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1+TCR
+ and V2+TCR+ T Lymphocytes from Healthy Donors and Multiple Sclerosis Patients: Involvement of Phosphatidylinositol 3 Kinase and Calcium Calmodulin-Dependent Kinase II1
* Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy;
Laboratory of Tumor Immunology, Scientific Institute San Raffaele, Milan, Italy;
Laboratory of Neuroimmunology, IRCCS Santa Lucia Foundation,
Department of Neurosciences "Lancisi," Ospedale San Camillo, and
¶ Department of Neurosciences, University of Tor Vergata, Rome, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2+TCR
+ T lymphocyte subset,
expressing the NK receptor protein 1a (NKRP1a; CD161), is expanded in
patients with relapsing-remitting multiple sclerosis and uses this
molecule to migrate through endothelium. In this work, we show that
V1+ and V2+ T lymphocytes use
distinct signal transduction pathways to accomplish this function.
Indeed, we have found that V1+ cells lack NKRP1a and
selectively express the platelet endothelial cell adhesion molecule 1
(PECAM1; CD31), which drives transendothelial migration of this cell
subset, at variance with V2+ T cells, which are PECAM1
negative and use NKRP1a for transmigration. Interestingly, when
V2+ T cells were pretreated with two specific inhibitors
of the calcium calmodulin-dependent kinase II KN62 and KN93, but not
with the inactive compound KN92, the number of migrating cells and the
rate of transmigration were significantly decreased. In turn, the
phosphatidylinositol 3 kinase blockers wortmannin and LY294002 exerted
a dose-dependent inhibition of V1+ cell migration.
Finally, NKRP1a and PECAM1 engagement led to activation of different
signal transduction pathways: indeed, oligomerization of NKRP1a on
V2+ T cells activates calcium calmodulin-dependent
kinase II, while occupancy of PECAM1 on V1+ cells
triggers the phosphatidylinositol 3 kinase-dependent Akt/protein kinase
B
activation. These findings suggest that subsets of T
lymphocytes may migrate to the site of lesion in multiple sclerosis
using two different signaling pathways to
extravasate. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cell subset in the
pathogenesis of MS (5, 6, 7).
Two main fractions of T cells have been described. One,
expressing the TCR variable regions V9 and V2, represents the
majority of peripheral blood lymphocytes; V1 T cells are
instead resident within epithelial tissues, where they may provide a
first line of defense against infectious agents and cancer
(8, 9, 10). This small subset of T cells represents a
relevant proportion of the mucosal-associated lymphoid tissue, and it
is unclear whether and how they recirculate. Notably, an increase of
circulating V1+ T lymphocytes has been
detected in AIDS (11), suggesting that this subpopulation
can also recirculate under certain pathological conditions.
In contrast, cells of the V2 subset infiltrate chronic lesions and
are detectable in the cerebrospinal fluid (CSF) in relapsing-remitting
MS (7, 8, 12). To reach the site of lesion(s), T
lymphocytes must leave the bloodstream and migrate across the
endothelial barrier. We have previously reported that, in the acute
phase of disease, the V2+ NKRP1a+ T
cell subset is expanded in the blood of MS patients; these cells
display a high transendothelial migratory capability, apparently in the
absence of chemotactic stimuli, and use the NK receptor protein 1a
(NKRP1a; CD161) for this function (13).
In mice, T cells recirculate preferentially through nonlymphoid
tissues and show a particular tropism for skin and gut
(14). The precise mechanism for this preferential
migration is unclear; in general, lymphocyte extravasation is initiated
by rolling on vascular endothelium, sustained through the engagement of
specific glycoproteins, including P-selectin glycoprotein ligand 1
(PSGL1), by selectins, followed by integrin-induced adhesion to
endothelial cells and leukocyte arrest (15, 16, 17). Then,
lymphocytes must locomote to intercellular junctions between
endothelial cells, where transmigration occurs (18). Among
the adhesion molecules known to participate in extravasation, the
platelet endothelial cell adhesion molecule 1 (PECAM1; CD31), which is
expressed both at the endothelial cell borders and at the surface of
leukocytes, creates a haptotactic gradient able to recruit circulating
cells and to drive transmigration (19). To complete this
process, leukocytes must reorganize their cytoskeletons and polarize
toward endothelial cell junctions (20); however, little is
known about the signaling events that promote successful
transendothelial migration after lymphocyte arrest and recruitment.
Recently, we reported that PECAM1/CD31 is associated to the
phosphatidylinositol 3 kinase (PI-3K) in human neutrophils
(21). PI-3K was first described as a kinase that
phosphorylates phosphoinositols at the D-3' position of the inositol
ring and produces novel inositides (22, 23). PI-3K can
also be activated via LFA1, in the earliest steps of adhesion
(23). Once activated, PI-3K induces phosphorylation and
activation of the serine-threonine kinase Akt/protein kinase
(PK)B (24). In contrast, in neutrophils, another
kinase, the calcium calmodulin-dependent kinase II (CAMKII) has been
shown to be crucial in mediating cytoskeletal rearrangement and cell
polarization during locomotion (25).
In this paper, we show that V1+ T lymphocytes
do not bear NKRP1a and selectively express PECAM1, which is
involved in their transendothelial migration, at variance with
V2+ T cells, which lack PECAM1 and use NKRP1a
for transmigration. We also demonstrate that V1 T lymphocytes use
PI-3K, while V2+ cells are CAMKII dependent,
for transmigration. Interestingly, NKRP1a occupancy leads to the
activation of CAMKII, whereas PECAM1 engagement triggers the
PI3-K-induced activation of Akt/PKB.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood samples were obtained from six healthy volunteers and from six patients with clinically active MS (Dipartimento di Neuroscienze Lancisi, Ospedale San Camillo, and Dipartimento di Scienze Neurologiche, Università Tor Vergata, Rome, Italy) according to protocols approved by the human experimentation committees of these two institutes. Patients were in the relapsing phase or in the first episode of disease, with abnormal magnetic resonance imaging brain scan; none had received immunosuppressive treatment for at least 3 mo before entering the study.
mAbs and reagents
The anti-NKRP1a mAb 191B8 and the anti-CD31 mAb M89D3
(IgG2a), the anti-CD11a mAb 70H12 (IgG2a), the anti-V1 mAb
A13 (IgG1), and the anti-V2 mAb BB3 (IgG1) were prepared as
described (26, 27, 28, 29). The anti-HLA class I mAb W6/32
(IgG2a)-producing hybridoma was from the American Type Culture
Collection (Manassas, VA). W6/32, 191B8, and M89D3 mAbs were purified
from ascites fluid by affinity chromatography, and pepsin-digested
F(ab')2 were prepared as described
(26). The anti-CD3 mAb (UCHT-1, IgG1) was a kind gift
from P. C. L. Beverly (Imperial Cancer Research Fund, London,
U.K.). Purified anti-CD161 mAb and purified P-selectin-IgG fusion
protein were from BD PharMingen (Milan, Italy). The affinity-purified
FITC- or PE-conjugated goat anti-mouse (GAM) anti-isotype
specific antiserum was from Southern Biotechnology Associates
(Birmingham, AL). Purified GAM anti-Ig (H and L chains) was
purchased from ICN Biomedicals (Aurora, OH). Recombinant IL-2 was from
PeproTech (London, U.K.), rRIL-12 was from R&D Systems (Oxon, U.K.),
and PHA was from Life Technologies (Grand Island, NY). All cells used
in our experiments were cultured in RPMI 1640 medium (Biochrom, Berlin,
Germany) supplemented with FCS (HyClone Laboratories, Logan, UT), human
AB serum (BioWhittaker, Walkersville, MD), glutamine, and
penicillin-streptomycin (Biochrom). The PI-3K inhibitors wortmannin and
LY294002 were from Sigma-Aldrich (St. Louis, MO), and the CAMKII
inhibitors KN62 and KN93 and the inactive compound KN92 were from
Calbiochem-Merck (Darmstadt, Germany).
Isolation and culture of polyclonal and clonal T cell
populations
PBMC from healthy donors or MS patients were isolated by
Ficoll-Hypaque (Biochrom) gradient. Adherent cells were depleted after
adhesion to plastic petri dishes for 2 h at 37°C. Highly
purified CD3++ T
cells were obtained from PBMC following staining with anti-V1
and anti-V2 mAbs and cell sorting using a MoFlo cell sorter
(Cytomation, Fort Collins, CO). To obtain clones and lines, cells were
seeded at either 1 or 10 cells/well, respectively, in the presence of
irradiated PBMC as feeder cells (105 cells/well)
in 96-well U-bottom microplates (Greiner, Nurtingen, Germany) and
cultured in RPMI 1640 medium supplemented with 200 mM
L-glutamine, 5% FCS, 5% AB serum, 1 µg/ml PHA, and 25
U/ml rIL-2. Cells were then expanded with rIL-2 and restimulated every
3 wk with PHA and irradiated feeder cells (5000 rad) according to
standard procedure (13). In some experiments, cells were
washed to remove rIL-2 and cultured in rIL-12-containing medium (5
ng/ml) for another 5 days.
Indirect immunofluorescence and cytofluorometric analysis
Immunofluorescence staining of cultured cells was performed as described elsewhere (27). Briefly, aliquots of 105 cells were stained with the corresponding mAb followed by FITC- or PE-conjugated anti-isotype-specific GAM serum (Southern Biotechnology Associates). Control aliquots were stained with isotype-matched irrelevant mAbs (BD Biosciences, Mountain View, CA) followed by FITC- or PE-GAM or with the fluorescent reagent alone. Samples were analyzed on a flow cytometer (FACSort; BD Biosciences) equipped with an argon ion laser exciting PE at 488 nm. Data were analyzed using Lysis II (version 1.1; BD Biosciences) and are expressed as log red fluorescence intensity (mean fluorescence intensity (MFI), arbitrary units (a.u.). Calibration was assessed with CALIBRITE particles (BD Biosciences) using the AutoCOMP computer program (version 2.1.2; BD Biosciences). In multicolor analysis, freshly isolated PBMC was stained with the following mAbs: anti-CD3 PE-Cy7, anti-CD31 PE (both from Caltag Laboratories, Burlingame, CA), and anti-CD161-allophycocyanin (BD Biosciences). Cells were analyzed with a MoFlo cytometer (Cytomation) and data were analyzed with FlowJo software (TreeStar, San Carlos, CA).
Transendothelial migration
HUVECs were isolated and cultured as described (30)
and used within four passages. Endothelial confluent monolayers were
tested for their integrity before the migration assay as described
(30), using Transwell cell culture chambers (polycarbonate
filters, 3-µm pore size; Costar, Cambridge, MA).
V1+ or V2+ T cells
from healthy donors or MS patients were used after culture in rIL-2 or,
when indicated, were recovered, washed twice, and cultured for another
6 days in the presence of rIL-12 (1 ng/ml). In some experiments,
V1+ or V2+ T cell
clones were preincubated for 30 min at 4°C with saturating amounts (5
µg/ml/106 cells) of the W6/32, 191B8, or M89D3
mAbs and washed before the transmigration assay. In other experiments
cells were exposed for 30 min to the PI-3K inhibitors wortmannin or
LY294002, to the CAMKII inhibitors KN62 or KN93, or to the inactive
compound KN92. To quantitatively express the results of transmigration
assays, V1+ or V2+ T
cell clones were labeled with 51Cr (sodium
chromate; NEN, Boston, MA) and added to the upper compartment of the
Transwell chamber, as described (26, 28). At different
time points, migrated cells were recovered from the lower compartment
of the chamber and lysed with 100 mM Tris-HCl (pH 7.4) containing 0.1%
Triton X-100 (Sigma-Aldrich). The radioactivity of the samples was
measured in a gamma counter. Results are expressed as the percentage of
migrating cells calculated as described (26). Statistical
analysis was performed using the Student t test and variance
analysis.
Akt1/PKB and CAMKII activation assays
PI-3K activity was tested indirectly by analyzing activation of
the serine/threonine kinase Akt1/PKB in cell lysates of
V1+ or V2+ T cells
with the commercial assay kit, using the specific substrate and
[-32P]ATP, after immunoprecipitation
with the specific anti-Akt Ab (Upstate Biotechnology, Lake Placid,
NY). Akt1/PKB activity was tested upon ligation of PECAM1 obtained
by incubation of the cells with 5 µg/ml of the specific mAb M89D3
followed by 10 µg/ml GAM Ig serum as described (21). As
a control, cells were exposed to GAM Ig serum after treatment with an
unrelated isotype-matched Ab (BD Biosciences). Some experiments were
conducted in the presence of the PI-3K inhibitor LY294002. CAMKII
activation in cells was tested upon cross-linking of NKRP1a,
PECAM1, or HLA-I obtained with the specific mAb 191B8, M89D3, or W6/32
(all IgG2a, 5 µg/ml) followed by GAM Ig serum. CAMKII activity was
measured with the CAMKII assay kit, using the specific substrate and
[-32P]ATP, after immunoprecipitation with
the specific anti-CAMKII Ab (Upstate Biotechnology) and
chromatography. Results are expressed as cpm x
10-3 and are the mean ± SD of 10
independent experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1+ and V2+ T cells
differentially express NKRP1a and PECAM1
We have analyzed
V1+TCR+ and
V2+TCR+ bulk
populations and clones for the expression of a panel of surface
molecule involved in transendothelial migration, including
CD161/NKRP1a, CD31/PECAM1, PSGL1, and CD11a/CD18 (LFA1) (13, 15, 18). Data depicted in Table I
show
that cloned V1+ T cells, while being
mostly NKRP1a negative (41 of 43 clones tested were
NKRP1a-), display high levels of PECAM1, which,
in turn, is absent from V2+ T cells
(57 of 60 clones were PECAM1-). This
evidence comes also from the ex vivo analysis of PBMC from MS
patients (Fig. 1). Indeed, multicolor
immunofluorescence showed that, in MS patients, the small fraction of
V1+ T lymphocytes was
PECAM1+NKRP1a- (Fig. 1, right panels). Conversely, V2+
T cells were NKRP1a+ and expressed very low
levels of PECAM1 (Fig. 1, left panels).
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2+ T
cells from normal donors were analyzed at the clonal level, a small
fraction (5%) was found to coexpress NKRP1a and PECAM1 (4 clones of 80
analyzed; data not shown). Furthermore, CD11a/LFA1 and CD162/PSGL1 are
expressed at higher levels on V2+ bulk
populations and clones (Table I
), while the expression of other
adhesion molecules, such as 
1 integrins or
ICAM-1, was comparable at the surface of the two T cell subsets
(data not shown). Altogether, these findings indicate that
V1+ and V2+ T
lymphocytes express differently two key molecules such as NKRP1a and
PECAM1, reported to be involved in transendothelial migration.
V2+ T cell transendothelial migration is dependent
on CAMKII
We have reported that the circulating V2+
T cell subset uses NKRP1a to transmigrate across endothelial
monolayers (13). In general, T cells expressing NKRP1a are
capable of transendothelial locomotion in the absence of chemotactic
stimuli (13, 26); this would imply that the adhesion
molecule(s) involved could deliver a signal leading to leukocyte
polarization (15, 16, 17, 18, 19, 20). Thus, we analyzed the signal
transduction pathway associated with NKRP1a-driven T cell
migration, in particular CAMKII and PI-3K, which have been reported to
be involved in regulating neutrophil motility (21, 25). To
this purpose, V2+ and
V1+ T cell clones, derived from healthy
donors and MS patients, were assayed for transmigration across HUVEC
monolayers in the presence of specific inhibitors of either CAMKII or
PI-3K.
Fig. 2 shows that transendothelial
migration of V2+ T lymphocytes (Fig. 2, A (MS patients) and C (healthy donors)) was
faster than that of V1+ T cells (Fig. 2, B and D). Of note, when
V2+ T cells were pretreated with the CAMKII
inhibitors KN62 and KN93, but not with the inactive compound KN92, the
number of migrating cells and the rate of transmigration were
significantly (p < 0.05) decreased. The
inhibition was dose dependent, as both KN62 and KN93 were effective
from 10 to 1 µM, but not at 0.1 µM (Fig. 2E). Consistent
with this, all of V2+ T cell clones, both from
healthy donors and MS patients, display a superimposable behavior
(Table II). Importantly, migration of
V2+ T cell clones was strongly inhibited
(>70%) by the covering of NKRP1a with the
F(ab')2 of the corresponding mAb (Table III). Conversely,
V1+ T cell lines (Fig. 2, B and
D) and clones (Table II) were insensitive to CAMKII
inhibitors; interestingly, the V1+ clone
MCL.6, which was found to express NKRP1a, displayed a higher rate of
transendothelial migration and was inhibited by KN93 (Table II). In
contrast, PI-3K blockers, such as Ly294002, had little or no effect on
V2+ T cell clones (Table II). Migration
patterns of V1+ and
V2+ T cell clones remained similar along the
culture period (2 mo), independently of the proliferation rate of each
cell line or clone analyzed (data not shown).
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2+ T cells with rIL-12
leads to up-regulation of NKRP1a expression and enhancement of
transendothelial migration (13), we asked whether also in
this case CAMKII inhibitors could be effective; indeed, KN62 and KN93,
at variance with the inactive KN92, impaired transendothelial migration
of rIL-12 cultured V2+ T lymphocytes of MS
patients (Fig. 2F) and normal donors (data not shown).
V1+ T cells transmigrate using PECAM1 and PI-3K
At variance with V2+,
V1+ T lymphocytes are mainly detected
in peripheral tissues (8, 9, 10); however, there is no
evidence, so far, that this subset is localized to CNS and/or in MS
lesions. Nevertheless, we addressed the question of whether their
transendothelial migration, detectable although reduced compared with
that of V2+ T cells, is driven by PECAM1 and
dependent on a selected kinase. Indeed, it is well known that PECAM1 is
responsible for haptotactic cell migration and that it is functionally
associated with PI-3K in neutrophils (19, 21). Table III
shows that the F(ab')2 of anti-PECAM1 mAb
M89D3 was indeed able to strongly inhibit transendothelial migration of
this cell subset; interestingly, the PI-3K blockers wortmannin and
LY294002 exerted a dose-dependent inhibition of
V1+ T lymphocyte migration (Fig. 3, A and circles in
C–F for MS patients; B and triangles in
C–F for healthy donors), at variance with that found
with CAMKII inhibitors (Fig. 2, B and D; see also
Table II for T cell clones). In contrast, migration of
V2+ T cell lines was also only partially
reduced upon treatment with the PI-3K inhibitors LY294002 or wortmannin
(Fig. 3, E and F). Cells incubated with DMSO
(solvent of LY294002 and CAMKII inhibitors) did not have any effect on
transendothelial migration (data not shown).
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1+ and V2+ T
lymphocytes use different adhesion molecules and signaling pathways to
migrate across vascular endothelium, in the absence of chemotactic
stimuli, implying that tissue localization of the two T cell
subsets may be selectively regulated.
Engagement of NKRP1a on V2+ T cells and of PECAM1 on
V1+ T cells leads to CAMKII and Akt/PKB activation,
respectively
We further investigated whether the engagement of NKRP1a or PECAM1
induces the activation of CAMKII or Akt/PKB (a substrate of PI-3K),
respectively, on
V2+TCR+ or
V1+TCR+ T
lymphocytes. As shown in Fig. 4A, the engagement of NKRP1a
by the use of specific mAb, at variance with an unrelated
isotype-matched mAb, elicits the activation of CAMKII. This
NKRP1a-mediated effect was found using
V2+TCR+ bulk
populations (data not shown) or clones from MS patients (Fig. 4) and
healthy donors (data not shown), and it was inhibited by the specific
CAMKII blocker KN93 (Fig. 4A). In contrast, we found that
triggering of PECAM1 on V1+ T cells leads to
activation of Akt/PKB (Fig. 4B), which is a hallmark of
PI-3K engagement. Indeed, LY294002 exerted a strong inhibition of
PECAM1-induced Akt/PKB activation (Fig. 4B). Importantly,
the ligation of either PECAM1 or NKRP1a on
V2+TCR+ or
V1+TCR+ T
lymphocytes did not lead to activation of CAMKII or PI-3K, respectively
(Fig. 4). Taken together, these findings further support the notion
that V1+ and V2+ may
use different biochemical pathways to transmigrate through endothelium
by the selective engagement of PECAM1 and NKRP1a, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1+ T
lymphocytes selectively express PECAM1, which drives transendothelial
migration of this cell subset, at variance with
V2+ T cells, which use NKRP1a for
transmigration. The two molecules activate different signal
transduction pathways: indeed, NKRP1a-mediated
V2+ T cell migration depends on the activation
of CAMKII, while PECAM1-driven migration of
V1+ cells induces Akt/PKB activation, which
is a downstream target of PI-3K (24).
In MS, T cells have been found in the lesions and in CSF
(7, 8, 12), suggesting not only that they contribute to
demyelinization but also that they egress from the bloodstream and
reach the CNS to exert their pathogenic role. In agreement with this,
we have previously found that circulating V2+
T cell population expressing NKRP1a is strongly expanded in MS patients
compared with healthy donors during the acute phase of the disease
(13). Notably, this + T cell
subset is able to spontaneously migrate across endothelial cell
monolayers, and the NKRP1a adhesion molecule is needed for this process
(13). Interestingly, cells of the
V1+ cell subset lack NKRP1a but express
PECAM1, which is known to mediate haptotactic migration of leukocytes
(19, 28). In both cases, cells must modify their shape and
polarize toward the endothelial cell junction to complete
transmigration.
Transendothelial migration of V2+ and
V1+ T cell subsets depends on the activation
of distinct kinases; indeed, the former is inhibited by blockers of
CAMKII and the latter is inhibited by PI-3K inhibitors. In turn, the
engagement of NKRP1a on V2+ lymphocytes leads
to activation of CAMKII, while PECAM1 oligomerization on
V1+ T cells triggers the activation of the
PI-3K-dependent Akt/PKB. Thus, the two subsets use different
adhesion molecules and signaling pathways to transmigrate, suggesting
that resident and circulating T lymphocytes are equipped with
distinct biochemical and molecular mechanisms to regulate their
selective tissue localization. This might also account for the finding
that in relapsing-remitting MS, T cells found in the lesions
differ from those in CSF (5, 6, 12, 31), supporting the
hypothesis that the two T cell subsets play distinct roles in
the pathogenesis of the disease.
Both the above-mentioned kinases have been implied in the regulation of
cell locomotion: in particular, CAMKII regulates vascular muscle cell
migration (32) and neutrophil motility
(25). It is conceivable that the shape of the migrating
cell is modified by regulating calcium-dependent microtubule assembly
(25, 33). Other studies report that chemotaxis of leukemic
T cells induced by soluble VCAM1 requires activation of CAMKII and
phosphorylation of vimentin (34), possibly contributing to
cell polarization and initiating amoeboid locomotion. In turn, PI-3K
seems to be coupled preferentially to haptotactic migration; indeed,
keratinocytes and osteoblast-like cells use a PI-3K-dependent pathway
to trigger cell movement driven by matrix components such as laminin
(35, 36). This is of interest because in our experimental
system PI-3K apparently regulates transendothelial migration of the
V1+ T cell subset, which is driven by a
molecule, PECAM1, known to create a haptotactic gradient in endothelial
cell junctions (19, 28). In this case, the mechanism
underlying cell shape modulation seems to be focused on the
reorganization of actin microfilaments, controlling filopodia formation
and reducing focal adhesion (20, 37). In the last years,
it has become evident that PECAM1 is important in signal transduction
(38); in particular, we have reported that in neutrophils
this adhesion molecule is associated with PI-3K and regulates
integrin-mediated cell adhesion to endothelial cells and subendothelial
matrix (21).
It is of interest that PI-3K is also coupled to chemokine receptor
signal transduction. Recently, it has been reported that
chemokine-induced high-affinity state of the 2
integrin LFA1 is controlled by a PI-3K-dependent signaling pathway
(39). This might account, at least in part, for the faster
kinetics of transendothelial migration displayed by
V2+ T cells, which we showed to highly express
LFA1. Indeed, a rapid integrin-driven lymphocyte arrest conceivably
facilitates the interaction between other adhesion molecules and their
endothelial ligand(s) involved in the progression of transmigration.
Likewise, the presence of PSGL1 on this subset might contribute to
start transendothelial motility, in keeping with other data
(16).
The preferential usage of a PI-3K-dependent pathway by the resident
subset of T lymphocytes might also imply that they have been
recruited to the tissues by soluble factors (e.g., chemokines) produced
by T lymphocytes or other cell types, especially during acute
inflammation (3, 40), as in the acute phase of MS.
Finally, the identification of signaling pathways that differently
regulate the homing of the two T cell subset might be of
interest to selectively block the recruitment, at the site of lesion,
of cells involved in the pathogenesis of MS (4, 41).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Alessandro Poggi, Laboratory of Immunology, National Institute for Cancer Research, Largo R. Benzi 10, I-16132, Genoa, Italy. E-mail address: poggi{at}vega.cba.unige.it
3 Abbreviations used in this paper: MS, multiple sclerosis; CAMKII, calcium calmodulin-dependent kinase II; NKRP1a, NK receptor protein 1a; PECAM1, platelet endothelial cell adhesion molecule 1; PSGL1, P-selectin glycoprotein ligand 1; GAM, goat anti-mouse; PI-3K, phosphatidylinositol 3 kinase; CSF, cerebrospinal fluid; PK, protein kinase; a.u., arbitrary unit; MFI, mean fluorescence intensity.
Received for publication January 2, 2002. Accepted for publication April 3, 2002.
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 H. Sicard, S. Ingoure, B. Luciani, C. Serraz, J.-J. Fournie, M. Bonneville, J. Tiollier, and F. Romagne In Vivo Immunomanipulation of V{gamma}9V{delta}2 T Cells with a Synthetic Phosphoantigen in a Preclinical Nonhuman Primate Model J. Immunol., October 15, 2005; 175(8): 5471 - 5480. [Abstract] [Full Text] [PDF]
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 M. Eberl, R. Engel, S. Aberle, P. Fisch, H. Jomaa, and H. Pircher Human V{gamma}9/V{delta}2 effector memory T cells express the killer cell lectin-like receptor G1 (KLRG1) J. Leukoc. Biol., January 1, 2005; 77(1): 67 - 70. [Abstract] [Full Text] [PDF]
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 A. Poggi, C. Venturino, S. Catellani, M. Clavio, M. Miglino, M. Gobbi, A. Steinle, P. Ghia, S. Stella, F. Caligaris-Cappio, et al. V{delta}1 T Lymphocytes from B-CLL Patients Recognize ULBP3 Expressed on Leukemic B Cells and Up-Regulated by Trans-Retinoic Acid Cancer Res., December 15, 2004; 64(24): 9172 - 9179. [Abstract] [Full Text] [PDF]
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 A. Poggi, R. Carosio, D. Fenoglio, S. Brenci, G. Murdaca, M. Setti, F. Indiveri, S. Scabini, E. Ferrero, and M. R. Zocchi Migration of V{delta}1 and V{delta}2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1-infected patients: competition by HIV-1 Tat Blood, March 15, 2004; 103(6): 2205 - 2213. [Abstract] [Full Text] [PDF]
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