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Department of Surgery, Section of Surgical Oncology, Medical University of South Carolina, Charleston, SC 29425
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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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A recently identified cytokine, IL-15, has been well characterized as a
T cell growth factor in vitro and in some studies in vivo
(38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49). While IL-15 and IL-2 share little primary
sequence homology, structurally they are similar, and both are members
of the four 
helix bundle family. Each uses a heterotrimeric
receptor composed of a shared 
- and 
-chains, but incorporating a
private -chain. Although signaling can occur through engagement of
only the - and -chains, inclusion of the -chain allows for
high affinity binding of the complementary cytokine (50, 51). While IL-2 is mainly produced by T cells, IL-15 is not
produced by T cells, but is produced by a wide range of non-T cells,
including monocytes, skeletal muscle, kidney, lung, and heart among
other tissues (39, 45, 52). These and other (46, 47) properties associated with IL-2 and IL-15 suggest that there
may be differential toxicities associated with the exogenous
administration of IL-15.
In addition to being potentially less toxic, IL-15 may act without the
regulatory qualities associated with IL-2, thus providing another
potential rationale for its use in T cell vaccination strategies.
Evidence supporting this possibility is most strikingly apparent in
IL-15 KO mice. In contrast with IL-2 KO mice, IL-15 KO mice have only
minor immune deficiencies and no autoimmunity (53).
(Similar differences are observed in the IL-2 and IL-15 specific
-chain receptor KO mice (26, 54, 55).) Another
difference between IL-15 and IL-2 is their functional activity on
memory T cell survival. In contrast with IL-2, which inhibits the
survival of memory T cells in vivo, IL-15 augments the proliferation of
memory T cells (28, 30, 56). The mechanisms responsible
for these widely discrepant functional properties are poorly
understood. The ability of IL-2 to induce susceptibility to
activation-induced cell death (AICD) and the ability of IL-15 to induce
resistance to AICD are commonly cited as potential mechanisms, but
multiple factors are probably involved (20, 21, 22, 23, 24, 27, 57, 58, 59, 60, 61, 62, 63).
Despite significant in vitro data supporting the utility of IL-15 as a T cell growth factor, there are relatively few published data evaluating the function of IL-15 on T cells in vivo (41, 43, 44, 64). In fact, to our knowledge, despite its potential utility as an immunotherapeutic adjuvant, there have been no reports addressing the ability of systemically administered IL-15 to augment primary T cell-mediated responses. The importance of delineating the in vivo role of IL-15 is underscored by recent work showing that the pattern of cytokine receptor subunit expression observed in vitro was much different from that observed in vivo (19). Thus, the requirements for T cell growth and their resulting functional characteristics may be very dependent on locale, and in vitro experiments may therefore be of limited value compared with in vivo studies. To address the role of IL-15 in vivo, we evaluated the ability of systemically administered IL-15 to augment a CD8+ T cell-specific vaccine response in mice. We show that the administration of exogenous IL-15 for 1 wk significantly augmented the expansion of the primary responding CD8+ T cell population. Importantly, in qualitative terms, the responding T cells exhibited characteristics associated with therapeutically valuable T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All mice used were 6–14 wk old, purchased from The Jackson
Laboratory (Bar Harbor, ME), and maintained in specific pathogen-free
conditions at the Medical University of South Carolina in accordance
with National Institutes of Health guidelines. C57BL/6-Ly5.1
(B6.SJL-PtprcaPep3b/BoyJ)
are congenic to wild-type C57BL/6-Ly5.2 mice at the Ly5 (CD45) allele
(65), the use of which allowed us to distinguish donor T
cells from host cells following adoptive transfer. OT-1 TCR transgenic
mice express the OT-1 TCR (V2/V5) transgene, encoding a TCR
specific for the OVA epitope (SIINFEKL-H2Kb)
(66). Hemizygous OT-1 TCR transgenic mice were maintained
on a C57BL/6-Ly5.1 background and assessed for transgene status by flow
cytometric analysis of peripheral blood with an Ab against the V2
subunit.
Abs, cytokines, and other reagents
The following mAbs were used for this study: A20, anti-Ly5.1
(CD45.1); 53-6.7, anti-CD8; XMG1.2, anti-INF; 11B11,
anti-IL-4; 2.4G2, B20.1, anti-V2; 145-2C11, anti-CD3;
3C7, anti-CD25; MEL-14, anti-CD62L; IM7, anti-CD44; R1-2,
anti-CD49d; 3/23, anti-CD40; RA3-682, anti-CD45R/B220; HL3,
anti-CD11c; 16-10A1, anti-CD80; GL1, anti-CD86; S4B6,
anti-IL-2; and FC Block (all from BD PharMingen, San Diego, CA).
Human IL-15, murine IL-2 (mIL-2), mIL-4, and mGM-CSF were
reconstituted in 0.1% BSA/PBS and stored at 4°C immediately
before use according to the manufacturer’s recommendations (R&D
Systems, Minneapolis, MN). The SIINFEKL peptide (OVA
H-2Kb epitope) was synthesized by American
Peptide (Sunnyvale, CA).
Cell lines
All cell lines were maintained in complete medium consisting of RPMI (Cellgro, Herndon, VA), 10% FBS (HyClone, Logan, UT), 300 µg/ml L-glutamine (Cellgro), 100 nM nonessential amino acids (Life Technologies, Grand Island, NY), 5.5 x 10-5 M 2-ME (Life Technologies), 1 mM sodium pyruvate (Life Technologies), 100 IU/ml penicillin (Cellgro), 10 µg/ml streptomycin (Cellgro), and 10 µg/ml gentamicin reagent solution (Life Technologies). The EL-4 tumor (American Type Culture Collection, Manassas, VA) is a thymoma derived from C57BL/6-Ly5.2 mice (67). OVA-transfected EL-4 cells, E.G7-ova (American Type Culture Collection), were grown in complete medium supplemented with 500 µg/ml Geneticin (or G418; Life Technologies) (68).
Generation of dendritic cells (DC)
Bone marrow-derived DC were generated as previously described (69, 70). Briefly, bone marrow cells were flushed from the femurs and tibias of mice and then depleted of RBC by lysis with ACK buffer (Biofluids, Camarillo, CA). Cells were then supplemented with mGM-CSF (20 ng/ml) and mIL-4 (20 ng/ml) and plated out at 1 x 106 cells/ml. On day 4 of culture, complete medium with 20 ng/ml mGM-CSF and 20 ng/ml mIL-4 was added to increase the total volume by 50%. On day 7, nonadherent and loosely adherent cells were harvested and layered onto a gradient (14.5% metrizamide in complete medium; Sigma-Aldrich, St. Louis, MO) and centrifuged. Enriched DCs were washed and, except in control conditions, pulsed with 5 µg/ml SIINFEKL peptide for 3 h, then washed three times in complete medium. The maturity and phenotype of the enriched DC were confirmed by the flow cytometric expression of CD80, CD86, CD40, and CD11c and the lack of CD45R.
Adoptive T cell transfer, vaccination, and cytokine administration
Adoptive T cell transfers were performed using modifications of
previously described protocols (71, 72). Spleen cells were
harvested from OT-1 mice (Ly5.1), prepared as a single-cell suspension,
and lysed with ACK buffer to remove RBC. Subsequently, 
2.5 x
106 spleen cells resuspended in 300 µl HBSS
were injected i.v. into unirradiated C57BL/6 (Ly5.2) mice. Mice were
then rested for 2 days and then vaccinated with 1.4 x
106 Ag-pulsed or sham (unpulsed) DC resuspended
in 400 µl. Following vaccination, mice received i.p. injections of
cytokine (0.5 µg human IL-15 or 0.2 or 1 µg mIL-2) every 12 h
for 7 days. Recombinant cytokine was diluted with HBSS into 100-µl
doses prepared fresh for each injection. In some experiments mice were
injected with vehicle alone as a control.
Flow cytometry
At various time points after vaccination, mice were anesthetized, and peripheral blood was harvested by retro-orbital draw. At other time points, mice were sacrificed, and spleen and lymph nodes (inguinal, axillary, and brachial) were isolated and homogenized into a single-cell suspension. RBC from the peripheral blood and spleen were removed by lysis using ACK buffer. Following the lysis step, a portion of splenocytes was diverted for use in functional assays as described below. The remaining cells were then analyzed by flow cytometric analysis as previously described (73). Briefly, cells were washed in FACS buffer consisting of 0.5% BSA and 0.02% sodium azide in HBSS. Cells were prestained with FC block for 5 min at 4°C, incubated with mAb for 30 min at 4°C, and washed twice before analysis. Cell surface immunofluorescence was measured using a FACSCalibur flow cytometer (BD Biosciences, San Jose, CA) and was analyzed with CellQuest software (BD Biosciences).
Cytotoxicity assay
Cytolytic T cell activity was determined by 4-h 51Cr release assay, as previously described (73). Briefly, 51Cr-labeled target cells, either EL4 cells or EL4 cells pulsed with SIINFEKL peptide, were incubated with fresh splenocytes in 96-well U-bottom plates for 4 h at 37°C with 5% CO2. Culture supernatant was then harvested, and radioactivity was determined. The percentage of specific 51Cr release was calculated according to the equation: percent specific lysis = [(experimental release - spontaneous release)/maximum release minus spontaneous release] x 100. Spontaneous release was determined by incubation of targets in the absence of effectors, while maximum target release was determined by treatment of cells with 9% Triton X solution.
Intracellular cytokine assay
Intracellular cytokine expression was detected using the
Cytofix/Cytoperm Plus Kit with GolgiStop (BD PharMingen), using a
modification of previously described methodology (74).
Splenocytes (1 x 105) were combined with
1 x 105 target cells in a 96-well,
round-bottom plate in a total volume of 200 µl. Target cells
consisted of either EL4 cells alone or EL4 cells pulsed with SIINFEKL
peptide. Following coculture of effectors and targets for 12 h,
cells were stained with anti-Ly5.1 Ab to distinguish adoptively
transferred donor T cells (Ly5.1) from either host splenocytes (Ly5.2)
or EL4 target cells (Ly5.2). Subsequently, intracellular cytokine
expression was determined using Abs against IFN- and IL-4 and the
use of the Cytofix/Cytoperm Kit with GolgiStop (BD PharMingen).
Positive control conditions for this protocol were initially
established using the Leukocyte Activation Cocktail (BD PharMingen;
contains PMA and ionomycin) to induce intracellular cytokine
expression. Cell surface immunofluorescence was measured using a
FACSCalibur flow and was analyzed with CellQuest software.
AICD assay
AICD was assessed by ex vivo restimulation of splenocytes with anti-CD3 plate-bound Ab, and subsequent assessment of apoptosis was performed with propidium iodide (PI) using a modification of previously described methodology (59). Briefly, 96-well, round-bottom plates (plate 3799; Costar, Corning, NY) were precoated with anti-CD3 (clone 145-2C11; BD PharMingen), after which 2 x 105 splenocytes were added. Following a 24-h incubation, cells were stained with anti-Ly5.1 Ab to distinguish donor T cells from either host or target cells, and apoptosis was determined by staining with PI (Sigma-Aldrich) according to the manufacturer’s directions. Cell surface immunofluorescence was then measured using a FACSCalibur flow cytometer and was analyzed with CellQuest software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To address the utility of administering systemic IL-15 as an
adjuvant to vaccination, we used a murine adoptive T cell
transfervaccine model. By first adoptively transferring naive
CD8+ TCR (OT-1) transgenic T cells (Ly5.1) into
C57BL/6 (Ly5.2) congenic mice, we established a baseline of easily
identifiable T cells of uniform Ag specificity. Upon vaccination with
DC pulsed with the relevant peptide (SIINFEKL), these OT-1 T cells
proliferated vigorously in a manner easily discernible by flow
cytometric analysis by virtue of their unique congenic Ly5.1 marker.
Using this model, we typically observed that in PBL, the responding
OT-1 T cells expanded to a peak of 10% by day 4 (Fig. 1
and data not shown).
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). This increase was not limited to the peripheral blood, as a
similar phenomenon was seen in the spleen and to a lesser extent in the
lymph nodes (Fig. 2). In addition,
administration of the well-established T cell adjuvant, IL-2, augmented
the vaccine response in a similar manner to IL-15 (Fig. 2).
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The responding OT-1 T cells were assessed by flow cytometric
analysis for phenotypic changes subsequent to IL-15 administration.
Among activation markers, a minor reduction in expression of the
adhesion molecule CD62L (L-selectin) was observed with both IL-15 and
IL-2 administration (Fig. 3). Although we
examined the expression of other activation markers (CD44, CD69, CD11b,
and CD49d) that were modulated as a result of vaccination, we did not
observe any detectable impact upon these as a result of systemic
cytokine administration (data not shown). Additionally, we were unable
to detect expression of the IL-2 -chain receptor subunit (CD25) on a
significant percentage of responding T cells in any condition, although
expression was readily detectable when T cells were stimulated in vitro
(data not shown).
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-chain
receptor subunit, we anticipated that IL-15 might also up-regulate
Bcl-2 in vivo (79). As others have observed in vitro
(55, 80), we found that in vivo administration of IL-15
augmented Bcl-2 expression in a manner similar to that observed with
IL-2 (Fig. 4). This increase in Bcl-2
expression was observed only at the time points when cytokine was being
administered (data not shown). These results suggest, at least
partially, that a shared mechanism used by both IL-15 and IL-2 augments
the magnitude of the responding T cells.
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Having shown that exogenous IL-15 resulted in a quantitative
increase in the frequency of responding T cells, it was also important
to evaluate the responding T cells qualitatively. Two characteristics
identifying responding T cells as qualitatively valuable are
Ag-specific cytotoxicity and Tc1-biased cytokine production
(81, 82, 83). We demonstrated the first of these by showing
that responding T cells, harvested from the spleens of mice vaccinated
7 days earlier and treated with IL-15, functioned in a cytotoxic manner
against target cells pulsed with relevant Ag (25% target lysis at an
E:T cell ratio of 100:1; Fig. 5A). As reported previously
(5, 6), similar results were obtained with mice treated
with IL-2 (20% target lysis at an E:T cell ratio of 100:1; Fig. 5B). Sham-vaccinated mice and mice receiving vaccination
without cytokine did not show evidence of a cytotoxic response with
these assay conditions (data not shown).
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in response to relevant Ag for all vaccine conditions
(>60% of the OT-1 T cells stained positively for intracellular
IFN- cytokine production compared with <5% in the control groups;
Fig. 6). As none of these T cells
produced significant amounts of IL-4, they exhibited a phenotype
consistent with a strong Tc1 bias (81, 82, 83). Thus, despite
the increase in frequency of responding OT-1 T cells induced by IL-15,
these T cells maintained a qualitative phenotype consistent with that
observed in therapeutically valuable T cells.
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The responding OT-1 T cells from each group were also tested for
susceptibility to AICD. AICD occurs when T cells previously activated
are reactivated through TCR signaling and is characterized by the
induction of apoptosis in a large fraction of T cells
(84). In contrast with IL-2, which is thought to confer
susceptibility to AICD (27), there are conflicting reports
regarding the role of IL-15 in AICD. Some reports suggest that IL-15
may promote resistance to AICD (57, 58, 59, 61), and other
reports suggest that IL-15 may not have a regulatory role in AICD
(31). To evaluate these potential properties in our model,
we induced AICD ex vivo in responding T cells 7 days postvaccination.
Although stimulation of T cells with plate-bound anti-CD3 enhanced
apoptosis in T cells from vaccinated mice (62% PI positive in contrast
to 34% PI positive from sham-vaccinated mice), we did not observe any
significant differential AICD in mice received vaccination plus either
IL-15 or IL-2 (70 and 68% PI positive, respectively; Fig. 7).
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The final qualitative property we assessed in the T cells
responding to vaccination was their ability to make the transition into
memory T cells. In contrast to mice receiving a sham vaccine, mice
receiving the vaccine alone generated a relatively stable population of
donor T cells after 1 mo (Fig. 8).
These results are similar to what was previously observed
(85). These cells were characterized by the expression of
CD44 and a reinduction of CD62L expression indicative of a memory T
cell phenotype (57, 85, 86). Using these criteria, we
assessed the effects of administration of IL-15 or IL-2 during the
primary response on the generation of memory T cells. No statistically
significant change in the percentage of memory T cells as a result of
IL-15 or IL-2 administration in four independent experiments was
observed (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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While our results clearly established the ability of IL-15 to augment the T cell response following vaccination, we found no CD8+ T cell response advantage between IL-15 and IL-2. Both cytokines induced comparable kinetic responses, suggesting that in our model each cytokine was acting through a similar mechanism, possiblly including use of the Bcl-2 pathway. Aside from similar phenotypic changes, both IL-15 and IL-2 yielded comparable results upon analysis of cytotoxicity and cytokine production in the responding T cells. Additionally, we found no evidence for a differential effect of these cytokines on AICD. Finally, in our model upon the assessment of memory T cell generation, we found no advantage of IL-15 over IL-2. As cytokine was administered before the conversion of responding T cells to the memory cell phenotype, our results suggest that the negative regulatory effects of IL-2 on memory T cells may not be mediated through the precursors of memory T cells.
The lack of preferential T cell response induced by IL-15 relative to
IL-2 may reflect unique attributes specific to our model as opposed to
inconsistencies with previous studies. For example, in contrast with
most previous in vivo studies, our study did not employ blocking Abs or
KO mice. Thus, if IL-2 is acting negatively in a dominant fashion, the
endogenous IL-2 might be sufficient to satiate the negative signaling
to responding T cells. In this case, the addition of IL-15 may augment
T cell expansion, but only in a similar manner to that observed from
the positive effects of exogenous IL-2. Although the possible ability
of IL-2 to act in a dominant negative fashion might be detrimental to
the therapeutic application of IL-15, this potential problem could be
circumvented by the use of blocking reagents against the IL-2 pathway.
Our model may prove useful in testing this hypothesis. Another
potential difference observed in our model was lack of specific IL-2
-chain receptor (CD25) expression on responding T cells. This may
either be a necessary factor or an indicator of T cell susceptibility
to the regulatory ability of IL-2 (19).
Based on the data obtained, the most practical potential application of
IL-15 is as a less toxic alternative to IL-2. Although IL-2 has a
reproducible level of clinical efficacy (1, 2, 3, 4), its
application has been limited by the significant toxicities associated
with its systemic administration. While preliminary evidence suggests
the possibility of favorable toxicity associated with IL-15 (88, 89), these studies would need to be expanded upon to determine
the therapeutic index of IL-15 relative to IL-2. Should IL-15 prove
advantageous, it might be an interesting alternative to one recent
approach involving the creation of an IL-2 mutein by targeted
mutagenesis (90). This mutein selectively engages T cells
expressing the specific IL-2 receptor -chain (CD25), which may not
be advantageous compared with IL-15.
In addition to reduced toxicity, another potential advantage of IL-15
over IL-2 as a vaccine adjuvant is highlighted by its unique functional
properties. Unlike IL-2, IL-15 has not been shown to exhibit regulatory
qualities on T cell function. While the negative regulatory effects of
IL-2 have been extensively reported, these studies have been focused
almost exclusively on nontherapeutic settings (19, 23, 25, 26, 27, 28, 29, 30, 31, 32, 53, 54, 55). However, in support of the ability of IL-2 to induce
suppressive effects in a therapeutic model, there are several murine
studies demonstrating an IL-2-mediated inhibitory effect on T cell
function (24, 34, 35, 36, 37, 91, 92). The ability of IL-15 to
promote T cell activity in vivo may provide a mechanism to circumvent
not only the inhibitory effects seen in these murine models, but also
the potential inhibitory effects of IL-2 that may otherwise be masked
in clinically relevant settings. In agreement with this hypothesis, a
recent report by Li et al. (19) not only confirmed the
negative regulatory role of IL-2 in vivo, but showed in a mouse model
that IL-15 provides the necessary signals to sustain initial T cell
proliferation following stimulation. These results were particularly
significant, in that they demonstrated that, contrary to many in vitro
results, IL-2 did not mediate the critical signals supporting T cell
proliferation in vivo. Consequently, not only do these results propose
potential drawbacks to the use of IL-2 to augment T cell-mediated
responses, but they also provide evidence supporting the utility of
IL-15 as an alternative. While the study by Li et al. (19)
provides evidence for a direct negative role of IL-2 on responding T
cells, an as yet poorly characterized avenue is the indirect effects of
suppressor T cells, which are interestingly often characterized by the
expression of the specific IL-2R -chain (CD25). Initial evidence
supporting the role of suppressor T cells in mediating IL-2 regulation
of CD8+ memory T cells has recently been
published (63). It will be interesting to evaluate in what
other circumstances suppressor T cells might mediate the negative
regulatory effects of IL-2, and whether IL-15 might differentially
regulate the effects of such suppressor T cells.
Regardless of the ability of IL-15 to improve upon T cell functional ability relative to IL-2, our results clearly demonstrate the potential for IL-15 to function as an adjuvant to T cell-directed immunotherapies. Additional questions yet to be addressed include the optimal timing and duration for administration of IL-15. The beneficial effects of IL-2 have been reported to be primarily during the first 7 days following vaccination (5). Given the potential for differential regulatory mechanisms, IL-15 might prove superior when administered in an extended manner. Furthermore, the ability of IL-15 to function in a preferred manner to IL-2 may be more apparent in a tumor model where Ag persists. Although our work failed to reveal a role of IL-2 in susceptibility to AICD in vitro, a recent report in which Ag persisted in vivo by virtue of a tumor clearly demonstrated a negative regulatory role for extended IL-2 administration (24). Ultimately, however, evaluation of the therapeutic index of IL-15 may yield the most important criteria for incorporation of IL-15 into human therapeutic trials, as toxicity of IL-2 is the most fundamental clinical limitation. Moreover, as IL-15 and IL-2 may induce different types of toxicity, it might be of value not only to evaluate them as individual agents but when given concomitantly.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: KO, knockout; AICD, activation-induced cell death; DC, dendritic cells; m, murine; PI, propidium iodide.
Received for publication May 13, 2002. Accepted for publication August 26, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B. W. Blaser, S. Roychowdhury, D. J. Kim, N. R. Schwind, D. Bhatt, W. Yuan, D. F. Kusewitt, A. K. Ferketich, M. A. Caligiuri, and M. Guimond Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease Blood, January 15, 2005; 105(2): 894 - 901. [Abstract] [Full Text] [PDF]
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R. M. Teague, R. M. Tempero, S. Thomas, K. Murali-Krishna, and B. H. Nelson Proliferation and Differentiation of CD8+ T Cells in the Absence of IL-2/15 Receptor {beta}-Chain Expression or STAT5 Activation J. Immunol., September 1, 2004; 173(5): 3131 - 3139. [Abstract] [Full Text] [PDF]
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C. A. Klebanoff, S. E. Finkelstein, D. R. Surman, M. K. Lichtman, L. Gattinoni, M. R. Theoret, N. Grewal, P. J. Spiess, P. A. Antony, D. C. Palmer, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T Cells PNAS, February 17, 2004; 101(7): 1969 - 1974. [Abstract] [Full Text] [PDF]
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M. Jinushi, T. Takehara, T. Tatsumi, T. Kanto, V. Groh, T. Spies, T. Suzuki, T. Miyagi, and N. Hayashi Autocrine/Paracrine IL-15 That Is Required for Type I IFN-Mediated Dendritic Cell Expression of MHC Class I-Related Chain A and B Is Impaired in Hepatitis C Virus Infection J. Immunol., November 15, 2003; 171(10): 5423 - 5429. [Abstract] [Full Text] [PDF]
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A. A. Ashkar, G. P. Black, Q. Wei, H. He, L. Liang, J. R. Head, and B. A. Croy Assessment of Requirements for IL-15 and IFN Regulatory Factors in Uterine NK Cell Differentiation and Function During Pregnancy J. Immunol., September 15, 2003; 171(6): 2937 - 2944. [Abstract] [Full Text] [PDF]
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