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Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455
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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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CD8 T cells make IL-2 to support autocrine-driven clonal expansion upon interaction with Ag and costimulatory ligands and can often mount an initial virus- or tumor-specific response that does not depend upon CD4 T cell help. However, prolonging a response sufficiently to make it effective often requires help from CD4 T cells (8, 9, 10, 11, 12). At least in some cases, perhaps most, this is because CD8 T cells lose the ability to make IL-2 themselves within a few days of their initial encounter with Ag and costimulation; they develop a state of activation-induced nonresponsiveness (AINR) (13). AINR cells still have Ag-specific effector functions and can still proliferate in response to exogenous IL-2 but cannot support their own autocrine-driven expansion. Therefore, AINR appears to act as a regulatory checkpoint in the response, where further expansion can occur only if permission is received in the form of IL-2 from Th cells (13, 14). Thus, provision of IL-2 should potentially provide therapeutic benefit in situations where development of AINR and lack of a sufficient Th cell response limit efficacy of the CD8 response. However, IL-2 can also stimulate apoptotic death of activated T cells (15, 16, 17). Thus, IL-2 is potentially a double-edged sword with respect to hoping to achieve therapeutic benefit by enhancing a CTL response.
The approach of adoptive transfer of small numbers of TCR-transgenic T cells into normal recipients has made it possible to directly visualize and quantitate in vivo T cell response (18, 19). The recipient’s immune system is not highly skewed by the presence of the transgenic T cells, which account for <1% of the T cells present, but the Ag-specific TCR-transgenic cells can be readily identified, enumerated, and characterized by flow cytometry. We have previously used this approach (11, 20) to study the response of OT-I CD8 T cells, expressing a TCR specific for H-2Kb/OVA257–264 (21), to E.G7 tumor (22) (EL-4 thymoma transfected with OVA) growing in the peritoneal cavity (PC). Within 3–4 days of challenging adoptive transfer recipients with tumor, the OT-I cells migrated into the PC where they underwent Th-independent clonal expansion, developed effector function, and controlled tumor growth. However, 2–3 days later the OT-I CTL became AINR and tumor growth control was lost; continued OT-I expansion and control of tumor growth could be maintained only if a CD4 Th response was also induced, and the help was dependent upon IL-2.
This requirement for IL-2-dependent CD4 T cell help to sustain the tumor-specific OT-I response provided a model for developing a better understanding of the parameters that influence the therapeutic use of IL-2 to extend CTL responses to tumors. As described in this report, IL-2 can be used to overcome AINR in CTL and achieve therapeutic benefit. However, IL-2 can also induce apoptosis in the activated CTL in vivo; therefore, administration must be of limited duration for the CTL response to be maintained and the therapeutic benefit to be gained.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OT-I mice having a transgenic TCR specific for Kb/OVA257–264 (21) were a kind gift from Dr. F. Carbone (Monash Medical School, Victoria, Australia). OT-I (Thy1.2) mice were crossed with Thy1 congenic B6.PL-Thy1a/Cy (Thy1.1) mice and these were used as the source of transgenic T cells in all experiments. OT-I lymph node (LN) cells were harvested, washed, and adoptively transferred by i.v. (tail vein) injection of 3 x 106 OT-I (Thy1.1) cells into sex-matched naive C57BL/6 or C57BL/6 CD4-/- (Thy1.2) mice (The Jackson Laboratory, Bar Harbor, ME). Recipient mice were rested for 1 day and then challenged by i.p. injection of 3 x 106 E.G7 tumor cells in 0.5 ml PBS. E.G7 (Thy1.2) is the EL-4 thymoma transfected with the gene for OVA (22) and was maintained in vitro in RPMI medium with 10% FCS. Recombinant murine IL-2 (R&D Systems, Minneapolis, MN) was administered i.p. or i.v. (tail vein) at indicated doses and times after tumor challenge. All mice were housed under specific pathogen-free conditions.
Analysis by flow cytometry
Mice were sacrificed on the indicated days after challenge with tumor, and the spleen (SPL) and draining LN (periaortic, mesenteric, axillary, and brachial) were collected, homogenized, and ammonium chloride-treated to remove RBCs. The PC was washed twice with 25 ml of PBS each time and the resulting peritoneal exudate lymphocytes were adherence-depleted for 90 min in complete medium at 37°C. The total number of cells obtained from each site was determined by counting using a hemocytometer. A detailed description of the identification of the OT-I cells in the adoptive transfer recipients has been previously described (20). Briefly, 1 x 106 cells from each site were stained with anti-CD8-CyChrome, anti-Thy1.1-PE, and a third FITC-labeled mAb specific for a phenotypic marker. After 1 h on ice, the cells were washed twice, resuspended in 0.2 ml of 1% formaldehyde, and analyzed by three-color flow cytometry using the CellQuest software package (BD Biosciences, San Jose, CA). OT-I cells were identified as the CD8+Thy1.1+ cells, and these were gated to determine their numbers and phenotype. In all experiments, cells were stained with anti-CD8-CyChrome mAb and either anti-Thy1.1-PE Ab or a PE-labeled isotype control Ab. With the control Ab, no events were found in the double-positive gate used to identify CD8+Thy1.1+ OT-I cells, even when large numbers of E.G7 tumor cells were present in samples from the PC. E.G7 tumor cells were identified by gating on large granular cells (high FSC/side light scatter) that were Thy1.2+CD8-. The total numbers of OT-I and E.G7 cells at each location were determined by multiplying the percentage of cells in the population by the total number of cells recovered from each site.
Phenotypic characterization of OT-I cells was done by staining with a third anti-CD44-FITC mAb or annexin V-FITC. To determine gate settings for annexin V staining, OT-I cells were cultured in vitro for 72–96 h in the absence of any stimulation and double-stained at various times with annexin V and 7-amino actinomycin D (to detect dead cells). After 48 h the number of annexin V+ cells began increasing, followed by the appearance of cells that were both annexin V+ and 7-amino actinomycin D+. The results of these experiments were used to define the gates for annexin V+ staining in the experiments shown. All fluorescent reagents were purchased from BD PharMingen (San Diego, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When mice having adoptively transferred OT-I T cells are
challenged by i.p. injection of E.G7 tumor the OT-I cells migrate to
the PC and undergo clonal expansion that peaks on day 4 or 5
(20). The cells have developed lytic effector function by
this time and are controlling tumor growth. However, after day 5,
expansion ceases as the cells become AINR; they migrate out of the PC
and are found in the LN and SPL. The AINR cells in the secondary
lymphoid organs retain effector function but are no longer at the site
of tumor, which begins to expand in the PC. We initially examined the
ability of low-dose IL-2 to influence the course of the OT-I response
to E.G7, administering 2,000 IU/day on two successive days by i.p.
injection. This is the equivalent of 70,000 IU/kg/day, a 10-fold lower
dose than is used in many human trials (23, 24). Mice were
sacrificed at varying times after IL-2 administration. The OT-I cells
at various sites were identified and enumerated by staining with
anti-CD8 and anti-Thy1.1 mAbs, and their activation status was
determined by measuring forward light scatter (FSC) to assess whether
they were undergoing blast transformation, and staining with mAb
specific for activation markers. The number of E.G7 cells in the PC was
also determined; this is the only site where tumor was found in these
experiments. As expected (20), OT-I cells were present in
the PC in large numbers by day 4 in untreated mice but were largely
absent by day 12 and later (Fig. 1
A). Administration of IL-2 on
days 1 and 2 did not change this pattern. The initial expansion of OT-I
cells in the PC is CD4 T cell independent and depends upon autocrine
IL-2 (11). The lack of effect of IL-2 administered on days
1 and 2 suggests that the IL-2 made by the OT-I cells is sufficient to
support an optimal response at this time.
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A). Thus, provision of
IL-2 for just 2 days during the time when the OT-I cells would become
AINR results in prolonged responsiveness. That they continue to respond
long after the IL-2 administration is demonstrated by the high
proportion of OT-I cells that are blasting and have high CD44 levels at
day 22 (Fig. 1C) and longer times (data not shown). This
prolonged responsiveness in the absence of further IL-2 administration
is consistent with results showing that AINR is reversed when cells are
stimulated in vitro with exogenous IL-2 to drive proliferation for 1–2
days (14). Furthermore, the number of E.G7 tumor cells in
the PC in these mice is substantially reduced in comparison to
untreated mice or mice that received IL-2 on days 1 and 2 (Fig. 1B). Delaying the IL-2 administration until days 8 and 9,
when the number of OT-I cells in the PC has already decreased
substantially, still results in a sustained response by OT-I in the PC
and some reduction in tumor load by day 22. In the experiment shown in
Fig. 1, the IL-2 was administered by i.p. injection, i.e., at the site
of tumor growth. This is not necessary for its effects on OT-I cell
location and expansion or reduction in tumor load; administration by
i.v. injection is as effective as by i.p. injection (Fig. 2).
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Host CD4+ T cells become tolerized to OVA
when mice are challenged with E.G7 but can provide IL-2-dependent help
to support the OT-I response if tolerance is prevented by blockade of
CTLA-4 (11). To rule out the possibility that the
therapeutic effects of IL-2 seen here might involve an effect on the
CD4 T cells, the OT-I response to E.G7 was examined in
CD4-/- mice. In the absence of IL-2
administration the OT-I cells respond to tumor in
CD4-/- mice with the same kinetics as they do
in normal mice (Ref. 11 and Fig. 3). As in the normal mice, administration
of IL-2 on days 1 and 2 had no effect on OT-I cell numbers or tumor
load on day 10 or later times (data not shown), while IL-2 on days 4
and 6 caused a large increase in the number of OT-I cells in the PC on
day 10 and a concomitant reduction in tumor load (Fig. 3). This
experiment included a group that did not receive OT-I cells by adoptive
transfer, and demonstrated that tumor reduction in response to day 4
and 6 IL-2 does not occur in the absence of the adoptively transferred
OVA-specific T cells. Thus, the therapeutic effects of IL-2 depend upon
OT-I T cells and do not require host CD4 T cells.
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Although 2,000 IU is a relatively low dose of IL-2, administration
of this amount on days 4 and 6 had substantial effects on increasing
OT-I numbers and decreasing tumor load to at least day 22. In fact,
increasing the dose 10-fold to 20,000 IU caused no greater increase in
OT-I cell numbers and no greater reduction in tumor load (Fig. 4). We also examined the effects of
delivering IL-2 over several days, with the somewhat surprising result
that the efficacy decreased dramatically. Delivery of 2,000 IU every
other day for a total of six injections ending on day 12 resulted in no
more OT-I in the PC on day 22 than in untreated controls (Fig. 4A), and tumor load was as high as in untreated mice (Fig. 4B). Thus, more prolonged administration abrogates the
therapeutic effect obtained when IL-2 is administered only twice.
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A). As expected,
tumor load on day 30 was significantly reduced in the mice treated with
IL-2 on days 16 and 18. Again, efficacy was lost when the treatment was
prolonged. Mice that received IL-2 every other day from days 16 through
24, a total of five injections, had no more OT-I in the PC by day 30
than the untreated controls (Fig. 5A), and tumor growth was
not controlled (Fig. 5B).
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IL-2 can induce apoptotic death in activated T cells in vitro
(15, 16), raising the possibility that prolonged treatment
in these experiments was having the same effect in vivo to result in
elimination of the tumor-specific effector cells. Phosphatidylserine
becomes accessible at the cell surface early in the course of apoptotic
death of a cell and can be detected by binding of annexin V
(25). Therefore, we examined the OT-I cells in the
experiment shown in Fig. 5 by staining with fluorescent annexin V. For
the untreated controls or the mice treated with multiple injections of
IL-2, too few OT-I cells remained in the PC by day 30 for reliable
analysis. However, there were small numbers of OT-I cells remaining in
the draining LN at this time, and the majority of these cells were
found to be positive for annexin V binding (67 and 86% respectively;
Fig. 5C). In contrast, only 9% of OT-I cells were annexin V
positive in the mice that received IL-2 on just days 16 and
18.
The small number of OT-I cells remaining by day 30 in the mice that
received multiple IL-2 injections hampered accurate determination of
the extent of apoptosis. In an independent experiment, groups of mice
were treated in the same way as in Fig. 5 but analysis was done on day
26. The group that received five injections of IL-2 already exhibited a
peritoneal tumor load comparable to untreated controls, while the group
that received just two injections of IL-2 had a substantially reduced
tumor load (Fig. 6B).
Furthermore, the number of OT-I cells in the PC of the group receiving
multiple injections was much lower than in the mice that received IL-2
on only days 16 and 18 (Fig. 6A), and 47% of them stained
positively with anti-annexin V mAb (Fig. 6C). In
contrast, none of the OT-I cells from the peritoneal cavities of
untreated mice or mice treated with IL-2 on days 16 and 18 were
positive for annexin V. Thus, prolonged treatment with IL-2 is
resulting in apoptotic death of the tumor-specific
CD8+ T cells. Furthermore, the fact that the
tumor load is already high and the OT-I numbers are low at day 26, 2
days after the final IL-2 injection, strongly suggests that the death
is due not to cytokine withdrawal, but rather to an active process of
induction of apoptosis in the Ag-activated cells.
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C), and these cells can respond
to IL-2 but not to Ag in vitro (20). When IL-2 is provided
in vivo as late as days 16 and 18 the cells can still be reactivated,
as demonstrated by increased numbers and a large fraction of the cells
being large blasts at later times. In fact, even 12 days after the last
administration of IL-2 about half of the OT-I cells are still blasts
(Fig. 5C). This suggests that relatively brief exposure to
IL-2 can reverse the AINR state that develops after the initial
response (13) so that the CD8+ cells
can then continue to respond to the Ag and control tumor for a
long time. The therapeutic benefit of IL-2 is lost upon prolonged administration
Multiple administrations of IL-2 also negate the extension of
survival that is obtained with limited IL-2. In one experiment (data
not shown), for mice left untreated or treated with IL-2 (2000 IU)
every other day for a total of six injections beginning on day 4, one
of six mice in each group died on day 22 and all were dead by day 35.
In contrast, mice that received IL-2 on just days 4 and 6 had none dead
by day 22, and only one had died by day 35. Later administration of
IL-2 to tumor-bearing mice on days 16 and 18 also extended survival,
while mice that received IL-2 five times on days 16–24 survived no
longer than untreated controls (Fig. 7).
Thus, therapeutic efficacy derived from limited administration is lost
upon prolonged treatment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), indicating that
the OT-I cells produce sufficient IL-2 at this early time to support a
maximal response. Although helper-independent CTL responses can be
initiated in many situations, these responses often fail to persist in
the absence of CD4 T cell help (26). The failure of the
CTL response to be self-sustaining is a result of the CD8 T cells
losing the ability to continue to produce IL-2 beginning 2–3
days after their initial response. This state, termed AINR
(13, 14, 27), resembles the classical anergy described for
CD4 T cells (28, 29), in that the cells can no longer make
IL-2 in response to Ag and costimulation. However, it differs in that
classical anergy is induced when T cells receive signal 1 (Ag) in the
absence of costimulation, while AINR occurs even though the initial CD8
T cell stimulus includes effective costimulation.
AINR develops 
3 days after the CD8 T cell response is initiated; at
this time the cells are effector cells and can lyse targets and secrete
IFN-
in response to TCR signals but can no longer up-regulate IL-2
mRNA or protein in response to Ag and costimulation (13).
However, if IL-2 is provided, they can continue to proliferate in
response to it. Furthermore, if proliferation is driven for 1–2 days
by provision of IL-2 the nonresponsiveness is reversed; the cells
regain the ability to make their own IL-2 to support continued
proliferation (14). Some rewiring of the signaling
pathways occurs during this process, because up-regulation of IL-2 mRNA
in naive cells requires costimulation while Ag alone is sufficient to
up-regulate IL-2 mRNA following reversal of AINR. The defect in AINR
cells is, at least in part, due to their inability to activate the
mitogen-activated protein kinase pathway upon TCR and CD28 ligation
(27), a signaling pathway required for IL-2 up-regulation.
The rewiring is also seen at this level; naive cells require CD28
signals to activate c-Jun N-terminal kinase and p38 mitogen-activated
protein kinases while both are effectively up-regulated via just TCR
engagement upon reversal of AINR (14). The results shown
in this report are consistent with these in vitro observations of AINR
and reversal. OT-I cells stop proliferating within a few days of their
initial response to the E.G7 tumor, but administration of IL-2 for a
brief periods results in continued proliferation that persists long
after the IL-2 would be gone (Fig. 1). Furthermore, it appears that the
cells can remain in the AINR state for many days and still regain
responsiveness if IL-2 is provided, because IL-2 administered as late
as days 8 (Fig. 1) or 16 (Fig. 5) resulted in resumption of response
and control of tumor growth (Figs. 1, 5, and 6).
Although brief (two times) administration of IL-2 resulted in prolonged
activation of OT-I cells, with control of tumor load and extension of
survival (Fig. 7), these effects were lost when administration was more
extended (five to six times) (
Figs. 5–7). In this case, OT-I cells
were greatly reduced or eliminated at longer times and tumor growth was
not controlled. This raised the possibility that prolonged exposure of
the reactivated OT-I cells to IL-2 might be promoting
activation-induced cell death (AICD), and support for this was obtained
from experiments demonstrating that OT-I cells in mice that had
received a prolonged course of IL-2 were dying by apoptosis (Figs. 5 and 6). AICD in CD4 T cells in response to IL-2 is mediated by Fas-Fas
ligand interactions (30, 31, 32), while AICD in CD8 T cells
appears to largely involve the TNFR pathway (33, 34, 35),
although Fas can play a role (36). A recent report by Dai
et al. (17) provided evidence that IL-2 promotes AICD of
CD8 T cells by up-regulating Fas and down-regulating the common
cytokine receptor -chain, which is important for survival. The
mechanism(s) involved in the IL-2-dependent death of OT-I cells
described here remains to be determined.
High-dose, prolonged administration of IL-2 can have therapeutic
benefits in murine tumor models and in the clinic (2, 3, 37), effects that may result largely from promoting NK or LAK
cell activation. IL-2 immunotherapy does result in a significant
response rate, with 10% of patients having long-term disease-free
remission and 10% having partial remission (6, 37). The
results obtained in the murine tumor model described here have
implications for the clinical use of IL-2 for immunotherapies that
target tumor-specific CD8 T cells, suggesting that greater benefit
might be gained by using more limited frequency and dose of
administration than is typically used. It is interesting to speculate
that a small fraction of patients that benefit from high-dose or
prolonged IL-2 administration may do so because the early CTL response
that is activated may be sufficiently vigorous to substantially reduce
or eliminate tumor before apoptosis of the T cells is induced as the
IL-2 administration is continued.
Recent clinical trials examining treatment of melanoma patients with immunodominant melanoma peptide Ag alone or along with IL-2 have yielded results suggestive of the observations reported here (38, 39). Treatment with peptide alone resulted in an increase in melanoma-reactive precursor T cells in peripheral blood, but significant clinical responses were not observed. In contrast, treatment with peptide followed by multiple high-dose administrations of IL-2 did yield a significant number of clinical responses, but increased precursors could not be detected in the blood. The authors speculated that the IL-2 might be either causing destruction of the tumor-specific T cells by inducing apoptosis once they had developed effector function or causing sequestration on newly generated T cells at the tumor site or elsewhere (39). The former possibility is supported by the results shown in this paper. However, we have also made observations in the model described here that are consistent with the suggestion that sequestration at the tumor site may occur upon IL-2 therapy. By day 8, when the OT-I cells have become AINR, they have migrated away from the PC and are found primarily in the LNs, SPL, and blood (20). When IL-2 is given at this time, the number of OT-I cells at these sites declines while the number increases in the PC where the tumor is growing (data not shown). Thus, if assessment of responses in the mice were confined to blood, a decline in tumor-specific CD8 T cells would be seen even when IL-2 is having a significant therapeutic effect.
The timing and extent of exposure to IL-2 can clearly have dramatic effects on whether or not it is efficacious in activating, or reactivating, tumor-specific CD8+ T cell responses, making it difficult to know how to use it clinically in an optimal manner. The recently developed ability to detect and characterize tumor-specific T cells in patients using peptide/class I MHC tetramers may help in optimizing IL-2 therapy (40, 41, 42, 43). It may be possible to monitor activation of the cells as therapy proceeds and to stop administering the IL-2 when activation has occurred but before extensive apoptosis has been induced. The results described here strongly suggest that examination of the clinical effects of very limited IL-2 exposure would be warranted in trials using strategies that attempt to activate tumor-specific CD8 T cell responses.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14623.
3 Address correspondence and reprint requests to Dr. Matthew F. Mescher, Center for Immunology, University of Minnesota, Mayo Mail Code 334, 420 Delaware Street S.E., Minneapolis, MN 55455. E-mail address: mesch001{at}tc.umn.edu
4 Abbreviations used in this paper: LAK, lymphokine-activated killer; AINR, activation-induced nonresponsiveness; PC, peritoneal cavity; LN, lymph node; SPL, spleen; AICD, activation-induced cell death; FSC, forward light scatter.
Received for publication April 4, 2002. Accepted for publication June 10, 2002.
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-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184:863.-herpesvirus reactivation in CD4-deficient mice. Proc. Natl. Acad. Sci. USA 95:15565.
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