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* Departments of Medicine and Microbiology-Immunology, University of California Medical Center, San Francisco, CA 94143; and
Departments of Pathology and Laboratory Medicine, University of Texas Health Science, Houston, TX 77030
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. Flexible
responsiveness of CD4 T cells from N and K mice, but not T mice, to
exogenous VIP in vitro and in vivo is shown by increased numbers of
IL-4-secreting CD4 T cells, greater secretion of IL-4 and IL-10, and
lesser secretion of IFN- after TCR stimulation with VIP. The level
of VIP recognized by CD4 T cells thus is a major determinant of the
relative contributions of Th subsets to the immune effector
phenotype. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4, respectively, have
been complex and sometimes conflicting (14, 15). Type I G protein-coupled VIP receptors (VPAC1 Rs) are highly expressed constitutively on T cells, especially Th cells, whereas the homologous type II G protein-coupled VIP receptors (VPAC2 Rs) are expressed marginally or not at all by unstimulated Th cells (16, 17, 18, 19, 20). In contrast, VPAC2 Rs are up-regulated to high levels, and VPAC1 Rs are down-regulated by Th cell stimulation, suggesting that VPAC2 Rs are the dominant transducer of effects of VIP on activated Th cells (21, 22, 23). The low bioavailability and in vivo potency of most VIP receptor-directed pharmacological antagonists suggested the utility of developing genetically based models. A transgenic (T) C57BL/6 mouse line was established in which normally inducible VPAC2 Rs are constitutively expressed in CD4 (helper-inducer) T cells at levels equal to or exceeding those observed in active T cell-dependent responses (24). The complementary VPAC2 R model in C57BL/6 mice is represented by the VPAC2 R-null state (K) generated by targeted insertion of a mutation in exon 1 of the VPAC2 R gene (25).
The initial characterization of immunity in VPAC2 R-null (K) mice and T cell-targeted VPAC2 R T mice showed no differences from wild-type C57BL/6 mice in the number of spleen and blood T cells or their principal T cell subsets. In contrast, major differences were identified between these models and wild-type (N) C57BL/6 mice in effector T cell phenotypes, including deviation from normal CD4 T cell cytokine secretion profiles toward Th1 in K mice and toward Th2 in T mice. T mice demonstrated significantly elevated blood IgE and eosinophil levels. Consequently, K mice have increased cutaneous delayed-type hypersensitivity and markedly decreased cutaneous immediate-type hypersensitivity, whereas T mice have decreased delayed-type hypersensitivity and very strikingly increased immediate-type hypersensitivity. Although the dependence of these altered hypersensitivity phenotypes on T cell VPAC Rs and cytokine profiles is clear, additional requisites for endogenous VIP, derived from either neural or T cell sources, have not been explored previously. Much of the VIP at or near compartmental immune responses is T cell derived normally in mice. The present results show that the effector immune phenotype of each VPAC2 R line of mouse is differently dependent on physiological levels of endogenous VIP or is flexibly altered by attainable concentrations of synthetic VIP.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The VPAC2 R-null or -knockout C57BL/6 (K) mice were generated by standard methods for disruption of the first coding exon of mouse VPAC2, production and breeding of chimeric mice, backcrossing of heterozygotes with the C57BL/6 strain, and breeding of the C57BL/6 heterozygotes to establish a colony of C57BL/6 homozygous VPAC2 R-null mice (25). The VPAC2 R-T C57BL/6 (T) mice were generated by injection of C57BL/6 oocytes with a minigene encoding the LCK tyrosine kinase proximal promoter 5' to the human VPAC2 R before implantation, breeding of founders, and identification and breeding of subsequent generations with high T cell expression of human VPAC2 R (24).
Quantification of cytokines secreted by CD4 T cells of N, K, and T mice
Spleens were removed from groups of four to six
VPAC2 R-null (K), T, and wild-type (N) mice at
6–12 wk of age and were physically disaggregated as previously
described (24). Replicate suspensions of
107 splenocytes were freed of erythrocytes and
granulocytes by centrifugation through Ficoll-Hypaque (Amersham
Pharmacia Biotech, Uppsala, Sweden), depleted of adherent cells, and
resuspended in 0.4 ml of 0.02 M sodium phosphate-buffered 0.11 M NaCl
(pH 7.3) with 2 mM EDTA and 5% (v/v) FBS (Cell Culture Facility,
University of California, San Francisco, CA; IC buffer). Twenty
microliters of a suspension of metallic beads coated with
anti-mouse CD4 mAb (Miltenyi Biotec, Auburn, CA) was added to each
portion of 107 splenocytes, followed by
incubation for 60 min at 8°C, washing twice, and resuspension in 0.5
ml of IC buffer. Each suspension of splenocytes labeled with
anti-CD4 Ab metallic beads was subjected to two cycles of magnetic
column chromatography, which yielded CD4 T cells at >96% purity, as
assessed by analytical flow cytometry. Replicate 0.5-ml aliquots of
3 x 105 CD4 T cells in complete RPMI 1640
medium were preincubated with
10-9–10-6 M purified
synthetic VIP or VPAC1 R- or
VPAC2 R-selective peptide analogs of VIP and
stimulated with 1 µg/well each of adherent anti-CD3 and
anti-CD28 mouse mAbs (BD PharMingen, San Diego, CA). VIP, the
VPAC1 R-selective peptide Ac-[p-N3-F6,
NL17]-VIP, and the VPAC2 R-selective peptide
Ac-[E8, OCH3-Y10, K12, NL17, A19, D25, L26, K27,28]-VIP cyclo
(21, 22, 23, 24, 25) were synthesized and purified as previously
described (26, 27). After 24 and 96 h at 37°C,
plates were centrifuged, and aliquots of supernatant medium were
harvested for ELISAs of IL-4, IL-10, and IFN- (Endogen, Cambridge,
MA). Cytokine concentrations are represented as picograms per
milliliter or nanograms per milliliter or as a percentage of the
TCR-stimulated, CD4 T cell-positive control (100%).
Enumeration of IL-4-secreting CD4 T cells by cell surface capture and flow cytometric quantification of IL-4
Replicate aliquots of suspensions of 107 T cell-enriched splenocytes per milliliter, which had been prepared in the same manner as in the cytokine secretion protocol, were preincubated without and with 10-8 M synthetic VIP in complete RPMI 1640 medium and stimulated for up to 96 h in 24-well plates coated with 1 µg/well each of anti-CD3 and anti-CD28 mouse mAbs (BD PharMingen). The T cells then were washed once in complete RPMI medium and replated at the same concentration onto fresh anti-CD3- plus anti-CD28-coated plates for 12 h of restimulation. Suspensions of T cells were collected from the wells, washed twice in 10 ml of ice-cold PBS (pH 7.2) containing 0.5% FBS and 2 mM EDTA (PBS++), and resuspended in 80 µl of PBS++. Each diluted suspension received 20 µl of a bifunctional Ab with dual specificity for IL-4 and the CD45 T cell surface common leukocyte Ag (Miltenyi Biotec), at a dilution predetermined to capture IL-4 in amounts linearly related to the quantity secreted, and anti-Fc receptor-blocking Abs (a mixture of anti-CD18 and anti-CD32 mAbs; BD PharMingen), followed by incubation for 5 min on ice. After addition of 100 ml of DMEM-21 containing 5% FBS to each T cell suspension, incubation was continued in slowly rolling capped vessels at 37°C for 45 min to allow cell surface capture of secreted cytokines. T cells then were washed twice and resuspended in 80 µl of PBS++, and IL-4 captured on CD4 T cells was detected by reaction with 20 µl of PE-conjugated anti-IL-4 (IL-4 detection Ab; Miltenyi Biotec) and 1 µl of FITC-conjugated anti-CD4 on ice for 10 min. T cells were washed with PBS++ and metallically tagged with anti-PE microbeads, followed by isolation of IL-4-positive cells using magnetic column chromatography (Miltenyi Biotec). IL-4-secreting cells eluted from the columns were counted microscopically, and their T cell composition was analyzed by flow cytometry (11). Gates were set on live lymphocytes, determined by forward and side scatter and exclusion of propidium iodide (0.5 mg/ml).
Quantification of IL-4-containing CD4 T cells by ELISPOT
Replicate suspensions of nonadherent splenic mononuclear cells
or immunomagnetically purified CD4 T cells from
VPAC2 R T, N, and K mice were plated at densities
of 1 x 105, 5 x
105, and 1 x 106/well
in 12-well plates that had been precoated with 2 µg/well of
anti-CD3 and anti-CD28 mouse mAbs (BD PharMingen), with and
without 10 min of preincubation with 10-8 M VIP
or 1 µM IgG-VIPase. Plates were incubated at 37°C for 72 h,
and then T cells were removed from the wells, washed once,
resuspended in 200 µl of complete medium, and added to anti-IL-4
Ab-coated ELISPOT plates, followed by an overnight incubation at
37°C. ELISPOT plates were developed according to the manufacturer’s
protocol (BD PharMingen), and the number of spots, which corresponds to
IL-4-secreting cells, was counted using an 
Fluorchem 8800 imaging
system (Innotech, Wohlen, Switzerland).
Determination of VIPase IgG concentration-dependence of degradation of VIP
125I-labeled VIP and T cell-derived
immunoreactive VIP were both examined for susceptibility to degradation
by catalytic VIPase IgG (clone c23.5) and an inactive IgG isotype
control. The VIPase IgG is a murine IgG2a 
Ab purified to
electrophoretic homogeneity by protein G-Sepharose chromatography
(28). The control IgG (clone UPC10; Sigma-Aldrich, St.
Louis, MO) has the same heavy and light chain isotypes as VIPase IgG.
Degradation of 106 cpm of
125I-labeled VIP (NEN, Boston, MA) with 1 nM synthetic
VIP1–28 was examined in replicate suspensions of
2 x 106 splenic CD4 T cells in 1 ml of
complete RPMI medium for 24 and 96 h at 37°C in 24-well plates
without and with 1 µg each of anti-CD3 plus anti-CD28
adherent mAbs and without and with 0.01–3 µM VIPase or isotype
control IgG. Degradation was quantified by extraction of peptides from
the suspensions and HPLC resolution, recovery, and quantification of
the residual intact radiolabeled VIP as previously described
(29). To assess the capacity of IgG VIPase to degrade
endogenous VIP, replicate suspensions of 2 x
106 splenic CD4 T cells in 1 ml of complete
RPMI medium were preincubated for 24 h at 37°C in 24-well plates
on 1 µg each of anti-CD3 plus anti-CD28 adherent mAbs to
allow secretion of VIP and then for 24 and 96 h at 37°C without
and with 0.01–3 µM VIPase or isotype control IgG (30).
Peptides were extracted and resolved from residual IgG VIPase by
adsorption chromatography on Sep-Pak columns as previously described
(29). Radioimmunoreactive VIP was quantified by RIA
(Phoenix Pharmaceuticals (Belmont, CA) or DiaSorin (Stillwater, MN)) to
allow for calculation of the percentage degraded by VIPase.
Generation of VIP by CD4 T cells
Replicate suspensions of 0.5 x 106 immunomagnetically purified splenic CD4 T cells from VPAC2 R T, N, and K mice were incubated in 1 ml of complete RPMI 1640 medium without and with 1 µg each of adherent anti-CD3 plus anti-CD28 mAbs for 24 and 96 h at 37°C. VIP in aliquots of supernatant from each suspension was recovered by reverse phase adsorption chromatography on Sep-Pak columns as previously described (29). VIP was quantified by RIA (DiaSorin or Phoenix Pharmaceuticals).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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VIPase degradation of T cell-derived VIP
Available VIP receptor antagonists have limited potency, and
therefore a catalytic IgG Ab with highly specific VIPase activity was
introduced into suspensions of N mouse splenic CD4 T cells before the
introduction of 125I-labeled VIP and into replicate
suspensions 24 h after the onset of TCR-dependent stimulation
sufficient to evoke secretion of VIP by the T cells (Table I
). In the latter protocol, without
VIPase or exogenous VIP, stimulated T cells generated a mean VIP
concentration (±SD) of 1.3 ± 0.5 ng/ml in the 24 h before
addition of VIPase to other samples and 3.4 ± 0.7 and 2.8 ±
0.4 ng/ml, respectively, in medium alone 24 and 96 h after VIPase
was added to other samples. Thus, steady state concentrations of VIP
had reached a plateau in control suspensions at 24 h after
addition of VIPase to experimental suspensions. VIPase IgG, but not
isotype control IgG, efficiently degraded VIP in T cell
suspensions, as assessed by cleavage of 125I-labeled VIP
and radioimmunoreactive endogenous VIP (Table I). For both assays, the
extent of degradation of VIP was highly significant at 0.1–3.0 µM
VIPase and attained maximal levels of 87–95% at 1 µM VIPase. Thus,
for all other studies of VIPase the concentration was set at 1 µM. As
both assays are least accurate at the lowest concentrations of VIP, 10
representative low level samples with apparent concentrations of
10–100 pM endogenous VIP were re-extracted on Sep-Pak columns to
achieve 10-fold concentration and were requantified by RIA. In the
eight samples with 12–34 pM VIP in the initial assay, repeat
determinations showed 21–66 pM VIP, equivalent to unconcentrated
values of 2.1–6.6 pM. Thus, it is estimated that maximal degradation
of VIP exceeds 95% at 1.0 µM VIPase.
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Stimulation of CD4 T cells with adherent anti-CD3 plus
anti-CD28 Abs for 96 h resulted in the secretion of
significantly different concentrations of IFN- with a rank order of
K > N > T mice (Fig. 1A). Ex vivo exposure of
replicate suspensions of CD4 T cells from the same three types of mice
to 1.0 µM VIPase, but not isotype control IgG, during 96 h of
stimulation increased IFN- secretion for T mice 
50%, up to
levels in N mice. No significant alterations in IFN- secretion by
CD4 T cells from N and K mice were evoked by VIPase-induced decreases
in VIP concentration of similar magnitude (Fig. 1A). Similar
stimulation of CD4 T cells from the same three types of mice led to
significantly different levels of secretion of IL-4, with T >
N > K (Fig. 1B). Exposure of CD4 T cells to VIPase,
but not isotype control IgG, during this stimulation decreased IL-4
secretion by a mean of 73% for T mice, down to levels in N mice. In
contrast, only a minor reduction in IL-4 secretion was observed for N
mice, and none was seen for K mice. The results of analyses of IL-10
secretion closely paralleled those of IL-4, with significant
differences for the three types of CD4 cells of T > N > K
in the absence of VIPase (Fig. 1C). VIPase, but not isotype
control IgG, lowered by a mean of 50% the level of IL-10 secretion
from CD4 T cells of T mice to the range of that seen in N mice (Fig. 1C). Thus, maintenance of the higher levels of secretion of
IL-4 and IL-10 and of the lower level of secretion of IFN- by CD4 T
cells of T mice than N and K mice is highly dependent on T
cell-generated VIP.
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). The percentage of IL-4-secreting CD4
T cells in N mice was between the respective levels in K and T mice.
When considered as a percentage of nonadherent stimulated splenocytes,
IL-4-secreting lymphoid cells were a mean (±SD) of 3.5 ± 0.5%
of the total for K mice, 5.7 ± 0.4% for N mice, and 19 ±
2.4% for T mice (p < 0.001 for T vs N and T
vs K). The effect of VIPase on levels of IL-4 positivity in CD4 T cells
stimulated by adherent anti-CD3 plus anti-CD28 Abs for 96
h also was quantified by an ELISPOT assay, which is less sensitive than
the IL-4 capture-flow cytometric assay and therefore detects only the
cells secreting IL-4 at high levels. The mean number of
ELISPOT-positive IL-4-secreting cells in populations of CD4 T cells was
twice as high for T mice as for either K or N mice without VIPase (Fig. 3). In the presence of isotype control
IgG, there was no significant change in the levels of IL-4-containing
CD4 T cells, and the level for T mice remained significantly higher
than those for N and K mice (p < 0.001; Fig. 3). VIPase very significantly decreased the number of IL-4-secreting
CD4 T cells for T mice without affecting those of N and K mice. Thus,
the basis for higher overall levels of secretion of IL-4 by stimulated
CD4 T cells from T mice than from N and K mice is a greater number of
both total and high level IL-4-secreting cells, rather than a much
higher level of secretion by a similar number of cells. Similarly, the
VIPase-induced reduction in overall IL-4 secretion by CD4 T cells of T
mice to levels seen in N and K mice, without any change in IL-4
secretion by the latter sets of CD4 T cells, is attributable
principally to a decrease in the number of IL-4-secreting CD4 T
cells.
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The concentrations of immunoreactive VIP established by
unstimulated CD4 T cells and the much higher levels attained by CD4 T
cells stimulated by adherent anti-CD3 plus anti-CD28 Abs were
not significantly different among the three types of mice at 24 h
(Table II). However, the concentration of
VIP attained by stimulated CD4 T cells from T mice was significantly
greater than those in cells from N and K mice at 96 h.
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To examine the possibility that in vivo administration of
bioavailable synthetic VIP agonists might alter the profile of
cytokines secreted by CD4 T cells stimulated ex vivo, groups of
6-wk-old N and T mice received either a VPAC1
R-selective or VPAC2 R-selective agonist or
saline vehicle alone for 8 wk before studies of cytokine secretion.
IFN- secretion by stimulated CD4 T cells was significantly higher
for N than T mice, as expected (Fig. 4).
The VPAC2 agonist, but not the
VPAC1 agonist, suppressed IFN- secretion from
N CD4 T cells, but neither agonist altered IFN- secretion by T CD4 T
cells. IL-4 and IL-10 secretion by stimulated CD4 T cells was
significantly higher for T than for N mice (Fig. 4). The
VPAC2 agonist, but not the
VPAC1 agonist, significantly enhanced the
secretion of IL-4 and IL-10 by N CD4 T cells, but neither agonist
altered the secretion of these cytokines by T CD4 T cells. Thus,
the profile of cytokines secreted by stimulated CD4 T cells of N mice
is pushed toward a T mouse pattern by in vivo exposure to
VPAC2 R, but the profile of cytokines from CD4 T
cells of T mice is not further influenced by exogenous VIP
agonists.
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A) and in
stimulated purified CD4 T cells of T than N or K mice (Fig. 5B), with no differences in any of the unstimulated sets.
VIP significantly increased the number of IL-4-secreting T cells in CD4
T cells from N and K mice without altering that in T mice (Fig. 5B). Thus at the T cell level, as well as from the
quantities secreted, exogenous VIP increases IL-4 and presumably IL-10
in CD4 T cells from N and K mice without further increases in T mice.
The increases observed in CD4 T cells from N mice are attributable to
VPAC2 R effects (Fig. 4
), whereas VIP-evoked
increases in IL-4-secreting CD4 T cells in K mice are assumed to be
mediated by their normally expressed VPAC1
Rs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The CD4 T cell secreted cytokine profile of T mice, which is biased
toward Th2 relative to that of N mice, is dependent on T cell-derived
VIP. Destruction of 99% of this endogenous VIP by VIPase results in
substantial normalization of this cytokine profile, as evidenced by
increases in IFN- and decreases in IL-4 and IL-10 (Table I and Fig. 1). In contrast, the Th1 cytokine-biased profile of stimulated CD4 T
cells from K mice is not influenced by similarly profound destruction
of VIP. That the fundamental difference in T mice is a greater
dependence of their cytokine-secreting CD4 T cells on VIP was confirmed
by finding a higher native level of IL-4-secreting CD4 T cells and
return to a normal level by VIPase destruction of endogenous VIP (Figs. 2 and 3). This greater functional dependence of CD4 T cells from T mice
on the VIP they secrete may, in turn, reflect two distinctive
characteristics of these CD4 T cells. The first is their higher output
of VIP than CD4 T cells of N and K mice (Table II), which may simply
reflect a higher percentage of Th2 cells that are the principal source
of VIP (22). Adaptation to a higher endogenous level of
VIP thus may result in an effectively greater dependence on VIP. The
second is the expression of a greater density of the functionally
dominant VPAC2 Rs by CD4 T cells of T mice than
by CD4 T cells of N and K mice, which may further increase their
sensitivity to VIP and thereby the dependence of their Th2 phenotype
on VIP.
Application of exogenous VPAC R-selective analogs of VIP in vivo (Fig. 4) and of VIP in vitro (Fig. 5) had effects reciprocal to those of
VIPase destruction of endogenous VIP. The secreted cytokine profile of
N mice was pushed toward that of a higher Th2/Th1 ratio by in vivo
VPAC2 R-selective agonist, but not by VPAC1
R-selective agonist, with significant decreases in IFN- and
increases in IL-4 and IL-10 (Fig. 4). No change in the cytokine profile
of CD4 T cells from T mice was observed after the same in vivo course
of VPAC2 R-selective agonist. Similar in vitro
introduction of VIP onto layers of stimulated CD4 T cells significantly
increased the number of IL-4-secreting cells for N and K mice, but not
for T mice (Fig. 5B). It was not possible to examine the
involvement of each type of VIP R as a transducer of native VIP effects
in CD4 T cells of N mice because of the lack of selective antagonists.
A cytokine regulatory role for VPAC1 Rs in some
settings also seems possible and is supported by VIP induction of more
IL-4-secreting CD4 T cells for K mice, which lack
VPAC2 Rs, but express a normal level of
VPAC1 Rs (Fig. 5).
VIP increases effector activities of Th2 cells over Th1 cells
preferentially by many mechanisms. The spectrum of VIP effects leading
to Th2 cell predominance includes enhanced differentiation of
thymocytes and T cells to the Th2 lineage, selective survival of Th2
cells, and their greater functional activation. Differential
stimulation of Th2 cell development by VIP is attributable both to
accelerated maturation of Th cells and to skewed promotion of
Ag-dependent differentiation to Th2 cells (22). Deviation
of differentiation to Th2 cells and away from Th1 cells by VIP is in
part due to enhancement of expression of APC coreceptors, such as B7.2,
which thereby promotes the production of Th2-enhancing and
Th1-suppressing cytokines (31). VIP accomplishes greater
survival of Th cells, with a preference for Th2 cells, by inhibition of
expression of the Fas/Fas ligand system (32).
Reinforcement of the Th2 cell selectivity of VIP mechanisms is provided
through both greater secretion of VIP by Th2 cells than Th1 cells and
the expression of higher levels of VIP receptors by Th2 cells than Th1
cells (22). The current results add substantially to our
understanding of the mechanisms by which VIP selectively increases the
number and activities of Th2 cells. A greater influence of the
VIP-VPAC2 R axis in T mice than N mice, which is
VIP and cytokine dependent, increases both the number of Th2 cells
based on cellular cytokine profiles of CD4 T cells and their secretory
activities based on the IL-4/IFN- concentration ratio in the medium.
These newly recognized effects of VIP on Th2 cells are Ag independent
and are highly dependent on VIP for maintenance. Their apparent
susceptibility to manipulation by VPAC R-selective antagonists paves
the way for analyses of pharmacological agents.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Edward J. Goetzl, University of California, UB8B, UC Box 0711, 533 Parnassus at 4th, San Francisco, CA 94143-0711. E-mail address: egoetzl{at}itsa.ucsf.edu
3 Abbreviations used in this paper: VIP, vasoactive intestinal peptide; K, knockout; N, wild type; T, transgenic; VPAC1 R, type I G protein-coupled VIP receptor; VPAC2R, type II G protein-coupled.
Received for publication September 16, 2002. Accepted for publication November 1, 2002.
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