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Department of Experimental Medicine, University of Perugia, Perugia, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1ß, or IFN-
,
ablated the enhancing effect of CD40 engagement on the APC function of
DC. These data suggest a major role for autocrine IL-12 in DC
modulation via CD40 ligation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(7), and IL-1ß
(8). We have previously shown that IL-12 primes dendritic cells (DC)3 in vitro for effective presentation of a poorly immunogenic tumor peptide upon transfer of the DC into recipient hosts (9, 10, 11). Nonameric P815AB represents a minimal core peptide recognized by CTL in vitro and is part of a protein encoded by gene P1A which, silent in most normal tissues except testis and placenta, is instead expressed by murine mastocytoma cells (11). We have previously shown that P815AB fails to initiate class I-restricted reactivity in vivo, presumably as a result of a poor ability to recruit CD4+ cells to the afferent induction of the response initiated by host transfer with P815AB-pulsed DC (9). However, the poor immunogenicity of the peptide under such priming conditions can be overcome by preexposure of the DC to rIL-12 (10).
The aim of the present study was to investigate whether CD40 engagement
on DC may also prime the cells for effective presentation of the tumor
peptide. By comparing CD40 ligation and rIL-12, we found that the
former stimulus was highly effective in priming DC, and that rIL-12
concentrations in the range of those induced by CD40 cross-linking
would likewise be an effective stimulus for DC priming. Most
interestingly, the presence of Ab to IL-12 during cross-linking in
vitro blocked the adjuvant effect of CD40 modulation in the DC. In
contrast, no effect was afforded by neutralization of TNF-, IL-1ß,
or IFN-. These data suggest an important role for autocrine IL-12 in
the adjuvant effect of CD40 engagement on DC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male DBA/2J (H-2d) mice were obtained from Charles
River Laboratories (Calco, Milan, Italy) and were used at the age of
2–4 mo. Murine rIL-12 was a generous gift from Dr. B. Hubbard
(Genetics Institute, Cambridge, MA). IL-12 was 98.8% pure, as assessed
by SDS-PAGE, and endotoxin contamination was <0.9 EU/mg on
Limulus amebocyte assay. The specific activity of the
purified rIL-12 preparation, measured as ability to stimulate
proliferation in human PHA-activated blasts, was 3.1 x
106 U/mg. Endotoxin was removed from all solutions
containing rIL-12 or anti-CD40 Abs with Detoxi-gel (Pierce
Chemical, Rockford, IL), resulting in endotoxin contamination below the
detection limit (0.05 EU/ml) of the assay (Coatest Endotoxin,
Chromogenix, Mölndal, Sweden) (12). Rat
anti-mouse IL-12 p40 mAb C17.8 and hamster anti-mouse IL-12 p35
(clone Red-T) were from Genzyme (Cambridge, MA). C17.8 mAb was
conjugated to biotin using conventional methods. Hamster
anti-murine CD40 (HM40-3) was from PharMingen (San Diego, CA) and
goat anti-hamster IgG was from Pierce Chemical. Affinity-purified
sheep anti-mouse IL-12 polyclonal Ab was generously provided by the
Immunology Department of Genetics Institute, and the control Ab (sheep
IgG) was purchased from Pierce Chemical. Neutralizing rat
anti-mouse TNF- (MP6-XT3, PharMingen), hamster anti-mouse
IL-1ß (Genzyme), and rat anti-mouse IFN- (XMG1.2)
(10) mAbs were also used. The nonameric P815AB peptide
(LPYLGWLVF) was synthesized and purified as described
(13).
DC preparation and in vitro treatments
DC were prepared from collagenase-treated spleens (collagenase type IV, Sigma Chemical, St. Louis, MO), as described (12). Briefly, DC were purified using a positive selection column and CD11c MicroBeads (Milten-yi Biotec, Bergisch Gladbach, Germany). The recovered cells were routinely >98% N418+. For CD40 cross-linking (14), DC were incubated on ice for 10 min in PBS plus 10% mouse serum, for 20 min with hamster anti-mouse CD40 mAb (5 µg/ml), and then overnight at 37°C with goat anti-hamster Ab (5 µg/ml) in Iscove’s medium plus 10% FCS. For IL-12 activation (9, 10), cells were incubated overnight with different concentrations of rIL-12. With both procedures, cells were washed between and after the incubations prior to peptide loading (5 µM, 2 h, at 37°C), irradiation, and i.v. injection (3 x 105/mouse) into recipient hosts, as described (9, 10).
Detection of IL-12 p70 in DC culture supernatants
Culture supernatants of DC (2 x 106/ml)
recovered at the end of the cross-linking procedure were assayed for
IL-12 p70 contents by ELISA using anti-p35 and biotinylated
anti-p40 mAbs (12). The sensitivity limit of this
assay was 
0.015 ng/ml. In measuring IL-12 induction by rIL-12 with
or without anti-CD40 Abs, the overnight cultures were washed
and incubated for 24 h in fresh medium alone, IL-12 p70 titers
being measured at 1 and 24 h.
Skin test assay
An assay system for measuring the class I-restricted DTH response was employed in which 50 µg of P815AB peptide in 30 µl of 6% DMSO in saline were inoculated into the left hind footpads of mice transferred with DC 2 wk earlier (15). The right hind footpad received the same volume of vehicle. The DTH reaction was recorded 24 h later, when the animals were killed, their hind feet were cut off at the hair line, and weights were recorded as a measure of swelling, edema, and cellular infiltration. Results were expressed as the increase in footpad weight over that in the vehicle-injected counterpart. Data are the means ± SD for at least six mice per group. The statistical analysis was performed using Student’s paired t test by comparing the mean weight of experimental footpads with that of control, vehicle-injected counterparts (9, 10, 15). The data reported are from representative experiments, and experiments with similar results were performed three to six times.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a preliminary series of experiments, we wanted to examine DC
production of IL-12 upon ligation of CD40 and to determine the
quantitative expression of this production. Highly purified DC cultures
were established from the spleens of DBA/2 mice, and the cells were
subjected to overnight cross-linking with hamster anti-mouse CD40
Ab plus goat anti-hamster Ab (14). The release of
IL-12 p70 was measured by ELISA at the end of the overnight
cross-linking (Table I
). In three
different experiments, the range for IL-12 production under the adopted
conditions was 0.41–5.64 ng/ml of p70 heterodimer. The baseline
production of unstimulated DC was 0.06–0.18 ng/ml.
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We have previously shown that transfer of DC sequentially exposed
to IL-12 and a tumor peptide (P815AB) initiates cell-mediated immunity
detectable by skin test assay at 2 wk after cell transfer
(9, 10, 11). In this model system, the adoptively transferred
mice are challenged intrafootpad with P815AB and the extent of the
footpad response, which requires CD4+ cells for afferent
induction (9) but is mediated by CD8+ effector
cells (9, 13), is taken as an indication of the APC
function of the DC. Under these conditions, IL-12 is most effective in
priming DC for presentation of P815AB in vivo (11).
We therefore wanted to examine whether CD40 ligation on the
DC would substitute for externally added IL-12 in the adjuvanticity for
P815AB priming. Following overnight cross-linking as indicated above,
the DC were loaded with P815AB and then injected into recipient hosts
that were assayed at 2 wk for footpad reactivity to the tumor peptide.
Fig. 1 shows that CD40 ligation was
highly effective in DC priming for P815AB presentation in vivo. We also
examined whether IL-12 added in concentrations of the same order of
magnitude as those found in supernatants of CD40-modulated cells
could result in DC activation in the in vivo assay. Fig. 1 shows that
IL-12 at concentrations 
1 ng/ml would result in skin test
responsiveness similar to that associated with anti-CD40 mAb
stimulation or with the use of 100 ng/ml IL-12, a concentration
routinely used in our previous experimentation
(9, 10, 11).
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The finding that CD40 engagement, which is known to induce IL-12
release by DC, and rIL-12 exert similar adjuvanticity on DC prompted us
to investigate the possibility that endogenous IL-12 is involved in the
effect of CD40 ligation. Anti-IL-12 Ab or control sheep IgG were added
to the cultures of DC during stimulation with anti-CD40 mAb. Cells
were then pulsed with the tumor peptide prior to injection into mice
that were assayed at 2 wk for skin test reactivity to the peptide. Fig. 2 shows that the anti-IL-12 Ab, but
not control IgG, would completely block the adjuvant effect of CD40
engagement on DC.
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, IL-1ß, or IFN- neutralization on
anti-CD40 mAb-induced adjuvanticity
Because TNF- (7) and IL-1ß (8) are
known to be induced by CD40 ligation, Abs to these cytokines as well as
to IFN- (which is known to synergize with CD40 ligation)
(16) were assayed for possible interference with the
effect of CD40 cross-linking. Equal concentrations (10 µg/ml) of each
of these mAbs or anti-IL-12 Ab were added to the DC cultures in
concurrence with CD40 stimulation. The recovered cells were then loaded
with the peptide and used in the in vivo assay. Fig. 3 shows that neutralization of TNF-,
IL-1ß, or IFN- did not affect the APC function of CD40-modulated
DC. Again, the response was completely blocked by the use of
anti-IL-12 Ab during CD40 stimulation.
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Similarly to CD40 engagement, rIL-12 induces the production of
IL-12 by DC cultures (12). We therefore became interested
in ascertaining the combined effects of rIL-12 and CD40 cross-linking
on this production. We measured p70 titers in culture supernatants of
DC treated overnight with anti-CD40 Abs, rIL-12 (100 ng/ml), or a
combination of both and then washed extensively prior to incubation in
medium alone for an additional 24 h. Supernatants were harvested
at 1 and 24 h. No IL-12 was found in any group at 1 h, thus
excluding the presence of residual cytokine bound or internalized by
the cultures. Under the adopted conditions of testing, the production
of IL-12 by CD40-modulated DC was rather limited, approximately
one-third of that induced by rIL-12 alone (Table II). Remarkably, coexposure to
anti-CD40 Abs and rIL-12 led to a 3.6-fold increase in this
production.
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The finding of synergic effects between anti-CD40 Abs and
rIL-12 on IL-12 production prompted us to investigate the combined
effects of the two modalities of DC activation on P815AB presentation
in vivo. Using an experimental model similar to that adopted in Fig. 1
, DC exposed to different concentrations of rIL-12 and/or CD40
cross-linking were loaded with P815AB and then injected into recipient
hosts that were assayed at 2 wk for footpad reactivity to the tumor
peptide. Fig. 4 shows that CD40 ligation
apparently increased the ability of rIL-12 to trigger footpad
reactivity to P815AB. However, with the lowest IL-12 concentration
(i.e., 0.1 ng/ml), the extent of the footpad response resulting from
concomitant CD40 ligation was not significantly different from that of
the latter treatment alone.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DC are professional APC specialized in Ag capture, migration to
secondary lymphoid organs, and T cell priming (17, 18).
One major function of DC is the production of IL-12 (19).
This production is up-regulated via MHC class II and CD40 signaling and
down-regulated by Th2 cytokines (20). A recent report from
our laboratory has shown that not only are DC a major cell type
producing IL-12 but they also express a high affinity receptor for
IL-12 (12). Signaling through this receptor leads to
nuclear localization of NF-
B and changes in DC function, including
expression of a greater amount of fully mature class II molecules
despite a decline in class II
biosynthesis.4 Activation of DC
through IL-12 exposure also confers increased APC function on these
cells, resulting in effective presentation of a tumor peptide following
transfer of peptide-loaded DC into recipient hosts
(9, 10, 11).
Because DC respond to stimulation via CD40 signaling by producing very high levels of bioactive IL-12 (5), the possibility exists that the endogenously produced IL-12 affects T cell activation not only in a paracrine fashion but also via direct effects on the CD40-modulated DC. In addition, because activation of the IL-12R and CD40 engagement appear to share signaling pathways in APC (12, 21), it is possible that IL-12 mediates, contributes to, or interferes with the modulation of DC activity via CD40 ligation.
Transfer of DC exposed in vitro to IL-12 and the tumor peptide P815AB
confers CD8+ cell-mediated reactivity on prospective
recipients of an intrafootpad challenge with the peptide, which is
accompanied by increased resistance to challenge with tumor cells
expressing the otherwise poorly immunogenic rejection Ag P815AB
(11). To investigate possible effects of CD40 engagement
on the APC function of DC, we resorted to this experimental model by
exposing DC to CD40 cross-linking prior to peptide loading in vitro. We
found that this maneuver resulted in an adjuvanticity comparable with
that induced by treatment with rIL-12 (Fig. 1). To ascertain whether
endogenous IL-12 is involved in the adjuvanticity associated with CD40
cross-linking, we measured IL-12 concentrations in supernatants of
CD40-modulated DC and used the same range of rIL-12 concentrations for
DC activation (Table I and Fig. 1). We found that these concentrations
were fully capable of activating DC, thus suggesting that endogenous
IL-12 might contribute to the effects of CD40 engagement.
In addition to IL-12, the cytokines TNF- (7) and
IL-1ß (8) are also known to be induced by CD40
signaling. IFN-, on the other hand, is known to synergize with CD40
engagement in modulating DC activity (16). It appeared
therefore of interest to analyze the effects of IL-12 neutralization on
the adjuvanticity associated with CD40 engagement and to compare these
effects with those of Abs to TNF-, IL-1ß, or IFN-. We found
that the presence of anti-IL-12 Ab, but not of anti-TNF-,
anti-IL-1ß, or anti-IFN- mAbs, completely blocked the
adjuvant effect of CD40 stimulation in the priming to P815AB (Figs. 2 and 3). This suggests that, at least in terms of improved APC function,
the endogenous production of IL-12 acting in an autocrine fashion is
responsible for most of the effect resulting from CD40 signaling.
Alternatively, although less likely, a basal production of IL-12 by DC,
as observed in Table I, might be a necessary costimulus for modulation
of DC. If so, the mere engagement of CD40 would be an insufficient
stimulus for increasing the APC function of DC.
Although the present data seem to indicate that IL-12 mediates the
effect of CD40 cross-linking in the model of peptide presentation in
vivo, indirect evidence suggests that the two mechanisms of DC
modulation, IL-12-mediated activation and CD40 engagement, may be
operationally distinct relative to other DC functions. Considering that
rIL-12 induces the production of IL-12 by DC (12), we have
tested the effect of rIL-12 exposure and CD40 cross-linking, either
alone or in combination, on the production of IL-12. We have found that
the combined modality of DC activation resulted in IL-12 levels much
higher than either maneuver alone (Table II). Furthermore, we have been
able to detect DC functions that are differentially affected by CD40
modulation and rIL-12, including B7-1 expression. While boosted by CD40
ligation, this expression is not modified by DC exposure to rIL-12
(Ref. 12 and our unpublished observations). On the other hand, the
combined modality of DC activation (CD40 cross-linking plus IL-12
treatment) resulted in only a limited increase in the effect of rIL-12
alone on tumor peptide presentation in vivo (Figs. 1 and 4). This could
be due to the remarkable potency of IL-12 in the activation of the in
vivo response, with nearly maximal responses being induced by
relatively low IL-12 concentrations. In order to clarify this issue, we
are currently investigating the combined effects of CD40 ligation and
rIL-12 on a series of in vivo functions, including resistance to
challenge with P815AB-expressing tumor cells and generation of CTL
activity.
In addition to previous evidence that the CD40-CD40 ligand interaction represents an important means by which T-T help occurs via APC activation (5, 22, 23) and a temporal bridge between CD4+ and CD8+ cells (12, 24), our data suggest that bidirectional influences take place between T cells and APC via IL-12 release at the site of T cell priming. The IL-12 released as a consequence of CD40 engagement may condition not only the developing Th response, but also the DC to differentiate to a state in which they may express a greater amount of fully mature class II molecules (see Footnote 4). Improved presentation of class II-restricted epitopes of P815AB to CD4+ cells is, in fact, a likely mechanism through which rIL-12 primes DC for effective presentation of the tumor peptide (10). As a whole, the present findings suggest a new role for CD40 ligation in regulating DC function and may be relevant to the design of therapeutic strategies using cultured DC.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Paolo Puccetti, Department of Experimental Medicine, Pharmacology Section, University of Perugia, Via del Giochetto, I-06126 Perugia, Italy. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cell(s); DTH, delayed-type hypersensitivity.
4 U. Grohmann, C. Orabona, R. Bianchi, M. L. Belladonna, M. C. Fioretti, and P. Puccetti. IL-12 induces SDS-stable class II ß dimers in murine dendritic cells. Submitted for publication.
Received for publication April 29, 1999. Accepted for publication June 15, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production and diminishes IL-4 inhibition of such priming. Proc. Natl. Acad. Sci. USA 90:10188.B and primes DC for IL-12 production. Immunity 9:315.[Medline]
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