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9V
2 T Cells Impair Intracellular Multiplication of Brucella suis in Autologous Monocytes Through Soluble Factor Release and Contact-Dependent Cytotoxic Effect1
Institut National de la Santé et de la Recherche Médicale Unité 431, Microbiologie et Pathologie Cellulaire Infectieuse, Université de Montpellier II, Montpellier, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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9V
2 T cells are considered to play an important role
in brucellosis, as this population is dramatically increased in
peripheral blood of patients during the acute phase of the infection.
This T lymphocyte population has been largely demonstrated to be
activated by small m.w. nonpeptidic molecules from natural or synthetic
origin. We recently identified a nonpeptidic fraction of
Brucella suis that specifically activates human
V9V2 T cells. Using a two-separate-chambers system, we showed
that Brucella fraction, as well as isopentenyl
pyrophosphate-activated V9V2 T cells, impaired the multiplication
of B. suis in differentiated THP-1 cells through TNF-
and IFN- release. In the present study, using circulating V9V2
T cells and autologous monocytes infected with B. suis,
we provide evidence that 1) intramonocytic multiplication of B.
suis is impaired by supernatants of activated V9V2 T
cells in part via TNF- and IFN-, this impairment occurring
without host cell lysis; 2) unstimulated V9V2 T cells can impair
intracellular bacterial multiplication after their activation by
soluble factors released by infected monocytes; and 3) activated
V9V2 T cells lyse Brucella-infected monocytes in a
contact-dependent manner. Taken together, these results provide
evidence that V9V2 T cells, in addition to being directly
activated by soluble nonpeptidic molecules, can be stimulated to become
highly cytotoxic in the specific presence of infected monocytes;
moreover, they suggest how V9V2 T cells could be triggered and
respond as antibacterial effector cells in the early stages of
Brucella infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR account for 0.5–4% of the
peripheral blood T cells. The majority (about 90%) of these
circulating T cells in an adult use a TCR comprising the pair of
V9 and V2 regions (1, 2). The specific role of these
V9V2 T cells and their real impact in the development of the
infectious process are still not understood. Several observations have
shown that T cells dramatically increase in the blood of
patients infected with Mycobacterium tuberculosis
(3), Brucella melitensis (4),
Francisella tularensis (5), Listeria
monocytogenes (6), Leishmania donovani
(7), Plasmodium falciparum (8),
and others; the increased T cell population carries the
V9V2 TCR, suggesting that this specific cell subset is triggered
early to respond to infection by intracellular pathogens.
Interestingly, it was demonstrated that this T cell
subpopulation responds to naturally low m.w. nonpeptidic ligands; some
of these ligands have been isolated from pathogens (mostly from
mycobacteria) (9, 10, 11, 12), but other molecules of synthetic
origin also appear to specifically stimulate V9V2 T cells
(13, 14, 15). These different ligands do not display a
consensus structure that could predict them as activating molecules.
Nevertheless, they appear to specifically but polyclonally stimulate
the entire V9V2 T cell population (16) and not
ß T cells or V1V1 T cells, the other main human T
cell subset. As a consequence, this low percentage T cell population,
which is polyclonally stimulated in response to microbial Ags,
proliferates and rapidly secretes large amounts of IFN- and TNF-
(17, 18, 19, 20).
Particularly, a dramatic increase in the number of T lymphocytes
expressing the V9 and V2 gene products was described by Bertotto
et al. (4) in peripheral blood of patients infected with
B. melitensis. We recently took advantage of this in vivo
model to demonstrate in vitro that Brucella suis bacteria
release a nonpeptidic fraction (B. suis fraction
(BSF)3) that is able
to specifically stimulate V9V2 T cells. We showed that upon
stimulation with BSF or with isopentenyl pyrophosphate (IPP) (a
well-described nonpeptidic phosphoantigen from Mycobacterium
smegmatis specifically stimulating V9V2 T cells)
(14), V9V2 T cells similarly secreted high levels of
TNF- and IFN-. Moreover, we brought evidence that these two
cytokines are partially responsible for the impairment of
intracellular multiplication of B. suis inside infected
cells of a differentiated myelomonocytic THP-1 cell line
(20).
In the present study, we demonstrate that V9V2 T cells can be
stimulated by soluble factors that are specifically released by
B. suis-infected autologous monocytes; moreover, we bring
evidence that activated V9V2 T cells are able to impair
intracellular bacterial proliferation via both secreted soluble factors
including TNF- and IFN- without host cell lysis, and via a direct
contact-dependent cytotoxic effect that goes with host cell lysis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Synthetic IPP was obtained from Sigma (St. Louis, MO).
Recombinant human TNF- (rhTNF-) was obtained from the National
Institute for Biologic Standards and Controls (Potters Bar, U.K.),
rhIFN- from Genzyme (Cergy, France), and rhIL-2 from Chiron
(Emeryville, CA). Monoclonal anti-rhTNF- and polyclonal goat
anti-rhIFN- were from R&D Systems (Minneapolis, MN).
Brucella culture
B. suis 1330 (American Type Culture Collection, Manassas, VA) were grown at 37°C in tryptic soy (TS) medium, and GFP-B. suis 1330 producing the green fluorescence protein (GFP) (21) were grown in the same condition in TS medium containing kanamycin. Bacteria from stationary cultures (OD540 nm of 1) were centrifuged, washed, then resuspended in PBS before being used in infection experiments.
Cells
PBMC from healthy donors were prepared by density centrifugation on Ficoll-Paque (Eurobio, Les Ulis, France). Monocytes were purified from PBMC by use of their adherence properties, as described previously (22). This preparation provided blood monocytes with a purity of >95%. Cells were cultured in complete medium (RPMI 1640/glutamate (Life Technologies, Paisley, U.K.), supplemented with 10% heat-inactivated FCS, 0.075% sodium bicarbonate, and 20 µg/ml gentamicin).
Autologous V9V2 T cells were purified from nonadherent PBMC using
anti-9 and/or anti-2 mAbs and goat anti-mouse
IgG-coated Dynal magnetic beads (Dynal, Compiègne, France),
according to the manufacturer’s protocol. After one night, the coated
cells were spontaneously separated from the magnetic beads and then
stimulated for 3 wk with IPP (40 µM) in a 24-well culture plate in
the presence of autologous monocytes (2 x
106/ml) and rhIL-2 (150 U/ml). After 3-wk
expansion culture in complete medium containing rhIL-2 (150 U/ml),
T cells were >98%
CD3+/V9+/V2+
T cells, as determined by FACS analysis. When indicated, expanded
T cells were stimulated with IPP (40 µM) at 2 x
106 cells/ml in complete culture medium without
rhIL-2.
Monocyte infections and culture
Purified monocytes were seeded in 24-well plastic plates at the
density of 5 x 105 cells/ml in complete
culture medium supplemented with 10-7 M 1.25
dihydroxyvitamine D3 (VD; generous gift of Hoffman La Roche, Basel,
Switzerland) for 72 h. The culture medium was then removed, and
the adherent cells were washed twice and infected with B. suis
1330 or GFP-B. suis 1330, with a multiplicity of
infection = 30, in 200 µl complete medium without gentamicin
(23). After a 1-h infection, the cells were washed with
PBS and incubated in 1 ml of complete medium alone, complete medium
containing 2 x 106/ml T cells, or
supernatant of T cells. In some experiments, T cells were
separated from macrophages in a two-chamber system using a 0.4-µm
culture plate insert from Millipore (Bedford, MA). Intracellular
bacteria were visualized by UV fluorescent microscopy (GFP-B.
suis 1330) or were estimated by CFU counting after cell lysis with
0.2% Triton X-100 (24). Serial 10-fold dilutions of
lysates were plated on TS agar. CFU were counted after 48-h incubation
at 37°C. Supernatants of coculture were harvested by centrifugation
and were assayed for cytokine quantification.
TNF- and IFN- assays
For quantification of TNF- concentration, serial 2-fold
dilutions of each supernatant were tested in quadruplicate. The assay
was performed as described previously using L929 fibroblasts
(20). For measurement of IFN- concentration,
supernatants were analyzed using a commercial ELISA kit according to
the manufacturer’s protocol (Genzyme, Cambridge, MA). In some
experiments, TNF-- and IFN--induced inhibition of bacterial
multiplication was blocked by anti-TNF- or anti-IFN- Abs,
respectively. For anti-TNF-, we used the concentration
recommended by the manufacturer, namely 3.2 µg/ml, which is given to
block 10,000 pg TNF- (a much higher amount than that normally found
in supernatants from activated T cells). We checked the blockade
efficacy of this concentration Ab on TNF--containing supernatants
using the L929 biological test (data not shown). For the
anti-IFN-, we used 0.3 µg/ml, a concentration given by the
manufacturer to block 2500 pg/ml IFN-. To check the efficacy of this
concentration on the IFN--containing supernatants, we measured the
inhibition induced by the Ab on the increase of HLA-DR expression
normally triggered by IFN- on monocytes (25, 26). It
has to be noticed that we obtained a maximum of 80% of blockade, even
when we used higher concentrations of the Ab.
Cytotoxicity assay
A total of 5 x 105 VD-differentiated
monocytes was incubated with 25 µCi radioactive
51Cr from ICN Biomedicals (Orsay, France) for
2 h at 37°C. After two washes, monocytes were infected with
B. suis 1330 and incubated with supernatants of T
cells or 2 x 106 T cells (ratio
E:T = 4). After 40–42 h, supernatants were harvested and
cytotoxicity was estimated by quantification of
51Cr release (model 5500 B; Beckman Coulter,
Villepinte, France). The percent of cytotoxicity-specific
51Cr release was calculated using the following
formula: 100 x ((experimental release - spontaneous
release)/(maximum release - spontaneous release)). Specific
51Cr release represents the mean from triplicate
wells.
Statistical analysis
Comparisons between groups in each single experiment were performed using unpaired Student t tests. All data are expressed as mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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9V2 T cells markedly impair the multiplication of
B. suis 1330 in autologous monocytes
It is well established that activated V9V2 T cells produce
TNF- and IFN- (17, 18, 19, 20). These two lymphokines are
known to activate macrophages to control survival and multiplication of
intracellular bacteria (27, 28, 29, 30, 31, 32, 33). In particular, it was
shown in our laboratory that pretreatment with TNF- can impair
B. suis 1330 multiplication in monocytic cells
(34). Recently, we demonstrated that these cytokines,
which are produced by V9V2 T cells upon stimulation either with
IPP or by the nonpeptidic BSF that we purified from B. suis
1330, partially impaired Brucella multiplication
in THP-1 cells (20). In the present study, we tested the
effect of purified V9V2 T cells on the multiplication of B.
suis 1330 in primary autologous monocytes, which represents a more
physiological model comparing with the use of tumoral cell lines.
Purified monocytes from healthy donors were infected with B. suis
1330, as previously described (20), then washed and
cultured alone or cocultured with nonactivated or IPP-activated
V9V2 T cells in the presence of gentamicin to kill residual
extracellular bacteria. After 24 and 48 h, a strong decrease in
bacterial multiplication was observed when infected monocytes were
cultured in presence of activated autologous V9V2 T cells (Fig. 1
). However, a decrease was also observed
when infected monocytes were cocultured with nonactivated T
cells. This result suggests that V9V2 T cells could be activated
when cultured in the presence of infected monocytes. To check this
hypothesis, we analyzed supernatants from cocultures of nonactivated
T cells/noninfected monocytes and from cocultures of
nonactivated T cells/infected monocytes for the presence of
TNF- and IFN-. Fig. 2 shows that
supernatants from nonactivated T cells/noninfected monocyte
cocultures contained no TNF- (Fig. 2A) and small amounts
of IFN- (Fig. 2B). In contrast, in supernatants from nonactivated
T cells/infected monocyte cocultures, high levels of TNF-
(Fig. 2A) and IFN- (Fig. 2B) were detected.
Because neither of these two cytokines were present in the supernatants
from infected monocytes alone (Fig. 2, A and B),
these results strongly suggest that TNF- and IFN- were produced
by V9V2 T cells that were activated by infected monocytes. To
check this conclusion, we used supernatants from 24-h infected
monocytes for stimulation assays on autologous V9V2 T cells. As
expected, supernatants from infected monocytes triggered V9V2 T
cells to produce TNF- (Fig. 3A) as well as IFN- (Fig. 3B). In these experiments, IPP was used as a positive
control, and medium alone or noninfected monocytes as negative
controls. Taken together, these data represent lines of evidence that
infected monocytes release soluble factors that may activate V9V2
T cells, which are then able to impair B. suis 1330
intracellular multiplication.
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and IFN- released from activated V9V2 T cells are
partially responsible for the impairment of B. suis 1330
multiplication in infected monocytes
To determine whether the impairment of bacteria multiplication
observed in presence of activated V9V2 T cells involves TNF-
and IFN-, we investigated the effect of supernatants from
nonactivated or activated V9V2 T cells on intracellular
multiplication of B. suis 1330. As shown in Fig. 4, supernatants from activated V9V2
T cells impaired proliferation of the bacteria, while supernatants
from nonactivated T cells did not. Inhibition of bacteria
multiplication was significantly (p 
0.02)
but partially reversed by pretreating the supernatants with
anti-TNF- or anti-IFN- mAbs (Abs alone or irrelevant
isotype-matched Abs did not have any effect on the supernatant-induced
inhibition of bacteria multiplication; data not shown). The reversal
effect was maximum, but still partial, when the supernatants were
pretreated with both mAbs. Even though we could not totally reverse the
effect of IFN- by anti-IFN-, this suggests that other soluble
factors could be involved in this inhibition. This is supported by the
fact that combined recombinant TNF- and IFN-, used in the same
concentration ranges as those found in the supernatants from
IPP-activated V9V2 T cells, display a less impairment effect than
that triggered by the supernatant (not shown). In addition, we
demonstrated that inhibition of bacteria multiplication by soluble
factors present in the supernatants from IPP-activated V9V2 T
cells is not due to a direct lysis of the host cells through a
cytotoxic effect. Indeed, UV fluorescence microscopy (Fig. 5) shows that there is a strong decrease
in the number of intracellular bacteria in the monocytes cultured with
supernatants from activated T cells; these treated monocytes are
spindle shaped, which generally reflects a stimulated and
differentiated state, but their structure does not appear disrupted at
all. This conserved cellular integrity was confirmed by cytotoxic
assays in which no 51Cr release could be detected
(Table I).
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9V2 T cells cultured in contact with infected monocytes is due
to both released soluble factors and direct cell cytotoxicity
The preceding results established that soluble factors including
TNF- and IFN- are, at least in part, responsible for impairment
of bacterial multiplication; these data were stated using supernatants
from activated T cell cultures. However, a possibility existed
that when cultured in contact with infected cells, V9V2 T
lymphocytes could also develop a direct cytotoxicity. Therefore,
inhibition of intracellular multiplication was assayed in the presence
of V9V2 T cells cultured either in contact with or separated from
infected cells by a semipermeable membrane. Fig. 6 shows that the impairment of bacteria
multiplication is higher when T cells are in contact with the
Brucella-infected monocytes rather than separated by a
membrane. This strongly suggests that, in addition to a soluble
factor-related inhibition of multiplication, T cells can exert
another effect, possibly through contact-dependent cytotoxicity. To
study this specific point, the same experiment was realized using
infected monocytes previously loaded with 51Cr.
After 42-h culture, cytotoxicity induced by V9V2 T cells in
contact with or separated from infected cells was estimated by
51Cr release. Noninfected monocytes were used as
control. Table I
shows that IPP-activated cells were highly cytotoxic
when cultured in contact with the infected cells. This result was also
visible in contrast-phase microscopy (Fig. 7). Moreover, a high cytotoxicity could
also be observed in presence of nonexogenously activated T
cells. This cytotoxicity observed in presence of the so-called
nonactivated T cells could be explained by their possible
stimulation induced by the soluble factors released by infected
monocytes, as we demonstrated in the first paragraph. In parallel,
Table I demonstrates that when T cells are separated from
infected monocytes by a semipermeable membrane, almost no cytotoxic
effect was noticed. It is noteworthy that in presence of noninfected
monocytes, nonstimulated T cells do not induce cytotoxicity, and
only a mild 51Cr release is observed when the
V9V2 T cells are stimulated with IPP. Altogether, these results
represent an evidence that, in addition to soluble factor-mediated
impairment of bacterial multiplication, V9V2 T cells exert a
contact-dependent cytotoxic effect toward infected cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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9V2 T cells could behave in vivo in the process of infection by
an intracellular pathogen. It appears that these cells can act both
through soluble factors acting at a distance on the host cells
triggering them to inhibit intracellular bacterial multiplication, and
also via a contact-dependent cytotoxic effect, which of course leads to
host cell lysis. These two effects are stronger when the T cells
have been exogenously activated by a nonpeptidic ligand; however, it
appears that in cocultures of infected monocytes and T cells,
the V9V2 T cells are never in a real unactivated state. The
activation of V9V2 T cells when cultured with monocytes cannot be
attributed to the presence of allogeneic cells, because we used
syngeneic monocytes in cocultures. However, it has been described that
infected monocytes can activate V9V2 T cells (35, 36). In our experiments, activation could result from
Brucella Ags, which could have been released from infected
damaged cells. Indeed, in a preceding paper (20), we
established the presence in B. suis lysate of a low m.w.
nonpeptidic fraction (BSF) that is able to specifically stimulate
V9V2 T cells. Moreover, several cytokines released from the
infected monocytes can greatly enhance this possible BSF-mediated
activation according to the recent work published by Pichyangkul et al.
(37) on activation of V9V2 T cells by
Plasmodium schizont-state-associated Ag. A possibility also
existed that the nonactivated V9V2 T cells when cultured in
presence of infected monocytes could have been activated through
TNF- released from infected monocytes (38). Actually,
we observed that Brucella-infected monocytes did not produce
TNF-, which confirmed a result recently demonstrated in our
laboratory that Brucella inhibits TNF- production by
monocytes, which represents a way for bacteria to survive inside
infected cells (34, 39). We demonstrate in this study that
V9V2 T cells, when activated either directly by an exogenous
nonpeptidic Ag (IPP) or indirectly by the presence of infected cells,
produce TNF- and IFN-. These two cytokines appear to be involved
in the inhibition of bacterial multiplication; therefore, at least in
the case of Brucella infection, activated V9V2 T cells
can counterbalance the bacteria-induced inhibition of TNF-
production. We have shown that TNF- and IFN- are only partially
responsible for the soluble factor-induced inhibition of intracellular
bacterial multiplication. This suggests that other cytokines are
possible candidates acting in the phenomenon (40, 41, 42).
We established, using supernatants of activated V9V2 T cells,
that there is an inhibition of bacterial multiplication inside the host
cell. This phenomenon is probably correlated to activation, by the
soluble factors present in the supernatants, of the monocytes that are
then able to act on the phagocytosed bacteria (27, 28, 29, 30, 31, 32, 33).
The spindle shape taken by the monocytes when cultured in presence of
activated V9V2 T cell supernatants favors this hypothesis. One of
the questions raised is whether the monocytes only block the
multiplication of the few bacteria that actually infected the host
cells (bacteriostatic effect) or whether they are also able to kill and
eliminate the bacteria even after several bacterial multiplication
cycles (bactericidal effect). This could be an important point, because
the release of soluble factors from the activated T cells is not
immediate and during that delay the bacteria can multiply inside
the cell.
We have demonstrated that in addition to soluble factor-induced
inhibition of bacterial multiplication, V9V2 T cells can also
exert a cytotoxic effect against Brucella-infected
monocytes. First of all, one can question how relevant this killing
could be for protection against Brucella. Indeed, it is
known that several bacteria (Shigella (43),
Legionella (44), Yesrsinia
(45), Bordetella (46),
Listeria (47), and Salmonella
(48)) promote the destruction of monocytic phagocytes by
apoptosis, thus circumventing the first line of defense of the immune
system. However, some other intracellular bacteria that infect
monocytes have a completely opposite strategy and prevent apoptosis of
their respective host cells. It was postulated that inhibition of host
cell apoptosis benefits the intracellular pathogen because it protects
it from external immune attacks and favors optimal multiplication of
the bacteria. Recently, it was demonstrated in our laboratory that
Brucella belongs to this kind of bacteria (49).
Therefore, this strongly suggests that killing and destruction of
Brucella-infected monocytes by T cells can be
considered as a protection mechanism against B. suis
infection. We demonstrated that the soluble factors that are released
by V9V2 T cells are not involved in the cytotoxic effect.
Particularly, this is true for TNF-, which is present in cocultures
of infected monocytes and V9V2 T cells. This is in line with
recent results that have shown that T cell-induced cytotoxicity
against M. tuberculosis-infected macrophages is not due to
TNF- release (50). We showed that cytotoxicity is
triggered only when the V9V2 T cells are physically in contact
with the infected cells (no cytotoxicity is noticed when T cells
are separated from the infected monocytes by a semipermeable membrane);
this result suggests the involvement of a perforin/granulysin-dependent
mechanism, as it was recently demonstrated by Dieli et al.
(50). We noticed that IPP-activated T cells, even
though they trigger a mild 51Cr release from
noninfected monocytes, induce a much higher cytotoxicity against
infected cells (Table I). A hypothesis for this specific high
cytotoxicity induced against infected cells could be related to
modified expression of class I Ags in Brucella-infected
cells. Indeed, it has been demonstrated that V9V2 T cells express
CD94/NKG2 complex that interacts with normal class I molecules
(51, 52), and that such an interaction inhibits the
cytotoxicity of effector cells, as is the case with NK cells (53, 54). Modification in class I expression has been reported for
several bacteria infections, including Listeria, Salmonella,
Yersinia, Klebsiella, and Chlamidia
(55, 56, 57). Another possibility is that during infection,
new molecules could be expressed or there could be a modification in
the expression of certain cell surface molecules; these molecules could
interact with receptors other than the TCR that can trigger human
T cell-mediated cytolysis or increase their cytotoxic
capabilities. Such group of receptors, named natural cytotoxicity
receptors, exists on NK cells (58), and one of them
(NKp44) has been detected on the surface of two TCR clones
derived from a melanoma patient (59). However, the natural
ligands of these kind of receptors have not been identified yet.
Moreover, we cannot of course totally rule out the possibility that the
infected macrophages can be simply more susceptible to cytotoxic lysis,
because our results show that nonstimulated T cells have no
effect on uninfected macrophages, while there is a nonnegligible effect
of these cells on infected cells.
Altogether, these data point out as a possible physiological model the
existence of a specific intercellular system by which infected
monocytes recruit and activate, through soluble factor release,
unstimulated V9V2 T cells, which then can exert a
contact-dependent cytotoxicity against the infected cells.
It is noteworthy that impairment of Brucella multiplication,
either through soluble factor effects or cytotoxic effects or via both
effects, has been observed in our study with V9V2 T cells that
have been activated with IPP. The same results were obtained when the
cells were activated by the BSF we prepared (data not shown). In the
present study, we chose to use IPP instead of BSF because IPP is a
purified molecule and its effect cannot be attributed to contaminants.
Actually, these results confirm that there is a large cross-reactivity
of the nonpeptidic ligands toward V9V2 T cells. Moreover, they
bring evidence that an infection (Brucella infection in this
typical case) can be modulated by V9V2, which have been activated
by Ags from another pathogen. This strengthens the idea that
nonpeptidic ligands from a given pathogen could be taken into account
in immunological therapeutic strategies against several other pathogens
and particularly as adjuvants in vaccinal preparations for several
infectious diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jean Favero, Institut National de la Santé et de la Recherche Médicale Unité 431, Microbiologie et Pathologie Cellulaire Infectieuse, Université de Montpellier II, Place Eugène Bataillon, CC 100, 34095 Montpellier cedex 05, France.
3 Abbreviations used in this paper: BSF, Brucella suis fraction; GFP, green fluorescence protein; IPP, isopentenyl pyrophosphate; rh, recombinant human; TS, tryptic soy; VD, dihydroxyvitamine D3.
Received for publication June 12, 2000. Accepted for publication September 15, 2000.
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  D. Huang, C. Y. Chen, Z. Ali, L. Shao, L. Shen, H. A. Lockman, R. E. Barnewall, C. Sabourin, J. Eestep, A. Reichenberg, et al. Antigen-specific V{gamma}2V{delta}2 T effector cells confer homeostatic protection against pneumonic plaque lesions PNAS, May 5, 2009; 106(18): 7553 - 7558. [Abstract] [Full Text] [PDF]
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 H. Wei, D. Huang, X. Lai, M. Chen, W. Zhong, R. Wang, and Z. W. Chen Definition of APC Presentation of Phosphoantigen (E)-4-Hydroxy-3-methyl-but-2-enyl Pyrophosphate to V{gamma}2V{delta}2 TCR J. Immunol., October 1, 2008; 181(7): 4798 - 4806. [Abstract] [Full Text] [PDF]
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Z. Ali, L. Shao, L. Halliday, A. Reichenberg, M. Hintz, H. Jomaa, and Z. W. Chen Prolonged (E)-4-Hydroxy-3-Methyl-But-2-Enyl Pyrophosphate-Driven Antimicrobial and Cytotoxic Responses of Pulmonary and Systemic V{gamma}2V{delta}2 T Cells in Macaques J. Immunol., December 15, 2007; 179(12): 8287 - 8296. [Abstract] [Full Text] [PDF]
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 J. Liautard, S. Ouahrani-Bettache, V. Jubier-Maurin, V. Lafont, S. Kohler, and J.-P. Liautard Identification and Isolation of Brucella suis Virulence Genes Involved in Resistance to the Human Innate Immune System Infect. Immun., November 1, 2007; 75(11): 5167 - 5174. [Abstract] [Full Text] [PDF]
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 K.-J. Puan, C. Jin, H. Wang, G. Sarikonda, A. M. Raker, H. K. Lee, M. I. Samuelson, E. Marker-Hermann, L. Pasa-Tolic, E. Nieves, et al. Preferential recognition of a microbial metabolite by human V{gamma}2V{delta}2 T cells Int. Immunol., May 1, 2007; 19(5): 657 - 673. [Abstract] [Full Text] [PDF]
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S. Dudal, C. Turriere, S. Bessoles, P. Fontes, F. Sanchez, J. Liautard, J.-P. Liautard, and V. Lafont Release of LL-37 by Activated Human V{gamma}9V{delta}2 T Cells: A Microbicidal Weapon against Brucella suis J. Immunol., October 15, 2006; 177(8): 5533 - 5539. [Abstract] [Full Text] [PDF]
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I Tikhonov, C. Deetz, R Paca, S Berg, V Lukyanenko, J. Lim, and C. Pauza Human V{gamma}2V{delta}2 T cells contain cytoplasmic RANTES Int. Immunol., August 1, 2006; 18(8): 1243 - 1251. [Abstract] [Full Text] [PDF]
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 G. Pappas, N. Akritidis, M. Bosilkovski, and E. Tsianos Brucellosis N. Engl. J. Med., June 2, 2005; 352(22): 2325 - 2336. [Full Text] [PDF]
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 J. Oliaro, S. Dudal, J. Liautard, J.-B. Andrault, J.-P. Liautard, and V. Lafont V{gamma}9V{delta}2 T cells use a combination of mechanisms to limit the spread of the pathogenic bacteria Brucella J. Leukoc. Biol., May 1, 2005; 77(5): 652 - 660. [Abstract] [Full Text] [PDF]
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J. Dornand, V. Lafont, J. Oliaro, A. Terraza, E. Castaneda-Roldan, and J.-P. Liautard Impairment of Intramacrophagic Brucella suis Multiplication by Human Natural Killer Cells through a Contact-Dependent Mechanism Infect. Immun., April 1, 2004; 72(4): 2303 - 2311. [Abstract] [Full Text] [PDF]
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V. Lafont, S. Loisel, J. Liautard, S. Dudal, M. Sable-teychene, J.-P. Liautard, and J. Favero Specific Signaling Pathways Triggered by IL-2 in Human V{gamma}9V{delta}2 T Cells: An Amalgamation of NK and {alpha}{beta} T Cell Signaling J. Immunol., November 15, 2003; 171(10): 5225 - 5232. [Abstract] [Full Text] [PDF]
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H. Wang, H. K. Lee, J. F. Bukowski, H. Li, R. A. Mariuzza, Z. W. Chen, K.-H. Nam, and C. T. Morita Conservation of Nonpeptide Antigen Recognition by Rhesus Monkey V{gamma}2V{delta}2 T Cells J. Immunol., April 1, 2003; 170(7): 3696 - 3706. [Abstract] [Full Text] [PDF]
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 J. Ko and G. A. Splitter Molecular Host-Pathogen Interaction in Brucellosis: Current Understanding and Future Approaches to Vaccine Development for Mice and Humans Clin. Microbiol. Rev., January 1, 2003; 16(1): 65 - 78. [Abstract] [Full Text] [PDF]
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E. Espinosa, J. Tabiasco, D. Hudrisier, and J.-J. Fournie Synaptic Transfer by Human {gamma}{delta} T Cells Stimulated with Soluble or Cellular Antigens J. Immunol., June 15, 2002; 168(12): 6336 - 6343. [Abstract] [Full Text] [PDF]
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Y. Kato, Y. Tanaka, F. Miyagawa, S. Yamashita, and N. Minato Targeting of Tumor Cells for Human {gamma}{delta} T Cells by Nonpeptide Antigens J. Immunol., November 1, 2001; 167(9): 5092 - 5098. [Abstract] [Full Text] [PDF]
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F. Miyagawa, Y. Tanaka, S. Yamashita, and N. Minato Essential Requirement of Antigen Presentation by Monocyte Lineage Cells for the Activation of Primary Human {{gamma}}{{delta}} T Cells by Aminobisphosphonate Antigen J. Immunol., May 1, 2001; 166(9): 5508 - 5514. [Abstract] [Full Text] [PDF]
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) or IPP
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