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Departments of
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Immunohematology and Blood Transfusion and
Rheumatology, Leiden University Medical Center, Leiden, The Netherlands; and
Divisions of Immunology, Cellular Biochemistry, and Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In general, systemic and persistent exposure of T cells to Ag in the absence of costimulation tends to result in T cell tolerization, whereas local expression of lower doses of Ag can lead to T cell activation. For example, lymphocytic choriomeningitis virus (LCMV)4 strains that cause rapid and overwhelming infections in the lymphoid organs exhaust the antiviral CTL response completely, whereas slowly replicating LCMV strains induce long-lasting immunity (6). Furthermore, mice injected repetitively and systemically with high doses of an LCMV-glycoprotein-derived peptide are no longer able to induce glycoprotein-specific CTL responses after subsequent LCMV infection. However, when administered s.c. in IFA at lower doses, specific immunity is induced by this peptide (7).
Apart from the Ag, the type and level of costimulation received during first encounter with Ag are key determinants in the outcome of an immune response. This depends largely on the activation status of the professional APC that present the antigenic peptide to naive T cells. The costimulatory state of professional APC is promoted by activated CD4+ Th cells, in particular by interaction between CD40L on Th cells and CD40 on the APC (8, 9, 10, 11). This type of T cell help is essential for CTL induction under noninflammatory conditions, whereas lack of CD4+ T cell help can lead to CTL tolerization (1). For example, naive OVA-specific CTL are rendered tolerant when transferred to transgenic mice that express a membrane-bound form of OVA in pancreatic islets. In contrast, autoimmunity is induced when OVA-specific Th cells are injected as well, indicating that the presence of helper activity favors the induction of an effective CTL response (12). We and others have shown that provision of T cell help through triggering of CD40 in vivo converts a tolerizing peptide vaccine into a vaccine that induces specific CTL immunity (5, 13). Direct demonstration that the activation status of APC influences the outcome of Ag recognition by CD8+ T cells was obtained in studies in which vaccination with mature dendritic cell (DC) induced CTL immunity, whereas infusion of immature DC failed to do so (10, 14).
The general picture emerges that long, systemic expression of high dose Ag and expression on nonprofessional or immature APC render naive T cells unresponsive, whereas T cell responses are promoted when Ag is presented locally in low doses and in an environment that leads to activation of APC.
The conditions involved in setting the balance between tolerance and immunity seem to be different for activated T cells, because circumstances that tolerize naive T cells may not be tolerogenic for memory T cells. For example, treatment of naive mice with a peptide derived from LCMV results in specific T cell tolerance, whereas the same treatment in LCMV-immune mice induces severe immunopathological damage (15). These findings indicate that T cells, once activated, may become resistant to signals that tolerize naive T cells.
It is not known, however, how T cell immunity develops when naive T cells are primed instead of tolerized, in case conditions that normally induce tolerance are reverted into conditions that promote a T cell response. Such a transition could, for example, be a consequence of activation of APC after exposure to strong inflammatory stimuli (16). Previously, we have shown that combination of a tolerogenic peptide vaccine, containing a minimal essential CTL epitope, with an activating Ab against CD40 converts CTL tolerization into strong CTL priming (13). We have now studied the longevity of this CTL response. Surprisingly, the CTL induced by the peptide/CD40 vaccine finally disappeared. Ultimate tolerization of the CTL was strongly associated with the remarkably persistent and systemic presentation of the peptide.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All in vitro cultures and assays were performed in IMDM (Life Technologies, Gaithersburg, MD) supplemented with 8% FCS, 50 µM 2-ME, glutamine, and penicillin.
The D1 cell line, a long-term, growth factor-dependent immature splenic DC line derived from C57BL/6 mice, was cultured as described (17).
Mice
C57BL/6 (H-2b) mice were purchased from IFFA Credo (Paris,
France). Strain 42 mice are TCR-transgenic mice expressing the TCR 
-
and 
-chains derived from the H-2Db-restricted,
Ad5E1A234–243-specific CTL clone 5 (18, 19).
Vaccinations
Peptides Ad5E1A234–243 (sequence SGPSNTPPEI; E1A peptide) or HPV16 E749–57 (sequence RAHYNIVTF; control peptide) were dissolved in DMSO and diluted in PBS. For peptide vaccination, mice were injected s.c. with 100 µl peptide (20 µg) diluted in PBS mixed to 100 µl IFA or with 20 µg E1A peptide diluted in 200 µl PBS.
For CD40 activation, mice received 100 µg of the CD40-activating Ab FGK-45 given i.v. in 200 µl PBS on days 0, 1, and 2 after peptide vaccination (20). Polyriboinosinate-polyribocytidylate (poly(I:C); 100 µg; Sigma, St. Louis, MO) was injected i.p. in 200 µl PBS on days 0, 1, and 3 and subsequently twice a week. Ad5ts125 (1 x 108 PFU; Ref. 21) was injected i.m. in the hind leg.
For induction of CTL responses using the DC cell line D1 as source of DCs, untreated D1 cells or D1 cells treated for 48 h with 30 µg/ml FGK-45 or 10 µg/ml poly(I:C), were loaded with E1A peptide for 2 h at 37°C and washed five times. D1 cells (106) were injected i.v. in PBS.
Tumor challenge
In tumor challenge experiments, C57BL/6 mouse embryo cells, which express Ad5E1A and EJras (18), were collected and washed in PBS; 107 cells were injected s.c. into C57BL/6 mice. Tumor volumes were measured with a caliper. Mice were sacrificed when their tumors grew larger than 1000 mm3.
Cytotoxicity assay
Splenocytes from immunized mice were cocultured at a
concentration of 5 x 106 cells/well with
irradiated Ad5E1-transformed stimulator cells at a ratio of 10:1 in
24-well plates. After 6 days of coculture, viable lymphocytes were
collected and tested for cytotoxicity on
Eu3+-labeled target cells as described
(22). Untransformed C57BL/6 mouse embryo cells that had
been treated with IFN-
for 48 h were used as target cells. The
mean percentage specific lysis of triplicate wells was calculated as:
% specific lysis = [(cpm experimental well - cpm
spontaneous release)/(cpm maximal release - cpm spontaneous
release)] x 100. The SD of triplicates was in all cases <5%. In
each experiment, two mice per group were tested.
Flow cytometry analysis
PE-conjugated E1A234–243-loaded H-2Db tetramers were prepared as described (23, 24) with the following modifications. During the refolding and subsequent purification steps, a mixture of protease inhibitors (Boehringer Mannheim, Mannheim, Germany) was added. BSA and glycerol were added to final concentrations of 0.5% and 16%, respectively. Tetramers were aliquoted, stored frozen, and used at a final concentration of 5–10 µg/ml. Directly conjugated APC-labeled mAb against CD8 was used (BD PharMingen, San Diego, CA). Data acquisition and analysis were performed on a FACScan (BD Biosciences, San Jose, CA) using CellQuest software (BD Biosciences).
CFSE labeling and proliferation assay
Spleen and lymph node cells from E1A-specific TCR-transgenic strain 42 mice were isolated. Erythrocytes were depleted by ammonium chloride treatment. Spleen and lymph node cells were washed in cold PBS and incubated with 0.5 µM CFSE (Molecular Probes, Eugene, OR) in PBS at 37°C for 30 min; 5% FCS was added, and the cells were washed twice in PBS. Cell suspensions containing 4 x 106 E1A-specific CD8+ T cells were injected i.v. Three days later, spleen and lymph node cells were analyzed for the presence of CFSE-labeled CD8+ strain 42 cells by FACS analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice injected s.c. with the Ad5E1A-derived CTL epitope SGPSNTPPEI
(E1A peptide) in IFA are no longer able to generate E1A-specific CTL
responses, resulting in outgrowth of E1A-expressing tumors
(18). Remarkably, when this tolerogenic peptide vaccine is
combined with CD40 ligation in vivo, which "empowers" professional
APC to prime CTL, no CTL tolerance is observed. Instead, vaccinated
animals generate strong E1A-specific CTL immunity (Fig. 1
; Ref. 13). To determine
whether reversal of a tolerizing environment into a milieu that
supports efficient CTL priming is sufficient to induce long term
tumor-protective CTL activity, we challenged vaccinated mice with
E1A-expressing tumor cells. Vaccination with live adenovirus, as
control, completely protected against tumor outgrowth. Mice that had
received E1A peptide in adjuvant only developed tumors more rapidly
than mock vaccinated mice (Fig. 2) due to
the induction of E1A-specific tolerance (18).
Intriguingly, mice immunized with E1A peptide in combination with CD40
ligation were able to prevent tumor outgrowth for a longer time than
peptide-vaccinated mice, but eventually all E1A peptide/CD40-treated
animals developed a lethal tumor (Fig. 2). Anti-CD40 or control peptide
alone did not have beneficial effects on tumor growth (data not shown).
Thus, although a strong E1A-specific CTL response was induced following
peptide/CD40-vaccination, this response was not sufficient to mount
long-lasting antitumor immunity.
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A, 10 days after vaccination the number of E1A-specific CTL
generated by the peptide/CD40 vaccine was comparable to the number of
CTL elicited by vaccination with live adenovirus. The CTL expanded on
restimulation in vitro equally well (Fig. 1B) and exerted
strong effector functions as measured in a cytotoxicity assay (Fig. 1C). Likewise, phenotypic analyses of E1A-specific CTL
revealed no differences between peptide/CD40- and virus-activated CTL.
Both TCR avidity and level of CD8 expression were comparable between
adenovirus and peptide/CD40-primed CTL, as evidenced by the tetramer
stainings shown in Fig. 1A. Furthermore, similar levels of
CD44, CD62L, CD45RB, and CD49d were detected in the
CD8+, tetramer+ population
(data not shown). Thus, no apparent functional, quantitative, or
phenotypical differences were observed between CTL primed by
adenovirus- and peptide/CD40 vaccination 10 days after injection. Rapid decline of peptide-induced E1A-specific CTL activity
Because no overt phenotypic or quantitative abnormalities of
E1A-specific CTL were found, we analyzed whether loss of E1A-specific
CTL activity in time could have contributed to the inability to install
long term protection. To this end, we analyzed the CTL response induced
by the peptide/CD40 vaccine 30 days after vaccination. At this time
point, E1A-specific CTL were readily detected in virus-vaccinated mice.
In contrast, no specific CTL were detectable in spleen or lymph nodes
of mice vaccinated with the E1A peptide/CD40 vaccine as determined
directly ex vivo by tetramer staining (data not shown). Even when
splenocytes derived from E1A peptide/CD40-vaccinated animals were
restimulated with E1A-expressing tumor cells in vitro, a procedure that
leads to strong expansion of E1A-specific CTL, no E1A-directed CTL
response was detected phenotypically by tetramer staining (Fig. 3A) or functionally in a cytotoxicity
assay (Fig. 3B). Apparently, all E1A-specific CTL reactivity
had disappeared from E1A peptide/CD40-vaccinated mice. Taken together,
these data show that E1A-specific CTL, activated upon E1A
peptide/CD40-vaccination, are eventually tolerized despite the fact
that their initial appearance is indistinguishable from CTL induced
after adenovirus vaccination. As a consequence, peptide/CD40-vaccinated
mice are unable to control tumor-outgrowth.
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The finding that E1A peptide vaccination in combination
with CD40 ligation mounts strong, but transient CTL immunity is
intriguing and could be explained in several ways. Loss of E1A-specific
CTL activity on peptide/CD40 vaccination could, for example, be
explained by inappropriate APC activation after CD40 triggering, by
transient APC activation because of APC turnover, or by altered TCR
triggering by the E1A peptide. However, CD40 triggering did not
negatively affect the capacity of live adenovirus to elicit
E1A-specific CTL immunity, because equally efficient induction of
effector and memory CTL was obtained either with or without
coadministration of the agonistic anti-CD40 Ab (data not shown). In
addition, vaccination with peptide-loaded DC, which had been matured in
vitro by the activating anti-CD40 Ab, generated long term
E1A-specific CTL (Fig. 4). Moreover,
vaccination with peptide-loaded (splenic or bone marrow derived) DC
resulted in long term E1A-specific CTL immunity and tumor protection
(25). Together, these data indicate that neither the CD40
stimulus nor an intrinsic feature of the E1A peptide hampered the
induction of a full blown, long-lasting and tumor-protective CTL
response.
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). When E1A peptide
vaccination was combined with poly(I:C) treatment, a strong
E1A-specific CTL response was induced by day 10 as measured by both
tetramer staining (data not shown) and cytotoxicity in vitro (Fig. 5A). These data indicate that
poly(I:C) treatment, like CD40 ligation, is able to switch tolerance
induction to immunity, most likely through activation of peptide-loaded
APC. However, prolonged systemic poly(I:C) treatment together with the
E1A peptide vaccine did not result in E1A-specific CTL memory, because
no CTL were detected by tetramer staining or in vitro cytotoxicity
(Fig. 5B) and no tumor protection was observed in these mice
(Fig. 5C). Thus, we conclude that the observed CTL
tolerization is not due to abberant APC function.
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Because the final outcome of T cell responses is dictated not only
by APC-T cell interactions but also by the dynamics of Ag encounter
(2, 3), we have investigated whether the duration of Ag
presentation could explain why no memory was installed after initial
CTL priming and expansion. We therefore determined the duration of
peptide presentation to CTL. To this end, we used CFSE-labeled cells
derived from mice, which carry a transgenic TCR specific for the E1A
peptide. To investigate how long the peptide was present in the
periphery, we administered the CFSE-labeled T cells to C57BL/6 mice at
various time intervals after s.c. injection of the E1A peptide in IFA.
Three days later, cell division of the TCR-transgenic cells was
analyzed by FACS. Because the CFSE-labeled cells start to proliferate
only when triggered by their specific Ag (data not shown), detection of
divided cells by FACS analysis reveals the presence of the E1A-Ag in
the mouse. Strikingly, these experiments showed that the E1A peptide
persisted for a very long time, because CFSE-labeled cells infused 209
days after peptide administration still proliferated (Fig. 6). Furthermore, massive proliferation
was detected both in draining and nondraining lymph nodes, indicating
the presence of the peptide in the periphery and supporting our
previous observations concerning the systemic distribution of this
peptide after s.c. administration (13). Thus, these
results indicate that the peptide is presented systemically over a long
period of time.
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A). Peptide vaccination in
PBS did not result in the induction of E1A-specific CTL, unless
combined with CD40 triggering in vivo. More importantly, a strong,
long-lasting CTL response was induced (Fig. 7B), which
completely protected mice against outgrowth of E1A-expressing tumors
(data not shown). These data show that the ultimate outcome of
vaccination is greatly influenced by the "adjuvant" used for
immunization. Peptide in IFA leads to a persistent, systemic Ag
presentation and tolerization, whereas peptide in PBS results in a
transient presentation and long-lasting immunity, indicating that the
duration of Ag exposure eventually determines the outcome of the immune
response.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A key variable implicated in the outcome of Ag encounter by T cells is the functional state of the APC (5, 14). Various findings indicate that provision of inflammatory signals such as microbial infection or adjuvants (e.g., CFA) that activate APC establish the necessary milieu to drive the response to completion including the generation of memory T cell responses (16, 28). Likewise, CD40 signaling is a powerful stimulus resulting in enhanced secretion of cytokines and up-regulation of costimulatory molecules required for proper CTL priming (11, 14). In this respect, the observation that E1A responsiveness on peptide vaccination in IFA combined with CD40 triggering is not preserved is unexpected. Even continued stimulation of APC by repeated injections of poly(I:C), mimicking a strong inflammatory milieu (27, 29), could eventually not prevent tolerization of E1A-specific CTL. These results emphasize that induction of a long-lasting proinflammatory environment, although sufficient to support efficient CTL priming, was not enough to sustain a long-lasting CTL response, in that tolerance was the final outcome.
It is unlikely that the CTL tolerance reported here mimics "classical" anergy induction, originally described for CD4+ T cell clones (30, 31). Inactivation of E1A-specific CTL responses occurred following CTL expansion and display of CTL effector functions, arguing that the CTL have received both "signals" 1 and 2. It is more likely that the dynamics of Ag encounter are crucial to our observations. Especially Ag persistence appears to be a key parameter determining activation or tolerization of CTL responses. Several reports show an association between systemic persistent Ag presentation and T cell tolerization (3, 6). For example, in case of donor cell chimerism following spleen cell transfusions, donor cell persistence was closely correlated with loss of peripheral CTL activity (3). When the donor cells disappeared, host anti-donor T cell responses reappeared. In the same model, tolerization with peptide in adjuvant was transient, presumably because peptide presentation was short-lived (15). Here, we have shown that the E1A peptide is not rapidly cleared from the system on s.c. injection in IFA but instead persists systemically for a long time. Using E1A-specific CFSE-labeled T cells, we detected the presence of this peptide for at least 200 days. In contrast, Ag presentation was transient and associated with long-term CTL memory induction when peptide was given in PBS in combination with CD40 triggering. These findings strongly indicate that the continued and systemic Ag presentation caused the final CTL tolerance, probably via overstimulation or terminal differentiation of all E1A-specific CTL leading to their subsequent elimination. A similar phenomenon has been described in mice infected with LCMV (6). Infection with LCMV-DOCILE, a virus isolate that spreads quickly throughout the lymphoid organs, ultimately led, after a phase of strong CTL proliferation, to clonal exhaustion of LCMV-specific CTL. Infection with LCMV-WE, a slowly replicating LCMV strain, induces long-lasting LCMV-specific CTL memory, indicating that virus spread and CTL induction or exhaustion are closely linked.
Many Ags, including peptides and proteins, are poorly immunogenic or not immunogenic at all when administered on their own (32). To improve their immunogenicity, such Ags are often mixed with adjuvants like IFA or CFA (7, 33). Although successfully applied in other settings, the use of such adjuvants in our model appears to be disadvantageous for the induction of a long-lasting CTL response. This is unexpected, because inflammatory signals provided by adjuvants activate professional APC and establish the necessary milieu required for the generation of memory responses (28). However, the E1A peptide, in contrast to other peptides (13), spreads quickly out of the adjuvant depot into the periphery, where it is presented outside the inflammatory environment induced by the adjuvant. Therefore, IFA no longer fulfills its adjuvant effect but only functions as a depot, causing the prolonged release of the peptide, which eventually leads to the tolerization of the CTL response. These results not only argue against the use of Ag delivery systems that cause peptides/Ag to be released systemically for prolonged periods of time but also indicate that optimal vaccine formulations depend on the pharmacokinetic behavior in vivo of the Ag used. Some peptides induce optimal T cell responses when given in adjuvant (22), whereas others give the best response when given in PBS, in combination with APC-activating agents.
Our findings are relevant for understanding the mechanisms underlying immunity or tolerance. Clearly, APC play an essential role in defining the outcome of Ag encounter, because peptide-induced tolerance could be prevented by APC activation through CD40 or poly(I:C). However, even though a strong CTL response was initiated, tolerization ultimately prevailed when the peptide was injected in IFA, because the systemic and prolonged presence of the Ag led to eclipse of the CTL response. Thus, in this setting, the systemic persistence of Ag presentation dominates the effects induced by APC activation. These results may have implications for our general understanding of the role of host immunity in chronic viral infections (e.g., infection caused by hepatitis B and C viruses and HIV), in which persistent systemic presence of Ag might cause exhaustion of virus-specific, CD8+ T cells (34, 35).
Our data are also important for the development of safe immune intervention strategies to prevent or treat autoimmunity, infectious diseases, or cancer. In these disorders the immune system needs to be redirected in various ways. This could be achieved through manipulation of the activation status of APC as well as by the duration of Ag exposure, both of which are crucial to stimulation or inhibition of T cell responses.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Annemieke Th. den Boer, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, E3-Q, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: boer_a{at}mail.medfac.leidenuniv.nl
3 A.Th.d.B. and L.D. contributed equally to this work.
4 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; DC, dendritic cell; poly(I:C), polyriboinosinate-polyribocytidylate.
Received for publication February 26, 2001. Accepted for publication June 21, 2001.
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)
(C). Data are representative of at least 25 independent
experiments in which duplicate mice were used for each
vaccination.
), or 1 x 108 PFU Ad5ts125 i.m. (
), 20 µg E1A
peptide in IFA s.c. and 100 µg poly(I:C) i.p. (•) or 1 x
108 PFU Ad5ts125 i.m. (
) or were left untreated (
