LCMV infection in the absence of
CD40-CD40L interaction (43, 44). In
CD40L-/- mice, the primary CD8 T cell response
is minimally affected, but the CD4 T cell response is reduced 10-fold
(Table II). These results suggest that CD8 T cells and CD4 T cells may
have distinct costimulatory requirements: some CD8 T cells depend upon
4-1BB costimulation, whereas the majority of CD4 T cells depend upon
CD40-CD40L interaction. This differential effect of 4-1BB costimulation
on CD8 T cells is consistent with other in vitro studies, in which
agonistic anti-4-1BB Abs were used (31). In addition,
we have shown in an allogeneic model that agonistic anti-4-1BB mAbs
exerted a strong proliferative effect on CD8 T cells, but a weaker
effect on CD4 T cell proliferation (our unpublished observations). A
possible explanation for these findings is that CD4 and CD8 T cells
express different amounts of 4-1BB. Forty-one percent of alloreactive
CD4 T cells express 4-1BB, whereas 71% of alloreactive CD8 T cells
express 4-1BB (unpublished observations). Another possibility is that
4-1BB may bind to intracellular signaling molecules that are present in
CD8 T cells, but not in CD4 T cells. 4-1BB has been shown to bind
p56lck (45) and TRAF1, TRAF2, and
TRAF3 (30, 46, 47). TRAF2 is required for effective 4-1BB
signaling (30), and 4-1BB induces NF-
B activation in a
TRAF-dependent manner (46, 47). However, no work has been
done on differential signaling of 4-1BB in CD4 and CD8 T cells.
Although blockade of 4-1BB signals reduced LCMV-specific CD8 T cell
responses, 50% of the CD8 T cell response was 4-1BBL independent.
It is possible that these cells received enough stimulation through
their TCR that they did not need costimulatory help. Viola et al.
showed that 1500 TCRs were necessary to push a human T cell clone to
their threshold value of activation in the presence of CD28
costimulation. In contrast, 8000 TCRs were required when no
costimulation was provided (48). It is therefore possible
that when a high Ag load or strong ligands are provided for the TCR on
CD8 T cells, as is the case during an LCMV infection, T cell activation
thresholds are reached. Costimulatory molecules would therefore not be
necessary to push these T cells to threshold values of activation. It
would be interesting to examine cases in which only low levels of Ag
are present to determine whether costimulatory molecules such as 4-1BB
play more prominent roles in CD8 T cell activation.
An effective Ag-specific immune response must be generated to eliminate a viral infection. Our results show that 4-1BB costimulation was required to generate approximately half of the CD8 T cell response, but that the other half of the CD8 T cell response was 4-1BBL independent. This suggests that 4-1BBL-independent CD8 T cell responses either do not require costimulation or that compensatory costimulatory molecules act to stimulate these cells. To determine whether compensatory costimulatory molecules synergize to activate 4-1BBL-independent CD8 T cell responses, we performed experiments blocking B7-dependent signals, the dominant costimulatory pathway by which T cells are activated (49). Studies examining CD28 costimulation have shown that CD4 T cell responses required this signal, but CD8 T cell responses do not require this signal (19). However, B7-dependent signals may be involved in generating CTL responses under certain circumstances, such as for CD4 Th-dependent CTL against cross-priming Ags, H-Y Ags, tumor Ags, or certain viral infections (50, 51, 52). In addition, CD8 T cells from CD28-/- mice proliferate poorly in an in vitro allogeneic model (our unpublished results), which suggests that at least some CD8 T cells may have a requirement for CD28 signals. Other studies have shown that both B7 and 4-1BBL expression on tumors were required to elicit a CTL response and clearance of these poorly immunogenic tumors from mice (42, 53). The results shown in this study indicate that expansion of virus-specific CD8 T cells was lowered a further 2- to 3-fold when signals from either costimulatory interaction were missing, indicating that part of the CD8 T cell response was B7 dependent and part was 4-1BBL dependent. In addition, blockade of both molecules reduced the number of LCMV-specific CD8 T cells even more, suggesting that these pathways, at least in part, operate independently of one another. In addition, both B7- and 4-1BBL-dependent signals are important for effective LCMV-specific CTL responses and expansion of CD8 T cells.
Our results show that 4-1BB costimulation contributes to the generation of LCMV-specific CD8 T cell responses. In addition, 4-1BBL- and B7-dependent signals induce expansion of CD8 T cells, generation of CTLs, and clearance of virus. Future studies should address the role of this interaction in T cell memory and their requirement during chronic viral infections. The importance of this interaction should also be examined in Th-dependent CTL responses to determine whether its expression depends upon other CD4-APC interactions. Recent studies looking at Th-dependent CTL responses (50, 51, 52) have shown that activation of these CTLs require CD40-CD40L interaction. Activation of the APC by CD40-CD40L interaction conditions the APC to activate CTLs. Although there is some evidence that CTL activation after APC conditioning involves B7 (especially B7.2), it may be possible that 4-1BB costimulation is also involved. It would also be interesting to determine in Th-independent infections, whether 4-1BBL is up-regulated on APCs and contributes to the generation of CTL responses in the absence of CD4 T cells.
In summary, our study suggests that in contrast to the CD40 costimulatory pathway, which affects the CD4 response, the 4-1BB pathway preferentially regulates the expansion and differentiation of CD8 T cells. In addition, simultaneous blockade of B7- and 4-1BB-dependent signals reduces both CD8 and CD4 T cell responses and points to these signals as good targets for immunotherapy to boost T cell responses for vaccination or to block and prevent allograft rejection.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Drs. Christian P. Larsen and Thomas C. Pearson, Department of Surgery, Emory University School of Medicine, Room 510S, 1639 Pierre 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; GP, glycoprotein; NP, nucleoprotein; TRAF, TNFR-associated factor.
Received for publication June 1, 1999. Accepted for publication August 24, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production during lymphocytic choriomeningitis virus infection. J. Immunol. 155:5690.[Abstract]
B. Biochem. Biophys. Res. Commun. 242:613.[Medline]
B. Mol. Cell. Biol. 18:558.This article has been cited by other articles:
|
|
 |
|
  G. H. Y. Lin, B. J. Sedgmen, T. J. Moraes, L. M. Snell, D. J. Topham, and T. H. Watts Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease J. Immunol., January 15, 2009; 182(2): 934 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bandyopadhyay, M. Long, H. Z. Qui, A. T. Hagymasi, A. M. Slaiby, M. A. Mihalyo, H. L. Aguila, R. S. Mittler, A. T. Vella, and A. J. Adler Self-Antigen Prevents CD8 T Cell Effector Differentiation by CD134 and CD137 Dual Costimulation J. Immunol., December 1, 2008; 181(11): 7728 - 7737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Robertson, R. J. Messer, A. B. Carmody, R. S. Mittler, C. Burlak, and K. J. Hasenkrug CD137 Costimulation of CD8+ T Cells Confers Resistance to Suppression by Virus-Induced Regulatory T Cells J. Immunol., April 15, 2008; 180(8): 5267 - 5274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Habib-Agahi, T. T. Phan, and P. F. Searle Co-stimulation with 4-1BB ligand allows extended T-cell proliferation, synergizes with CD80/CD86 and can reactivate anergic T cells Int. Immunol., December 1, 2007; 19(12): 1383 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tewari, Y. Nakayama, and M. Suresh Role of Direct Effects of IFN-{gamma} on T Cells in the Regulation of CD8 T Cell Homeostasis J. Immunol., August 15, 2007; 179(4): 2115 - 2125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Lee, R. J. Rossi, S.-K. Lee, M. Croft, B. S. Kwon, R. S. Mittler, and A. T. Vella CD134 Costimulation Couples the CD137 Pathway to Induce Production of Supereffector CD8 T Cells That Become IL-7 Dependent J. Immunol., August 15, 2007; 179(4): 2203 - 2214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, G. Zhu, L. Luo, A. S. Flies, and L. Chen CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype Blood, June 1, 2007; 109(11): 4882 - 4889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fuse, S. Bellfy, H. Yagita, and E. J. Usherwood CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand J. Immunol., April 15, 2007; 178(8): 5227 - 5236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Chow, S. Dhanji, J. Cross, P. Johnson, and H.-S. Teh H2-M3-Restricted T Cells Participate in the Priming of Antigen-Specific CD4+ T Cells J. Immunol., October 15, 2006; 177(8): 5098 - 5104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Lee, Y. Park, A. Song, H. Cheroutre, B. S. Kwon, and M. Croft Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses J. Immunol., October 1, 2006; 177(7): 4464 - 4472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J Sedgmen, W. Dawicki, J. L Gommerman, K. Pfeffer, and T. H Watts LIGHT is dispensable for CD4+ and CD8+ T cell and antibody responses to influenza A virus in mice Int. Immunol., May 1, 2006; 18(5): 797 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wuthrich, P. L. Fisette, H. I. Filutowicz, and B. S. Klein Differential Requirements of T Cell Subsets for CD40 Costimulation in Immunity to Blastomyces dermatitidis J. Immunol., May 1, 2006; 176(9): 5538 - 5547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pulle, M. Vidric, and T. H. Watts IL-15-Dependent Induction of 4-1BB Promotes Antigen-Independent CD8 Memory T Cell Survival. J. Immunol., March 1, 2006; 176(5): 2739 - 2748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Foulds and H. Shen Clonal Competition Inhibits the Proliferation and Differentiation of Adoptively Transferred TCR Transgenic CD4 T Cells in Response to Infection. J. Immunol., March 1, 2006; 176(5): 3037 - 3043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Myers, S. W. Lee, R. J. Rossi, L. Lefrancois, B. S. Kwon, R. S. Mittler, M. Croft, and A. T. Vella Combined CD137 (4-1BB) and adjuvant therapy generates a developing pool of peptide-specific CD8 memory T cells Int. Immunol., February 1, 2006; 18(2): 325 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Kemball, E. D. H. Lee, E. Szomolanyi-Tsuda, T. C. Pearson, C. P. Larsen, and A. E. Lukacher Costimulation Requirements for Antiviral CD8+ T Cells Differ for Acute and Persistent Phases of Polyoma Virus Infection J. Immunol., February 1, 2006; 176(3): 1814 - 1824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Bryce, M. K. Oyoshi, S. Kawamoto, H. C. Oettgen, and E. N. Tsitsikov TRAF1 regulates Th2 differentiation, allergic inflammation and nuclear localization of the Th2 transcription factor, NIP45 Int. Immunol., January 1, 2006; 18(1): 101 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Vidric, W.-K. Suh, U. Dianzani, T. W. Mak, and T. H. Watts Cooperation between 4-1BB and ICOS in the Immune Response to Influenza Virus Revealed by Studies of CD28/ICOS-Deficient Mice J. Immunol., December 1, 2005; 175(11): 7288 - 7296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Serghides, J. Bukczynski, T. Wen, C. Wang, J.-P. Routy, M.-R. Boulassel, R.-P. Sekaly, M. Ostrowski, N. F. Bernard, and T. H. Watts Evaluation of OX40 Ligand as a Costimulator of Human Antiviral Memory CD8 T Cell Responses: Comparison with B7.1 and 4-1BBL J. Immunol., November 15, 2005; 175(10): 6368 - 6377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bukczynski, T. Wen, C. Wang, N. Christie, J.-P. Routy, M.-R. Boulassel, C. M. Kovacs, K. S. MacDonald, M. Ostrowski, R.-P. Sekaly, et al. Enhancement of HIV-Specific CD8 T Cell Responses by Dual Costimulation with CD80 and CD137L J. Immunol., November 15, 2005; 175(10): 6378 - 6389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R Blazar and W. J Murphy Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD) Phil Trans R Soc B, September 29, 2005; 360(1461): 1747 - 1767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hendriks, Y. Xiao, J. W. A. Rossen, K. F. van der Sluijs, K. Sugamura, N. Ishii, and J. Borst During Viral Infection of the Respiratory Tract, CD27, 4-1BB, and OX40 Collectively Determine Formation of CD8+ Memory T Cells and Their Capacity for Secondary Expansion J. Immunol., August 1, 2005; 175(3): 1665 - 1676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Lee, A. T. Vella, B. S. Kwon, and M. Croft Enhanced CD4 T Cell Responsiveness in the Absence of 4-1BB J. Immunol., June 1, 2005; 174(11): 6803 - 6808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Williams and M. J. Bevan Shortening the Infectious Period Does Not Alter Expansion of CD8 T Cells but Diminishes Their Capacity to Differentiate into Memory Cells J. Immunol., December 1, 2004; 173(11): 6694 - 6702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Dawicki, E. M. Bertram, A. H. Sharpe, and T. H. Watts 4-1BB and OX40 Act Independently to Facilitate Robust CD8 and CD4 Recall Responses J. Immunol., November 15, 2004; 173(10): 5944 - 5951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Florido, M. Borges, H. Yagita, and R. Appelberg Contribution of CD30/CD153 but not of CD27/CD70, CD134/OX40L, or CD137/4-1BBL to the optimal induction of protective immunity to Mycobacterium avium J. Leukoc. Biol., November 1, 2004; 76(5): 1039 - 1046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Carrio, O. F. Bathe, and T. R. Malek Initial Antigen Encounter Programs CD8+ T Cells Competent to Develop into Memory Cells That Are Activated in an Antigen-Free, IL-7- and IL-15-Rich Environment J. Immunol., June 15, 2004; 172(12): 7315 - 7323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. H. Doody, J. T. Kovalchin, M. A. Mihalyo, A. T. Hagymasi, C. G. Drake, and A. J. Adler Glycoprotein 96 Can Chaperone Both MHC Class I- and Class II-Restricted Epitopes for In Vivo Presentation, but Selectively Primes CD8+ T Cell Effector Function J. Immunol., May 15, 2004; 172(10): 6087 - 6092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bansal-Pakala, B. S. Halteman, M. H.-Y. Cheng, and M. Croft Costimulation of CD8 T Cell Responses by OX40 J. Immunol., April 15, 2004; 172(8): 4821 - 4825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Bertram, W. Dawicki, B. Sedgmen, J. L. Bramson, D. H. Lynch, and T. H. Watts A Switch in Costimulation from CD28 to 4-1BB during Primary versus Secondary CD8 T Cell Response to Influenza In Vivo J. Immunol., January 15, 2004; 172(2): 981 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Finney, A. N. Akbar, and A. D. G. Lawson Activation of Resting Human Primary T Cells with Chimeric Receptors: Costimulation from CD28, Inducible Costimulator, CD134, and CD137 in Series with Signals from the TCR{zeta} Chain J. Immunol., January 1, 2004; 172(1): 104 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Wilcox, K. Tamada, D. B. Flies, G. Zhu, A. I. Chapoval, B. R. Blazar, W. M. Kast, and L. Chen Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo Blood, January 1, 2004; 103(1): 177 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hendriks, Y. Xiao, and J. Borst CD27 Promotes Survival of Activated T Cells and Complements CD28 in Generation and Establishment of the Effector T Cell Pool J. Exp. Med., November 3, 2003; 198(9): 1369 - 1380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Wiethe, K. Dittmar, T. Doan, W. Lindenmaier, and R. Tindle Provision of 4-1BB Ligand Enhances Effector and Memory CTL Responses Generated by Immunization with Dendritic Cells Expressing a Human Tumor-Associated Antigen J. Immunol., March 15, 2003; 170(6): 2912 - 2922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Shedlock, J. K. Whitmire, J. Tan, A. S. MacDonald, R. Ahmed, and H. Shen Role of CD4 T Cell Help and Costimulation in CD8 T Cell Responses During Listeria monocytogenes Infection J. Immunol., February 15, 2003; 170(4): 2053 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
Y.-J. Kim, R. R. Brutkiewicz, and H. E. Broxmeyer Role of 4-1BB (CD137) in the functional activation of cord blood CD28-CD8+ T cells Blood, October 16, 2002; 100(9): 3253 - 3260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
H. Harlin, E. Podack, M. Boothby, and M.-L. Alegre TCR-Independent CD30 Signaling Selectively Induces IL-13 Production Via a TNF Receptor-Associated Factor/p38 Mitogen-Activated Protein Kinase-Dependent Mechanism J. Immunol., September 1, 2002; 169(5): 2451 - 2459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Chan, C. D. Hopke, S. M. Krams, and O. M. Martinez CD30 Expression Identifies the Predominant Proliferating T Lymphocyte Population in Human Alloimmune Responses J. Immunol., August 15, 2002; 169(4): 1784 - 1791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Miller, J. Jones, T. Le, J. Whitmore, N. Boiani, B. Gliniak, and D. H. Lynch 4-1BB-Specific Monoclonal Antibody Promotes the Generation of Tumor-Specific Immune Responses by Direct Activation of CD8 T Cells in a CD40-Dependent Manner J. Immunol., August 15, 2002; 169(4): 1792 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 P C L Beverley Immunology of vaccination Br. Med. Bull., July 1, 2002; 62(1): 15 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Christensen, J. P. Christensen, N. N. Kristensen, N. J. V. Hansen, A. Stryhn, and A. R. Thomsen Role of CD28 co-stimulation in generation and maintenance of virus-specific T cells Int. Immunol., July 1, 2002; 14(7): 701 - 711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. A. Wilcox, A. I. Chapoval, K. S. Gorski, M. Otsuji, T. Shin, D. B. Flies, K. Tamada, R. S. Mittler, H. Tsuchiya, D. M. Pardoll, et al. Expression of Functional CD137 Receptor by Dendritic Cells J. Immunol., May 1, 2002; 168(9): 4262 - 4267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
T. Futagawa, H. Akiba, T. Kodama, K. Takeda, Y. Hosoda, H. Yagita, and K. Okumura Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells Int. Immunol., March 1, 2002; 14(3): 275 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Lee, S. K. Reiter, M. Anderson, and S. R. Sarawar CD28-/- Mice Show Defects in Cellular and Humoral Immunity but Are Able To Control Infection with Murine Gammaherpesvirus 68 J. Virol., February 22, 2002; 76(6): 3049 - 3053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Dadgostar, B. Zarnegar, A. Hoffmann, X.-F. Qin, U. Truong, G. Rao, D. Baltimore, and G. Cheng Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes PNAS, February 5, 2002; 99(3): 1497 - 1502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Suresh, J. K. Whitmire, L. E. Harrington, C. P. Larsen, T. C. Pearson, J. D. Altman, and R. Ahmed Role of CD28-B7 Interactions in Generation and Maintenance of CD8 T Cell Memory J. Immunol., November 15, 2001; 167(10): 5565 - 5573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
K. H. Edelmann and C. B. Wilson Role of CD28/CD80-86 and CD40/CD154 Costimulatory Interactions in Host Defense to Primary Herpes Simplex Virus Infection J. Virol., January 15, 2001; 75(2): 612 - 621. [Abstract] [Full Text]
|
|
|
|
|
|
M. A. Williams, J. Trambley, J. Ha, A. B. Adams, M. M. Durham, P. Rees, S. R. Cowan, T. C. Pearson, and C. P. Larsen Genetic Characterization of Strain Differences in the Ability to Mediate CD40/CD28-Independent Rejection of Skin Allografts J. Immunol., December 15, 2000; 165(12): 6849 - 6857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
B. R. Blazar, C. J. Lees, P. J. Martin, R. J. Noelle, B. Kwon, W. Murphy, and P. A. Taylor Host T Cells Resist Graft-Versus-Host Disease Mediated by Donor Leukocyte Infusions J. Immunol., November 1, 2000; 165(9): 4901 - 4909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
