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Pulmonary Center and Evans Memorial Department of Medicine, Boston University School of Medicine, Boston, MA 02118
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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,
ß, and 
expression on CD4+ T cells and of IL-16/IL-2
cotreatment of resting human PBMC obtained from normal individuals on
CD4+ T cell proliferation and cytokine production, in
vitro. IL-16 increased CD4+ T cell IL-2R and ß
expression, but had no effect on expression of IL-2R. There was
marked synergy of thymidine uptake and expansion of CD4+ T
cell numbers in the presence of IL-16 and IL-2 or IL-16 and IL-15
compared with the responses to any of the cytokines alone. By 4 wk,
IL-16/IL-2-cotreated PBMC cultures were predominantly CD4+,
CD25+ CD45RO T cells. Of the cytokines measured, IL-16
treatment alone was sufficient to induce synthesis of
granulocyte-macrophage CSF by 2 wk. IL-16/IL-2 cotreatment did not
appear to induce selective proliferation of any Th subset, as cytokines
of both Th1 (e.g., IFN-) and Th2 (e.g., IL-5) types were synthesized
by the expanded cell populations at 2 and 4 wk. These results suggest
that IL-16 can prime CD4+ T cells for IL-2 responsiveness,
and therefore may be a useful adjunct to IL-2 therapy for immune
reconstitution in disease or therapeutic conditions resulting in
CD4+ T cell depletion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the functional consequences of IL-16 interaction with CD4 on T
cells is the induction of IL-2R (CD25) (10, 11). Because there is an
absolute requirement for cell surface expression of CD4 for signaling
and functional responses to IL-16 (10, 12, 13, 14, 15), we hypothesized that
IL-16 might provide a selective synergistic signal for IL-2-induced
proliferation of CD4+ T cells over all other T cell
phenotypes. In the current studies, we determined the effects of IL-16
on IL-2Rß and , and then determined the effects of sequential
IL-16/IL-2 treatment of human blood T cells obtained from normal
individuals on CD4+ T cell proliferation, in vitro. IL-16
increased IL-2R and ß expression, but had no effect on IL-2R.
We observed selective enhancement of the proliferative response of
blood CD4+ T cells in the presence of both IL-16 and IL-2
compared with the responses to either cytokine alone. A similar effect
was noted in the presence of IL-16 and IL-15, while there was no
synergy with IL-4. Following 4-wk exposure to IL-16/IL-2, the expanded
cell population was predominantly
CD4+CD25+CD45RO CD95+. By 2 wk,
IL-16-treated cells synthesized GM-CSF, while IL-16/IL-2-cotreated
cells synthesized significant levels of IFN-, GM-CSF, and IL-5; low
levels of IL-10; but undetectable levels of IL-4. By 4 wk, the
synthesis of IL-10 increased following IL-16/IL-2 stimulation. The
presence of both Th-type cytokines suggests that IL-16/IL-2 treatment
does not result in any bias toward a single Th subtype over time in
culture. These results suggest that IL-16 may be a useful adjunct to
IL-2 therapy for immune reconstitution in states associated with
CD4+ T cell depletion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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rIL-16 containing an NH4-terminal polyhistidine tag linked via a factor Xa-susceptible cleavage site was produced in Escherichia coli, purified by metal-chelation chromatography, and isolated from the polyhistidine tag by enzymatic cleavage, as previously described (11). Thoroughness of removal of endotoxin by polymyxin binding was determined by assay with a BioWhittaker QCL 1000 LAL testing kit (Walkersville, MD). rIL-16 was stored in 7.5% glycerol with 0.1 mM HCl at -80°C and thawed immediately before use. The bioactivity of rIL-16 preparations was confirmed by chemotaxis of human T cells, as previously described (11). rIL-2 was purchased from Genzyme Corp. (Cambridge, MA); rIL-4 and rIL-15 were purchased from Biosource (Camarillo, CA).
Human PBMC isolation
As per institutional review board protocol, blood was obtained from volunteers after a description of the intent of the experiments was given and the informed consent forms were signed. Cells were isolated according to previously reported protocols (10, 12). Briefly, blood from normal volunteers was collected in heparinized syringes, and the PBMC were isolated using Ficoll-Hypaque density centrifugation. PBMC were washed and resuspended in RPMI 1640 supplemented with 25 mM HEPES buffer, 100 U/ml penicillin and streptomycin (HPS), and 10% FBS.
Cell culture and treatment
To determine the effects of IL-16 on [3H]thymidine incorporation into T cells, rIL-16 (10-10 M) or molar equivalent of a recombinant protein, ß-galactosidase, produced in an identical fashion in E. coli (11), was added to PBMC 24 h before the addition of rIL-2 (10 U/ml). Cells were cultured in presence of rIL-2 for 5 days and then pulsed with [3H]thymidine (1 uCi/well) for 24 h, harvested, and assessed by scintillation counting. In experiments in which we determined the proliferation of T cells in culture, human PBMC were plated at a concentration of 1 x 106 cells/ml in 3 ml of RPMI HPS/10% FBS. The cells were treated with either media alone (every Monday, Wednesday, and Friday); media (every Monday) plus rIL-2 (10 U/ml every Wednesday and Friday); media (every Wednesday and Friday) plus rIL-16 (10-10 M every Monday), or a combination of weekly rIL-16 (every Monday) and twice weekly rIL-2 (every Wednesday and Friday). Volumes of added media and cytokines were adjusted so that a total of 200 µl by volume was added each week. Equal volumes were maintained throughout the culture period as 200 µl was aspirated weekly for cell counts. Cell density was maintained at 1 x 106 cells/ml. The cells were enumerated by hemocytometer and FACS analyses. The data are expressed as the average cell counts from each culture dish (±SD) and then meaned with counts from cultures from other experiments under similar conditions and time intervals.
FACS analysis
PBMC were incubated with a combination of phycoerythrin
(PE)-conjugated or fluorescein-conjugated Abs directed at
membrane-expressed Ags. In general for each Ab, 200 µl of cell
suspension (1 x 106 cells/ml) was washed,
resuspended in PBS with 0.1% azide, and incubated with 5 µl of Ab
for 30 min at 4°C. Cells were washed three times, fixed with 10%
Formalin, and protected from light at 4°C until analysis with a
Becton Dickinson FACS cytometer. Conjugated Abs, CD3 FITC,
CD4-FITC, CD8-PE, CD16 PE, CD14 FITC, CD45RO
FITC, and CD45RA FITC were obtained from Biosource; CD3 PE and CD25 PE
from Becton Dickinson (Bedford, MA); and CD95 PE, CD57 PE, and CD40L PE
from PharMingen (San Diego, CA). Anti-IL-2Rß was a gift from Lee Anne
Beausang (Endogen, Cambridge, MA). Anti-IL-2R was purchased from
PharMingen (San Diego, CA). Calculation of the total numbers of CD4
cells in culture was based on the percentage of
CD3+CD4+ cells by FACS analyses.
ELISAs
One-hundred-microliter aliquots of supernatants of cultures were
used to assess cytokine concentrations, as determined by ELISA. The
IL-4, IL-5, IL-10, IFN-, and GM-CSF ELISA assays were obtained from
Biosource. In general, the ELISA kits had a lower limit of detection of
20 pg/ml. Assays were conducted as specified by the manufacturer.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have shown previously that IL-16 induces cell surface
expression of CD25 protein on T cells within 24 to 48 h (10, 11).
To demonstrate that this response was selective for
CD4+ T cells, as predicted by IL-16’s requirement for
CD4 to initiate its functions (10, 11, 12, 13, 14, 15), we exposed PBMC to
10-10 M rIL-16 for 24 and 48 h and labeled the cells
for expression of CD4 and CD25. The induction of CD25 at both the 24-
and 48-h time points occurred exclusively in the CD4+ T
cell population (Fig. 1
, upper
panel). Under these conditions, IL-16 stimulated the
expression of CD25 on 18% of the CD4+ cells at 24 h,
which increased to 30% of the CD4+ cells at 48 h. As
the IL-2R high affinity complex is comprised of two other chains, we
also determined whether IL-16 stimulation had an effect on IL-2Rß and
IL-2R expression. The level of IL-2R expression was high on all
of the T cells cultured under control, untreated conditions (Fig. 1, lower panel). The addition of IL-16 did not induce a
significant change in IL-2R expression. Conversely, IL-2Rß was
expressed at relatively low levels in untreated T cells. The addition
of IL-16 resulted in an increase in IL-2Rß expression from an average
of 2% positive cells for untreated cells to 11% positive cells
exposed to IL-16 for 24 h (Fig. 1, lower panel).
In general, the magnitude for the up-regulation of IL-2Rß was not as
great nor as consistent as was seen for IL-2R. The average increase
for IL-2Rß was 11%; however, the range was from 1.5 to 23% for the
24-h period. By 48 h, the percentage of positive cells was 16%
(data not shown). There was no significant change in IL-2R
expression at any time point examined.
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, rIL-16 had
no effect on thymidine uptake, while rIL-2 resulted in a minimal
increase, probably representing a response of the low percentage of
IL-2R+ cells in the starting cell population (1–7% in
these experiments). Sequential treatment with rIL-16 and rIL-2 resulted
in a sixfold increase in [3H]thymidine incorporation,
indicating that the IL-2R induced by IL-16 was functional. In addition,
we determined whether the proliferative responses to IL-4 and IL-15
were augmented by preincubation of PBMC with IL-16 under identical
conditions. There was no augmentation of IL-4-induced proliferation.
The meaned data for an IL-4 concentration of 100 ng/ml are shown in
Table I, but there was no response over a wide concentration range
(0.5–100 ng/ml). However, IL-16 did prime PBMC to incorporate
[3H]thymidine in the presence of IL-15 (50 ng/ml) (Table I). IL-15 (100 ng/ml) resulted in a twofold increase in
[3H]thymidine uptake that was further augmented to
10-fold by prior exposure to IL-16 (data not shown). Despite the large
range in the magnitude of IL-2Rß expression, all cultures receiving
IL-16 demonstrated enhanced proliferation to IL-15. In the following
experiments, we limited our observations to the study of the synergism
between IL-16 and IL-2.
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To determine whether these short-term effects could be maintained
over time and if they would result in increased numbers of
CD4+ T cells, we quantified cell numbers in extended
PBMC cultures in the presence of rIL-2, rIL-16, or rIL-16 and rIL-2 in
combination. In these experiments, rIL-16 was added on Mondays,
followed by rIL-2 on Wednesdays and Fridays of each week. Figure 2 depicts the total cell numbers from
PBMC cultures. There was a steady decline in the untreated and
rIL-16-treated cells, although cell numbers declined more slowly in the
presence of rIL-16 than in media alone. While twice weekly rIL-2
treatment led to rises in total cell numbers for the first 3 wk, these
increases were accentuated significantly by weekly cotreatment with
rIL-16 (Fig. 2). In cultures cotreated with rIL-16/rIL-2, the cell
numbers continued to rise for the duration of the culture period. Using
paired t test analysis, there was a significant difference
(p < 0.01) between rIL-16/rIL-2 treatment and
rIL-16 alone and media alone at every time point after week 3. By week
4, there were statistically significant increases in total cells in
rIL-16/rIL-2-treated cultures compared with IL-2 treatment alone.
IL-16/IL-2 costimulation also imparted increased viability to
CD4+ T cells, as more than 90% of the cells in the
cotreated cultures excluded trypan blue, while up to 50% of cells
treated with either cytokine alone did not exclude trypan blue at 2 wk,
and 90% of the cells were not viable by 4 wk.
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. In addition to the rise in total
CD4+ T cell numbers, the percentage of CD4+ T
cells rose continuously throughout the culture period in
IL-16/IL-2-treated cells (from 40–50% positive at time zero to more
than 95% CD4+ by 4 wk) (Table II). There were no significant increases
in the total numbers of CD14+ (monocytes) or
CD16+ (NK cells) with combination rIL-16/rIL-2 treatment at
either the 2- or 4-wk time point (Table II). Therefore, IL-16/IL-2
cotreatment resulted in selective expansion of CD4+ T
cells, resulting in a homogeneous population of CD4+ cells,
with no apparent effect on either monocytes or NK cells.
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We next identified the IL-16-responsive cell population by surface
phenotyping. During the first 4 wk of culture, it was observed that
unstimulated cells, while decreasing in viability and cell number,
demonstrated an increase in IL-2R and CD45RO expression. The rise in
CD40L expression was not statistically significant at 4 wk (Table III). Our starting cell populations had
high CD45RA expression that decreased over time. The addition of
rIL-16, rIL-2, or the two in combination had the effect of further
increasing the levels of IL-2R and CD95 expression at all time points.
The combination of rIL-16/rIL-2 also increased the expression of CD45RO
and CD40L (Table III). By the 6-wk time point, only the cultures
receiving both rIL-16/rIL-2 were viable. FACS analysis of the
population of the cells at 6 wk revealed that they were predominantly
CD4+, CD25+, CD45RO, and CD95+
(Fig. 4). In addition, at this time point
the cells were analyzed for their expression of CD57, a marker of
lymphokine-activated killer cells. Less than 10% of all of the cells
in these cultures were CD57+ (Fig. 4). By 6 wk, the
percentage of CD40L-expressing cells rose to 25% in a pattern that
suggested a continuum of expression of CD40L. While the data shown in
Figure 4 are a representative experiment, the percentage of cells
expressing these patterns differed by less than 10% among all
individual experiments. We observed a high percentage of CD45RA cells
following isolation. CD45RO expression increased over time in response
to rIL-16/rIL-2 treatment, which was associated with the presence of
significant numbers of CD45RO CD45RA double-positive cells by 2 and 4
wk, which were not observed at 6 wk. Beyond week 4, the expression of
CD45RO routinely increased to approximately 90%, while expression of
CD45RA decreased to less than 20% of the cells. We did not address the
mechanism of this phenotypic change in these experiments.
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Cytokine profile of expanded CD4+ cells
We next determined whether the expanded cell population
represented a bias in Th subtype by measuring cytokines synthesized
over time in the presence of rIL-16, rIL-2, or rIL-16/IL-2 under the
identical conditions noted above. rIL-16 treatment alone did not result
in synthesis of any IL-2 at any time point (data not shown). By 2 wk,
rIL-16 treatment resulted in significant GM-CSF synthesis (Table IV). rIL-2 induced synthesis of GM-CSF,
IL-5, and IFN-. Cultures treated with both rIL-16 and rIL-2
demonstrated similar cytokine production to rIL-2-treated cultures. By
4 wk, we were able to measure cytokines only in the
rIL-16/rIL-2-cotreated cultures because there were so few viable cells
remaining under the other culture conditions. These cells secreted
IL-5, GM-CSF, and IFN- and, at this time point, there were higher
levels of IL-10 in the cell supernatants than at 2 wk (Table IV).
Addition of exogenous IL-2 and IL-16 precluded measurement of
endogenous production of these cytokines. These data indicate that the
expanded cell population can synthesize both Th1 and Th2 cytokines, and
that there is no obvious bias toward expansion of one cell type over
the other.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study addresses the long-term consequences of IL-16 stimulation, and in the process determines the functionality of the up-regulated CD25 (resulting in high affinity IL-2R) and the Th subset bias of the responding CD4+ T cell population. In regard to the function of the induced IL-2R, IL-16 pretreatment is markedly synergistic with IL-2, as determined by increased [3H]thymidine incorporation and by increased numbers of CD4+ T cells as compared with treatment with IL-2 or IL-16 alone. The synergistic effect is more prominent with the length of time in culture past 2 wk. By 4 wk, most IL-16- or IL-2-treated PBMC cultures have few surviving cells, while the proliferating cells in IL-16/IL-2-costimulated PBMC are populated almost entirely by CD4+CD45RO CD25+ T cells. IL-16/IL-2 costimulation imparts increased viability to CD4+ T cells, as almost all exclude trypan blue, while in the other cultures, up to 50% of the cells by 2 wk and 90% of the cells by 4 wk do not exclude trypan blue. We believe that the mechanism for the increase in viability of IL-16/IL-2-treated cells relates to the levels of Bcl-2 (18, 19), as IL-16/IL-2-treated cells express high levels of Bcl-2 protein, whereas the levels in cells cultured with either IL-2 alone, IL-16 alone, or untreated are greatly diminished (N.A.P., manuscript in preparation).
IL-16/IL-2 cotreatment also results in rises in the percentages of
CD45RO cells. It is not clear from our experiments whether these cells
proliferated selectively or whether there was a phenotypic change
within cells from CD45RA to CD45RO (20, 21, 22). The presence of
double-positive cells by 4 wk (Table III
) does not answer this
question; and we had insufficient cells to address this issue
definitively in the current experiments. Interestingly, IL-16/IL-2
treatment does not appear to bias toward a specific Th subtype. IL-16
treatment alone results in significant levels of GM-CSF. We believe
that this is a consequence of the regulation of GM-CSF gene
transcription and protein synthesis following CD4-dependent signaling
rather than selective activity of one Th subset, because cytokines of
both Th1 and Th2 types are synthesized and secreted by cells treated
with combination rIL-16 and rIL-2 at similar levels at both 2 and 4 wk.
Furthermore, all of these data together indicate that the
IL-16/CD4-dependent signals that regulate transcription and expression
of IL-2R are not Th subset specific. The IL-16/IL-2-expanded
CD4+ T cells do not demonstrate the same TCR
unresponsiveness observed in cells cultured for several hours with
IL-16, as anti-CD3 stimulation of 4-wk cultures results in
increased cytokine synthesis (unpublished observations). This suggests
that IL-2 stimulation over an extended period of time is sufficient to
facilitate escape of CD4+ T cells from IL-16-induced TCR
unresponsiveness in vitro.
These studies did not address any potential role for IL-16 in normal
CD4+ T cell maturation or proliferation of mature
peripheral T cells. Definitive studies must await the development of
IL-16 knockout mice. These studies do imply, however, that IL-16 may be
a reasonable adjunct to IL-2-based immune reconstitution in states in
which CD4+ T cells are diminished selectively in numbers.
In that regard, IL-16 might induce IL-2 responsiveness in unactivated T
cells across TCR specificities; and thus, expansion would not be
limited to those T cell subsets that express IL-2R at the beginning or
during the therapeutic course. The synergism in
[3H]thymidine incorporation between IL-16 and IL-15
(Table I) implies that this combination of cytokines might also be of
value in immune reconstitution; however, it is not yet clear that
IL-16/IL-15 costimulation results in expanded numbers of
CD4+ T cells over time. The effect of IL-16 stimulation on
both the - and ß-chains of the IL-2R also implies that the cells
might be responsive to other cytokines that use various components of
the IL-2R as part of their receptor complex, such as IL-7, IL-9, and
IL-13 (23). Studies investigating the effect of IL-16 stimulation on
expression of these receptor complexes as well as functional responses
to cytokine stimulation are currently in progress. As IL-16 and IL-2
are predominantly of T cell origin, while IL-15 is predominantly of
macrophage origin, these studies imply that there might be synergy
between lymphocyte- and monocyte-derived cytokines in the proliferation
of CD4+ T cells.
The present studies used a single weekly low concentration of IL-16 to augment IL-2 responsiveness. Further studies are needed to determine the frequency and doses required to induce maximal effects; to determine whether IL-16/IL-2 combination therapy will be more effective in expanding CD4 populations across TCR specificities than IL-2 alone in PBMC from immunodeficient individuals; and whether IL-16/IL-2 therapy can rescue lost antigenic responsiveness.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. William W. Cruikshank, Pulmonary Center, R-304, Boston University Medical Center, 80 East Concord Street, Boston, MA 02118. E-mail address:
3 Abbreviations used in this paper: GM-CSF, granulocyte-macrophage CSF; CD40L, CD40 ligand; PE, phycoerythrin.
Received for publication June 5, 1997. Accepted for publication November 6, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. W. E. Paul, and C. G. Fathman, and H. Metzger, eds. Annual Review of Immunology 179. Annual Reviews Inc., Palo Alto.
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