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*
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and
Department of Neurology and Neurological Sciences, Stanford University, Beckman Center, Stanford, CA 94305
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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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Neuropeptides, unlike classical immunologic signals, are secreted from nerve endings in transient bursts and induce signaling in target T cells over a time frame of milliseconds to minutes. Neuropeptides act as conventional neurotransmitters, transducing signals from the environment, which can then be communicated to specific targets, including the immune system. Since neuropeptides are released from nerve endings present in lymphoid tissues and extravascular tissues (1), we examined whether neuropeptides such as SOM, CGRP, NPY, and SP could modify the T cell adhesiveness of to extracellular matrix (ECM) ligands, a prerequisite process for T cell extravasation and migration that involves activation-dependent modulation of the avidity of ECM binding to ß1 (VLA) integrins (12, 13, 14, 15).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following were obtained from the sources indicated: BSA,
fibronectin (FN), PMA, Gly-Arg-Gly-Asp-Ser, Gly-Arg-Gly-Glu-Ser, SOM,
CGRP, NPY, SP, SOM antagonist
(cyclo-[7-aminoheptanoyl-Phe-Trp-Lys-Thr(bzl)]), CGRP antagonist
(CGRP8–37), haloperidol, SP antagonist (also referred
to as spantide 1;
[D-Arg1,D-Trp7,9,Leu11]SP),
SP fragments (1, 2, 3, 4, 4, 5, 6, 7, 8, 9, 10, 11, 5, 6, 7, 8, 9, 10, 11, 6, 7, 8, 9, 10, 11, 7, 8, 9, 10, 11, 8, 9, 10, 11, 9, 10, 11),
genistein, staurosporine, and pertussis toxin (Sigma Chemical Co., St.
Louis, MO); NPY amino acid sequence 18–36 (Peninsula Laboratories,
Belmont, CA); wortmannin (Biomol Research Laboratories, Plymouth, PA);
GF109203X (bisindolymaleimide I; a gift from Dr. Y. Zick, The Weizmann
Institute of Science, Rehovot, Israel); recombinant human macrophage
inflammatory protein-1ß (MIP-1ß; PeproTech, Inc., Rocky Hill, NJ);
HEPES buffer, antibiotics, sodium pyruvate, and RPMI 1640 (Beit-Haemek,
Israel); Na251[Cr]O4 (Amersham,
Aylesbury, U.K.); and mAb to the human CD29 molecule (ß1
integrin), LFA-1, and 
2-, 4-, and 5-chains of the VLA
integrins (Serotec, Oxford, U.K.).
T cells
Human T cells were purified from the peripheral blood of healthy donors as follows. The leukocytes were isolated on a Ficoll gradient, washed, and incubated on petri dishes (37°C, humidified 10% CO2 atmosphere). After 2 h, the nonadherent T cells were removed and incubated on nylon-wool columns (Novamed Ltd., Jerusalem, Israel). Nonadherent T cells were eluted, washed, and passed through human CD3+ cell purification columns (Cedar-Lane, Willowbrook, Ontario, Canada). The resulting cell population was >92% T cells (15). Myelin basic protein (amino acid sequence 87–99)-specific CD4+ T cell lines of the Th2 phenotype were obtained from SJL/J mice.
Adhesion assay
Adhesion of these T cells to FN-coated microtiter flat-bottom wells (1 µg/well; Sigma) was assayed as previously described (15). Briefly, T cells were labeled with Na2[51Cr]O4, washed, resuspended in adhesion medium (RPMI 1640 supplemented with 2% BSA, 1 mM Ca2+, 1 mM Mg2+, 1% sodium pyruvate, 1% glucose, and 1% HEPES buffer), pretreated (30 min, 37°C) with neuropeptides (10-16-10-5 M), and added to the FN-coated wells. The microtiter plates were then incubated (37°C, 30 min, humidified 10% CO2 atmosphere) and washed with PBS to remove nonadherent T cells. The adherent T cells were lysed with 1% Tween-20 in 1 N NaOH, and the radioactivity in the resulting supernatants was determined in a gamma counter. For each experimental group, results were expressed as the mean percentage (±SD) of bound T cells from quadruplicate wells. Neuropeptide-treated T cell adhesion to BSA-coated wells and untreated T cell adhesion to FN-coated wells were always <6%. The percentage of cells that adhered was calculated as follows: (counts per minute of residual cells in the well/(total counts per minute of cells added to the well - spontaneous release of 51Cr)) x 100.
Blocking neuropeptide-induced T cell adhesion by specific antagonists
51Cr-labeled T cells were treated with neuropeptide antagonists (10-6 M) and 2 min later also with SOM, CGRP, or NPY (10-8 M). The treated cells were suspended in adhesion medium and incubated (30 min, 37°C) in a humidified 10% CO2 incubator. The cells were seeded in the FN-coated microtiter plates, and the plates were then returned to the incubator for an additional 30-min incubation. The amount of T cell adhesion was determined.
Involvement of specific integrins in neuropeptide-induced T cell adhesion to FN
51Cr-labeled T cells were treated (30 min)
either with the RGD- or the RGE-containing peptides (50 µg/ml) or
with mAb (15–25 µg/ml) specific to the human integrins (CD29, LFA-1,
and 2, 4, and 5 chains of the VLA integrins). The T cells were
then treated (30 min) with SOM, CGRP, or NPY (10-8 M) and
incubated (30 min, 37°C, humidified 10% CO2 incubator).
The treated cells were seeded in FN-coated microtiter plates. The
plates were returned to the incubator for an additional 30-min
incubation, and T cell adhesion was determined as previously
described.
Modulation of neuropeptide-induced T cell adhesion to FN by inhibitors of intracellular signaling pathways
T cells were exposed (10 min, 37°C) to genistein (100 nM), staurosporine (10 nM), pertussis toxin (2 mg/ml), GF109203X (20 nM), or wortmannin (100 nM), and then to SOM, CGRP, or NPY (10-8 M) or PMA (25 ng/ml; 30 min in a 37°C, humidified 10% CO2 incubator). These T cells were then seeded in FN-coated microtiter plates. The plates were returned to the incubator for an additional 30-min incubation, after which T cell adhesion was determined.
Inhibition of T cell adhesion to FN by SP or its fragments
T cells were treated (30 min) with SP (10-14-10-6 M) or SP C-terminus amino acid fragments (10-10 M: peptides 4–11, 5–11, 6–11, 7–11, 8–11, or 9–11). The T cells were then exposed to PMA, CGRP (10-8 M), or MIP-1ß (20 ng/ml). In a parallel set of experiments, T cells were treated with 10-6 M [D-Arg1,D-Trp7,9,Leu11]SP (spantide 1, a SP NK1 receptor antagonist) and, 2 min later, with SP (10-10 M). Thirty minutes later, these cells were exposed to PMA (30 min, 25 ng/ml) or CGRP (10-8 M) and seeded onto FN-coated microtiter wells. The plates were returned to the incubator for an additional 30-min incubation, and then treated as previously described.
Statistical analysis
Statistical significance was analyzed by Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate whether SOM, CGRP, NPY, and SP can influence the
adhesion of T cells to FN, freshly purified T cells obtained from the
peripheral blood of healthy human donors were radioactively labeled;
treated with 10-4 to 10-16 M SOM, CGRP,
NPY, or SP; and seeded on FN-coated surfaces. Thirty minutes later,
their adhesion to FN-coated surfaces was assessed. The results
indicated that physiologic concentrations (Refs. 1, 2, 5, 16) of SOM,
CGRP, or NPY (Fig. 1
, A and
B, respectively) induced marked levels of T cell adhesion to
FN, at a magnitude of 10- to 30-fold more than the background adhesion
(adhesion of neuropeptide-treated T cells to BSA and of untreated T
cells to FN-coated wells). Calculation of the percentage of T cells
that adhere to FN of the total T cell population present in the assay
(taking into account the radioactivity level of the cells added to the
well, the radioactivity of the residual cells in the well, and the
background radioactivity) showed that SOM, CGRP, and NPY induced
adhesion of 25 to 50% of the T cells, a level comparable to T cell-FN
interactions induced by chemokines (14, 15). Figure 1A shows
that SOM, CGRP, and NPY at 10-8 M induced 49, 47, and 33%
T cell adhesion, respectively. The adhesion induced by these
neurotransmitters was dose dependent with several peaks. The maximal
proadhesive effects of SOM, CGRP, and NPY were evident with
10-11, 10-8, and 10-5 M for SOM;
10-13, 10-10, and 10-7 M for
CGRP; and 10-12 and 10-8 M for NPY (data not
shown).
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In addition to being assayed on human T cells, SOM and CGRP were tested
for their effects on the adhesion of the anti-myelin basic protein
CD4+ murine T cell line. The unstimulated T cells were
treated with SOM and CGRP exactly as described for the human cells. The
results (Fig. 1
B) indicated that SOM
(10-11 M), CGRP (10-7 M), and NPY
(10-8 M) induced a 10-fold increase over the background
level of the murine T cell line, corresponding to adhesion of 35, 44,
and 38% of the total T cell population, respectively. Thus, the
neuropeptides tested induced the adhesion of resting T cells of human
as well as murine origin. In contrast, SP did not increase the level of
T cell adhesion to FN beyond the background level (Fig. 5A).
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Certain proadhesive mediators exert their effects while acting in
their soluble or matrix-bound forms (17, 18). Therefore, we examined
whether SOM, CGRP, and NPY (at 10-8 M) induce T cell
adhesion by interacting with immobilized FN, by direct effecting T
cells, or both. Significant adhesion of T cells to FN was evident only
if the T cells were pretreated with the neuropeptides, regardless of
whether the neuropeptides were removed by washing before the seeding of
the cells on immobilized FN (Fig. 2A).
Pretreatment of FN with a similar concentration of the neuropeptides
did not affect T cell adhesion, implying that the neuropeptides exert
their proadhesive role on T cells. Pre-exposure of T cells to SOM,
CGRP, and NPY followed by the removal of these neuropeptides is
sufficient to activate the integrins mediating the subsequent adhesion
to FN. Hence, after activating their respective receptors, the
neuropeptides do not have to be present at the time of T cell
adhesion.
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Specific neuropeptide receptor antagonists (at
10-6 M) were used to test whether the proadhesive
effects of SOM, CGRP, and NPY were indeed due to their interactions
with specific receptors expressed on T cells. The results (Fig. 2B) demonstrate that the proadhesive effects of SOM
and CGRP on T cells were specifically and significantly
(p < 0.05) inhibited in the presence of their
respective antagonists (7, 8, 11). Thus,
cyclo-[7-aminoheptanoyl-Phe-Trp-Lys-Thr(bzl)] (19), an antagonist of
SOM receptor, and CGRP8–37, an antagonist of the CGRP
receptor (20) inhibited SOM- and CGRP-induced T cell adhesion to FN,
respectively. NPY-induced T cell adhesion was specifically inhibited by
haloperidol, a dopaminergic receptor antagonist previously described
as having the ability to interfere with NPY-induced effects (21).
None of the antagonists alone influenced the background levels of T
cell adhesion to FN. Therefore, the proadhesive effects of SOM, CGRP,
and probably NPY are functionally linked to direct interactions with
their specific surface-expressed T cell receptors.
We further investigated the involvement of the NPY receptor in
NPY-induced T cell adhesion to FN as well as its subtype specificity.
In the absence of an available NPY-specific antagonist, we tested the
proadhesive effect of an NPY18–36 C-terminal fragment, a
selective NPY receptor agonist for the Y2 receptor subtype (22). Figure 2C shows that, similar to the effects of the intact NPY
molecule, the NPY18–36 fragment, which is highly active as
an inducer of histamine release from mast cells (23), markedly induced
a significant adhesion of T cells to FN. This finding suggests that T
cells express a functional NPY receptor of the Y2 subtype, which upon
activation may provide the T cells with a proadhesive signal.
Neuropeptide-induced T cell adhesion to FN is mediated by the
4ß1 and
5ß1 integrins
T cell recognition and adhesion to FN are mediated primarily by
the 4ß1 and
5ß1 integrins (12, 13). Whether SOM-,
CGRP-, and NPY-induced T cell adhesion was regulated by these
integrins was analyzed using mAb specific for 4,
5, and ß1 integrin moieties and a peptide
containing the cell binding motif of FN and related ECM and plasma
proteins, Arg-Gly-Asp (RGD), that is recognized by
5ß1 integrin. Figure 3 shows that adhesion to FN of resting T
cells induced by SOM, CGRP, and NPY was specifically and significantly
inhibited by the presence of an mAb against CD29 (the ß1
integrin chain), by an mAb specific to the 4 and
5 integrin chains, and by the RGD-containing peptide,
but not by the RGE-containing peptide. The adhesion was not influenced
by the mAb anti-VLA-2 (2ß1) and
anti-LFA-1 (Lß2) integrins.
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4ß1 and 5ß1
integrins. The neuropeptide-induced proadhesive effect is not
associated with elevated expression of these integrins, but probably
with induction of conformational changes. The activation of SOM, CGRP, and NPY receptors leading to T cell adhesion is mediated through diverse intracellular signaling pathways
For SOM, CGRP, and NPY to induce T cell adhesion to FN, two
distinct processes must take place: 1) the activation of their specific
T cell-expressed, G protein-coupled receptors and their characteristic
signal transduction pathways, and 2) the translation of the specific
receptor signaling into a chain of events culminating in the activation
of specific integrins mediating the subsequent adherence of T cells to
their ECM ligands. These processes probably involve propagation of
conformational changes from the cytoplasmic domains of the integrins to
their extracellular ligand binding sites by rearranging of the
cytoskeleton and forming cell-ECM focal adhesion sites (12, 23). To
examine the putative signal transduction pathways involved in this
biphasic process, we used specific signal transduction inhibitors and
tested their effects on the SOM, CGRP, and NPY-induced T cell adhesion
to FN. PMA-induced T cell adhesion to FN served as a control. Figure 4 shows that pretreatment of the T cells
with pertussis toxin, a specific inhibitor of
G1-coupled signaling (G protein-coupled receptor)
(15), abolished T cell adhesion subsequently induced by SOM, CGRP, and
NPY (all at 10-8 M).
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, A–C) in a dose-dependent
manner (data not shown). Note that wortmannin and, to a lesser degree,
genistein and pertussis toxin only partially interfered with the
PKC-activating PMA-induced T cell adhesion to FN (Fig. 4D). Together, these results suggest an interaction
between SOM, CGRP, and NPY and their specific T cell-expressed G
protein-coupled receptors, which leads to up-regulation of
4ß1 and 5ß1
affinities and to subsequent binding to FN mediated through diverse
intracellular signaling pathways involving characteristic G protein,
PTK, PKC, and PI-3 kinase signaling. SP, through activation of its NK1 receptor, abrogates T cell adhesion induced by CGRP, SOM, NPY, PMA, and MIP-1ß
SP, an undecapeptide, failed to induce T cell adhesion to FN.
Nevertheless, SP has been found at sites of inflammation and within
lymphoid organs where it is frequently colocalized in perivascular as
well as nonvascular nerve fibers together with other neuropeptides,
mainly CGRP (1, 11, 29, 30). In view of these findings, we decided to
examine the possible functional interaction between SP and CGRP as well
as that between SP and SOM or NPY regarding their effect on T cell
adhesion. We first tested the modulatory effect of SP on T cell
adhesion to FN induced by PMA and found that SP inhibited the
proadhesive effect of PMA in a dose-dependent manner, with an apparent
maximal inhibitory effect occurring at 10-8 M (Fig. 5A). To examine whether
SP exerted its effect on PMA-induced adhesion through specific
interaction with its T cell-expressed receptors, we used the
SP-derivative
[D-Arg1,D-Trp7,9,Leu11]SP,
referred to as spantide 1, a specific receptor antagonist for the NK1
receptor subtype. Figure 5A shows that spantide 1 abrogated
the inhibitory effect of SP on PMA-induced T cell adhesion to FN, thus
suggesting that the inhibitory effect of SP is indeed mediated through
a functional T cell-expressed SP receptor of the NK1 subtype.
The physiologic relevance of SP-induced inhibition of T cell adhesion
was examined by testing neuropeptide ability to interfere with the
proadhesive effect of CGRP, SOM, NPY, and MIP-1ß. The results
indicated that SP (10-10 M) inhibited the proadhesive
effects of each of the three neuropeptides (Fig. 5B).
Moreover, SP inhibited the proadhesive effect of MIP-1ß, a chemokine
that plays a role in directing the migration of leukocytes from blood
vessels to inflamed sites and induces T cell adhesion to ECM moieties
(14, 15, 31). Exposure of T cells to alternate sequential combinations
of SOM, CGRP, or NPY revealed that none of these molecule interfered
with the adhesive effects induced by the other, nor did these mediators
affect MIP-1ß-induced T cell adhesion to FN (data not shown).
Interestingly, the proadhesive effects of SOM, CGRP, NPY, and MIP-1ß
were not synergistic, since neither combination induced a higher
adhesion level than that observed by any of these effectors alone (data
not shown).
SP inhibits T cell adhesion either through its six-amino acid carboxyl terminus or via its N-terminal fragment
The carboxyl-terminal amino acid sequence of SP, which is
conserved in all members of the tachykinin family, is involved in
vasodilation, smooth muscle contraction, saliva secretion, and pain
transmission. In contrast, the naturally occurring
NH2-terminal fragments of SP are active in stimulating
histamine release from mast cells, modulation of catecholamine release,
and induction of antinociception (11). To determine whether the
C-terminus portion of SP can inhibit T cell adhesion to FN, and if so,
which amino acids within it are required to exert the inhibitory
potential, we tested the SP peptides 4–11, 5–11, 6–11, 7–11, 8–11,
and 9–11. The results showed that SP C-terminal fragments 4–11,
5–11, and, to a slightly lesser degree, 6–11 at a concentration of
10-8 M inhibited PMA- and CGRP-induced T cell adhesion to
FN as efficiently as the intact SP molecule (Fig. 6A). Shorter C-terminal
SP fragments, even at a concentration of 10-3 M, failed to
inhibit T cell adhesion to FN (data not shown). The inhibitory effect
of the 4–11, 5–11, and 6–11 SP fragments was abrogated by the
spantide 1 receptor antagonist. Thus, the six-amino acid long carboxyl
terminal of SP, through amino acids 4, 5, and 6, can inhibit T cell
adhesion at the same concentration range and through the same receptor
subtype as the intact SP peptide.
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B). The inhibitory effect
of the SP1–4 peptide was completely abrogated in the
presence of spantide-1 (Fig. 6B), suggesting that the
suppressive effect of the SP1–4 peptide was also mediated
through the SP NK1 receptor subtype. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to the indications regarding SOM, CGRP, and SP receptors, we have provided evidence for a functional response of T cells to NPY and suggest that it is mediated through an NPY receptor of the Y2 receptor subtype on T cells, since T cell adhesion could be also induced by the NPY carboxyl fragment, NPY18–36, a selective agonist for the NPY-Y2 receptor subtype. Receptors of the NPY Y1 subtype, but not that of the Y2, were previously reported to be expressed, in low levels, on rat splenic lymphocytes (31, 32). The NPY-Y2 receptor subtype is widely distributed in the brain and in the periphery, where it is localized at prejunctional sites at the sympathetic neuro-effector junctions, suppressing the release of neurotransmitters (33, 34). It is also localized on other nerve fibers, such as the parasympathetic and sensory C fibers (34, 35).
The T cell adhesion to FN induced by SOM, CGRP, and NPY was found to be
mediated by the 4ß1 and
5ß1 integrins involved in T cell-FN
interactions (12, 13). Moreover, the neuropeptide-induced T cell
adhesion probably involves diverse intracellular signal transduction
pathways, including characteristic G protein signaling, PTK, PKC, and
PI-3 kinase, since all the relevant inhibitors blocked the effect.
Integrin activation and subsequent T cell adhesion to ECM glycoproteins occurs after cell activation, since integrins expressed on resting T cells do not mediate strong adhesion to counter-receptors and ligands (36, 37). T cells may be activated by one of various possible mechanisms, such as activation with phorbol esters, chemoattractants, or cross-linking of functionally relevant surface receptors (e.g., Ag receptor/CD3 complex, CD2, Ig, or MHC class II molecules) (36). For any given cell type, multiple activation stimuli can up-regulate the functional activities of integrins. The activation-dependent regulation of integrin adhesiveness does not require an increase in the amount of integrins on the cell surface but, rather, qualitative changes in the integrin-receptor affinity or cytoskeleton-dependent clustering of integrins that serve to increase the overall avidity of these receptors (38, 39, 40). Our results imply that the binding of SOM, CGRP, and NPY to their respective T cell-expressed receptors induces T cell activation that subsequently leads to up-regulation of integrin functional activity. Such activation of T cells by these neuropeptides may lead to other T cell functions in addition to adhesion to ECM components.
In contrast to the proadhesive effect of SOM, CGRP, and NPY, SP blocked the adhesion of T cells to FN by activating its NK1, rather than the NK2 or NK3, receptor subtype, since a specific NK1 receptor antagonist abrogated the SP-induced effect. Our findings with the SP receptor contradict the claim that SP receptors are absent on human PBL (35). Inhibition of T cell adhesion was also induced by SP 4–11, 5–11, and 6–11 fragments (but not by shorter C-terminus peptides) and by its 1–4 amino-terminus portion. Interestingly, both the C- and the N-SP fragments could be generated in vivo by enzymatic cleavage of the intact molecule (41). The inhibitory effect induced by the intact SP (i.e., full-length) and its N-terminal and six- to eight-amino acid long C-terminal fragments were blocked by spantide-1, an SP NK-1 receptor antagonist. These results suggest that the parent SP peptide as well as its fragments mediate their inhibitory effect (at physiologic concentrations) through a T cell-expressed SP NK1 receptor and raise the possibility the human T cells harbor an SP receptor displaying an extended binding site to which various SP fragments can bind to induce its activation (11). Indeed, recent studies have demonstrated that both the parent SP molecule and its N- and C-terminal fragments at 1 nM can modulate striatal dopamine outflow (42, 43).
The precise mechanism(s) by which SP blocks T cell adhesion is currently under investigation. Nevertheless, the ability of SP to block (at physiologic concentrations) T cell adhesion induced by neuropeptides, MIP-1ß, and PMA suggest that this neuropeptide could inhibit T cell migration into inflamed sites. Neuropeptides with antagonistic functions may colocalize in nerve fibers innervating lymphoid organs, just as antagonistic neurotransmitters may colocalize in nerve fibers within the central nervous system (1). Previous studies have shown that SP and CGRP are cotransmitted from peripheral endings of sensory nerves, including those innervating most of the lymphoid tissues (1, 29). Our finding that these two neurotransmitters have opposing effects on T cell adhesion (CGRP induces adhesion, while SP blocks it) suggests that colocalizing neuropeptides may provide T cells with both positive and negative information and thereby regulate their function.
In conclusion, we suggest that neuropeptides, usually found and active in the sensory nervous system, can also function in lymphoid organs and in inflamed sites via binding and activating their respective T cell-expressed receptors. Neuropeptides may, thereby, play roles in T cell activation, adhesion, and migration. The physiologic relevance of these observations should be backed up by in vivo studies.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Lawrence Steinman, Department of Neurology and Neurological Sciences, Beckman Center, B002, Stanford University, Stanford, CA 94305–5429. E-mail address:
3 Incumbent of the Weizmann League Career Development Chair in Children’s Diseases.
4 Abbreviations used in this paper: SOM, somatostatin; CGRP, calcitonin gene-related protein; NPY, neuropeptide Y; SP, substance P; ECM, extracellular matrix; VLA, very late antigen; FN, fibronectin; GF109203X (bisindolymaleimide I; MIP-1ß, macrophage inflammatory protein-1ß; PTK, protein tyrosine kinase; PKC, protein kinase C.
Received for publication March 25, 1997. Accepted for publication October 6, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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