| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Institut National de la Santé et de la Recherche Médicale Unité 463, Institut de Biologie, and
Unité de Thérapies Cellulaire et Génique, Centre Hospitalier Régional Universitaire, Nantes, France
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
nor by IL-15. We also show, using the
redirected killing assay, that IL-12-induced expression of both CD94
and NKG2-A led to the acquisition by T cells of a functional inhibitory
receptor. Expression of the CD94/NKG2-A inhibitory receptor was also
induced by IL-12 during T cell Ag stimulation so that in the presence
of this cytokine a high proportion of melanoma-reactive CTL induced
from PBL by melanoma peptide stimulation expressed this receptor. This
study emphasizes the implication of IL-12 in the modulation of immune
responses through NKR induction. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In humans, NKRs belong to two distinct molecular families. Members of the Ig superfamily, including killer cell Ig-like receptors and leukocyte Ig-like receptors, also called Ig-like receptors, belong to the first one. Type II transmembrane proteins containing a C-type lectin domain, including CD94, NKG2, and NKRP1A, belong to the other one. It has been reported that CD94 can be expressed as a homodimer or as a heterodimer associated with various NKG2 molecules that determine the nature of the transduced signal: NKG2-A and NKG2-B mediating an inhibitory signal (6, 7), NKG2-C an activatory one (8). The class Ib molecule HLA-E is specifically recognized by CD94/NKG2-A, CD94/NKG2-B, and CD94/NKG2-C complex (9, 10, 11). HLA-E-bound peptides influence recognition by inhibitory and triggering CD94/NKG2 receptors (12). In contrast, the activating NKG2-D molecule does not associate with CD94, but forms homodimers that interact with inducible ligands MICA and MICB (13).
A potential role of NKRs in virus- and tumor-specific immune responses
in vivo has been suggested by recent data obtained on patients
suffering from HIV infections (14), melanoma
(15, 16, 17, 18, 19, 20, 21), or T cell lymphoma (22). Therefore,
it is important to define the mechanisms that lead to NKR expression in
T lymphocytes. In this context, we observed that >60% of human
melanoma-specific CD8+ T cell clones, generated
in vitro by stimulating PBL with peptide-pulsed presenting cells and
cytokines (IL-6, IL-12, IL-2, and IL-7), expressed the CD94/NKG2-A
receptor. In view of the already known implications of two cytokines,
IL-15 (2) or TGF-
(23, 24), in the
induction of the CD94/NKG2-A receptor on T cells, we checked whether
one of the four cytokines used in our assays to generate these clones
could achieve a similar effect. We demonstrate that IL-12, a cytokine
known to play a central role in polarization of Th1 response, induces
de novo expression of CD94/NKG2-A by human CD8+ T
cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
PBL were isolated from blood of healthy donors by a Ficoll (Eurobio, Les Ulis, France) density gradient. In some experiments, PBL were first depleted of CD94+ cells by negative selection using anti-CD94 mAb, and magnetic beads coated with goat anti-mouse Ig (Miltenyi Biotec, Bergisch Gladbach, Germany). Then, CD8+ cells were sorted from the CD94- cell population by positive selection using magnetic beads coated with anti-CD8 mAb (Miltenyi Biotec). In one experiment, NKG2-A-positive and NKG2-A-negative populations were also sorted using anti-NKG2-A mAb and magnetic beads coated with anti-mouse Ig (Dynabeads; Dynal Biotech, Oslo, Norway).
Abs and cytokines
mAb specific for CD94 (HP-3B1), NKG2-A (Z199), and mouse IgG2a isotypic control were obtained from Immunotech (Marseille, France). PE-conjugated mAbs specific for CD3, CD4, CD8, and CD94 were also obtained from Immunotech. FITC-conjugated rabbit F(ab')2 and mouse IgG were obtained from BioAtlantic (Nantes, France).
Anti-CD3 Ab used for T cell stimulation was a generous gift of L. Toujas (Centre Régional de Lutte contre le Cancer, Rennes, France).
Anti-human IFN- mAb was purchased from R&D Systems (Wiesbade
Nordenstadt, Germany). Anti-human IL-15 mAb was a generous gift of Y.
Jacques (Institut National de la Santé de la Recherche
Médicale, Nantes, France).
IL-2 was purchased from Chiron (Suresnes, France), and the three other cytokines (IL-6, IL-7, and IL-12) were purchased from Sigma-Aldrich (St. Louis, MO).
Stimulation by cytokines combined or not with anti-CD3 mAb
PBL or purified CD8+ T cells were plated in 24-well plates (106 cells/well) with RPMI 1640 medium containing 8% human serum (local production). At the onset of the culture, the following cytokines were added: IL-2, IL-6, IL-7, and IL-12 (Sigma-Aldrich), either separately or in combination. Concentrations used were 5 ng/ml for IL-2, IL-6, and IL-7, and ranging from 0.001 to 100 ng/ml for IL-12.
Purified CD8 T cells were cultured with a range of IL-12 concentrations using culture plates coated with anti-CD3 mAb (10 µg/ml).
In some experiments, anti-human IFN- or anti-IL-15 mAb was
added to the culture at a final concentration of 5 µg/ml.
Generation of melanoma peptide-specific T cells
PBL from HLA-A*0201 healthy donors or melanoma patients were stimulated by irradiated M17 melanoma cells loaded with the Melan-A/melanoma Ag recognized by T cells-1 (MART-1) peptide26–35 analog ELAGIGILTV. Loading was done by incubating M17 cells with the peptide (1 µM) at 37°C in serum-free medium for 2 h. Stimulator cells were washed twice to eliminate unbound peptide. Stimulations were performed in 24-well culture plates by mixing 5 x 105 peptide-pulsed stimulator cells and 1 x 106 responder PBL in RPMI medium containing 8% human serum and cytokines. Irradiated stimulator cells were added again twice, at 7-day intervals. Cytokines added to these cultures were as follows: either IL-6 and IL-12 (5 ng/ml each) for the first week and IL-2 (10 U/ml) and IL-7 (5 ng/ml) thereafter, or IL-6 only for the first week and IL-2 only (50 U/ml) thereafter.
Tetramers
HLA-A0201/peptide 
3-mutated monomers were a gift of F.
Lang (Institut National de la Santé et de la Recherche
Médicale, Nantes, France) and were generated as previously
described (25). Recombinant proteins were produced as
inclusion bodies in Escherichia coli
XA90F'LacQ1, dissolved in 8 M urea, and
refolded with 15 µg/ml Melan-A peptide analog (ELAGIGILTV) or NA17-A
peptide (VLPDVFIRC). Tetramerization was performed as previously
described (26). Briefly, HLA monomers were biotinylated
for 4 h at 30°C with 6 µg/ml BirA (Immunotech), purified on
monoQ column (Pharmacia, St. Quentin en Yvelines, France), and
tetramerized with PE-labeled streptavidin (Sigma-Aldrich) at a molar
ratio of 4:0.8.
Flow cytometry
For simple fluorescence labeling, cells were stained with the corresponding mAb (anti-CD94 or anti-NKG2-A), followed by an FITC-conjugated Ab as second-step reagent.
For double fluorescence labeling, cells were incubated with 1) primary (anti-CD94 or anti-NKG2-A) Ab and washed; 2) goat anti-mouse FITC-labeled Ab and washed; 3) mouse IgG; and 4) PE-labeled Abs (anti-CD3, anti-CD4, anti-CD8, or anti-CD94).
For tetramer staining, cells (0.5 x 106) were 1) stained with tetramers and the primary NK receptor-specific Ab for 30 min at 4°C and washed, and 2) stained with goat anti-mouse FITC-labeled Ab for 20 min at 4°C and washed.
After the end of the staining steps, the cells were washed and analyzed on a flow cytometer (FACScan; BD Biosciences, Mountain View, CA).
Assay for cytolytic activity
Cytolytic activity of T cell was tested against the
51Cr-labeled murine mastocytoma
FcR+ P815 cell line by a CD3 mAb-redirected
killing assay. Briefly, 103
51Cr-labeled P815 were incubated with T cells
(E:T ratio, 10:1), in the presence of purified anti-CD3 mAb (0.05
µg/ml). CD3-redirected lysis of labeled P815 cells was modulated by
the presence of indicated mAbs (0.1–10 µg/ml) added at the
initiation of the assay. After 4 h, 25 µl supernatant was mixed
with 100 µl scintillation liquid (Optiphase Supermix; Wallac, Turku,
Finland) for measurement of radioactive content. Data are expressed as
the percentage of specific lysis.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In keeping with previous studies suggesting that the CD94/NKG2-A
receptor might affect the response of melanoma-specific CTL, we
analyzed the expression of this receptor by a panel of 88
melanoma-reactive CTL clones. These clones have two distinct origins:
49 were derived from tumor-infiltrating lymphocytes (TIL) after a short
10-day culture of tumor fragments with IL-2, followed by a limiting
dilution culture of the TIL also in the presence of IL-2, or the other
39 clones were derived from healthy donor PBL stimulated three times at
1-wk intervals with melanoma-associated Ag peptide-pulsed allogeneic
melanoma cells or autologous mature DC, in the presence of IL-6 and
IL-12 for 1 wk and of IL-7 and IL-2 for 2 wk. As shown in Fig. 1
, despite a similar array of peptide
specificity, very different fraction of these two categories of clones
expressed the CD94/NKG2-A receptor: 60 and 5% of the PBL and TIL
clones, respectively.
|
To check whether one or several of the four cytokines used to
generate the PBL-derived clones were involved in the frequent
expression of CD94 and NKG2-A by these clones, we tested whether
various combinations of these cytokines, and each one separately, did
influence CD94 and NKG2-A expression by cultured PBL or TIL, following
or not a T cell stimulation. After 2 wk of culture with these
cytokines, unstimulated total PBL were analyzed by flow cytometry for
the coexpression of CD94 and CD3. Results from one representative
experiment are shown in Fig. 2a. The percentage of
CD94+ T cells among the
CD3+ T cells was higher in all IL-12-supplemented
cultures.
|
b, CD94
expression was induced in a dose-dependent fashion by IL-12 on
CD8+ PBL. By contrast, a very low fraction of
CD4+ PBL cells was CD94+,
irrespective of the amount of IL-12 added in the culture.
Similar experiments were also performed using lymphocytes from two
melanoma-invaded lymph nodes (M47 and M48). As shown in Table I, the fraction of
CD94+ TIL was significantly higher in the
presence than in the absence of IL-12 among one TIL population. For the
other, although the fraction of CD94/NKG2-A+ TIL
was not increased by IL-12, the level of expression of this receptor
was increased.
|
a show that high fractions of
CD3-stimulated CD8+ T cells expressed CD94 when
cultured with IL-12 concentrations as low as 1 pg/ml, and that this
fraction increased with the concentration of IL-12 until 0.1 ng/ml. As
shown in kinetic data in Fig. 3b, CD94 expression was
already detectable by a fraction of cultured T cell after 7 days of
culture, but such fraction increased until day 21 of the culture.
|
Abs. A normal V diversity (data not shown) was observed, which
allows us to exclude the existence of a pauciclonal expansion in these
cultures.
We finally tested whether IL-12 could induce CD94/NKG2-A expression by
melanoma-specific preestablished CTL clones. As shown in Table II, T cell clones that completely lacked
CD94 and NKG2-A expression in the absence of IL-12 were not induced to
express these molecules by an 8-day culture with IL-12. However, CTL
clones that already expressed CD94 in the absence of IL-12 showed an
increase both of the fraction of cells expressing this receptor and of
the level of CD94 expressed per cell after 8-day culture with IL-12.
This was also the case for NKG2-A expression.
|
nor IL-15 was relaying IL-12-induced expression of
CD94
Since IFN- is a strong mediator of IL-12 biological effects
(27), and since IL-15 is known to be an inducer of the
CD94/NKG2-A receptor, we investigated whether the effect of IL-12 on
CD94 expression by CD8+ T lymphocytes could be
mediated by one of these two cytokines. To this end,
CD94-CD8+ lymphocytes were
stimulated with anti-CD3 Ab and cultured in the presence of
different amounts of IL-12 (from 0.0001 to 1 ng/ml), with or without
saturating concentrations of anti-human IFN- or of
anti-IL-15 mAb. As shown in Fig. 3a, after 14 days of
culture, IL-12 concentrations as low as 1 pg/ml induced CD94 expression
by 
50% cultured CD8+ cells. Furthermore, a
similar fraction of PBL cells was induced to express CD94 by IL-12 in
the presence of anti-IFN- mAb (Fig. 3a), or in the
presence of anti-IL-15 mAb (data not shown). Consequently, the
effect of IL-12 on expression of CD94 by CD8+ T
cells was not dependent on IFN- or IL-15 production.
Lack of coordinated induction of CD94 and NKG2-A expression by IL-12
CD94 is usually expressed at the cell surface in association with
a NKG2 family member. We analyzed in this study whether IL-12 induced
in a coordinated fashion the expression of CD94 and NKG2-A. To this
end, we stained CD8+ PBL with CD94- and
NKG2-A-specific mAbs, after anti-CD3
mAb stimulation in the presence of IL-12. As shown in Fig. 4 and Table III, a significant fraction of cultured
PBL was CD94+ but NKG2-A-.
This suggested that some T cells were induced by IL-12 to express CD94
either as a homodimer or as a heterodimer containing another NKG2
molecule.
|
|
a. Both subpopulations
expressed the CD94, NKG2-C, and NKG2-E mRNAs, while NKG2-B and, as
expected, NKG2-A mRNAs were poorly expressed by the
NKG2-A- subset (data not shown). Therefore, the
CD94+NKG2-A- subpopulation
induced by IL-12 lacked expression of the CD94/NKG2-B receptor, but
could have expressed one of the activatory receptors, CD94/NKG2-C or
NKG2-E.
|
b, anti-CD3 mAb induced a strong cytolytic
activity by both the
CD94+NKG2-A- and
CD94+NKG2-A+ T cell
subpopulations. However, addition of anti-CD94 mAb did not affect
the lysis of the
CD94+NKG2-A-
subpopulation, while it inhibited in a dose-dependent manner that of
the CD94+NKG2-A+
subpopulation, as described previously. Consequently, this suggests
that CD94+NKG2-A- T cells
do not express a CD94/NKG2-C or CD94/NKG2-E activatory receptor. IL-12 addition to peptide stimulation cultures, commonly used to derive peptide-specific T cells, favors the generation of CD94/NKG2-A-expressing CTL
We described recently (28) a relatively simple and
efficient procedure to obtain high avidity Melan-A/MART-1-specific T
cells from PBL, for use in immunotherapy. During the first step of the
establishment of this procedure, four cytokines (IL-6 and IL-12 for the
first week of culture, and IL-2 and IL-7 afterward) had been used,
according to culture methods developed by others (29). In
a second step, to make this culture protocol simpler for immunotherapy
applications, we tested the contribution of these four cytokines for an
optimal production of Melan-A-specific CTL. We showed that IL-6 and
IL-2 were sufficient for optimal induction of high avidity T cells
specific for the Melan-A/MART-1 26–35 A27L analog (ELAGIGILTV)
(28). In this study, we compared the fraction of
PBL-derived Melan-A/MART-1 peptide-specific CTL induced by in vitro
peptide stimulation, in the presence or in the absence of IL-12 and
IL-7. Tetramers were used to label Melan-A/MART-1 peptide-specific CTL.
As shown in Fig. 6 and Table IV, a
significant fraction of Melan-A-specific CTL induced in the presence of
IL-12 expressed the CD94/NKG2-A (23 and 47%), while a very low
fraction of these CTL derived in the absence of IL-12 expressed this
receptor (0 and 5%).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
diversity of CD94+ T cells derived from
this population was normal. This effect was already detectable in most
cultures after 7 days of culture with IL-12 and in all of them after 14
days. Therefore, IL-12 induces de novo expression of NKG2-A and/or CD94
by CD8+ T cells. Furthermore, neither IFN-, a
key downstream factor induced by IL-12, nor IL-15, a known inducer of
the CD94/NKG2-A receptor, was implicated such in IL-12-mediated
induction of CD94 on T cells as far as anti-IFN- and
anti-IL-15 mAbs failed to abolish this effect. A short culture with
IL-12 also increased the expression of CD94 and NKG2-A by previously
established CTL clones. Both the fraction of cells and the level of
expression of these two molecules were significantly higher than in the
absence of IL-12. However, de novo expression of CD94 and NKG2-A failed
to be induced by IL-12 on preestablished CTL clones that lacked these
molecules.
IL-12-dependent induction of CD94 expression by
CD8+ PBL was observed as well in the absence of
any TCR stimulus than following a CD3- or a peptide-specific
stimulation. Nonetheless, much higher fractions of
CD8+ T cells were induced to express CD94
following a TCR stimulation (60–90 vs 15%). Therefore, TCR
stimulation strongly potentiates IL-12-dependent induction of CD94 and
NKG2-A expression by CD8+ T cells. This may be
due to the expression of IL-12R induced by TCR stimulation. This might
explain conflicting data that IL-12 failed to induce the expression of
CD94/NKG2-A receptor by superantigen-activated T cells
(2). This could be due to a lack of IL-12R induction by
the toxic shock syndrome toxin-1-stimulated T cells, as already
reported for the V
1+ T cell subset
(30).
Although CD3 stimulation in the presence of IL-12 might induce PBL to express CD94 only, peptide stimulation in similar conditions systematically induced T cells to coexpress CD94 and NKG2-A. The reason for this difference is unclear. It might be related to the nature or strength of the T cell stimulation: TCR cross-linking by an anti-CD3 mAb vs MHC-peptide presentation by a melanoma cell line or mature DC. It may be that these two modes of TCR triggering activate distinct signaling pathways or the same one at different levels, therefore resulting in the activation of both or only one gene. Since a stimulation by peptide-pulsed melanoma cells in the presence of IL-12 induced coexpression of CD94 and NKG2-A as efficiently as peptide-pulsed mature DC in similar conditions, it seems unlikely that costimulation was critical for IL-12-mediated NKG2-A induction as far as melanoma cells do not express known costimulation molecules. Expression of CD94, but not NKG2-A, has already been reported in T cells, especially in CD4+ T cells (2, 23).
Induction of CD94 expression in the absence of NKG2-A suggested that CD94 could have been expressed in association with another NKG2 member. However, although NKG2-C and NKG2-E mRNAs were expressed by CD94+NKG2-A- T cells, cross-linking of CD94 by a specific mAb failed to modulate the redirected lysis, suggesting that these cells did not express a functional CD94 containing inhibitory or activatory receptor. Therefore, it is likely that CD3-stimulated PBL had been induced to express a CD94 nonfunctional homodimer by IL-12.
Previous studies had shown that IL-12 is a strong inducer of NKRP1-A
molecule (CD161) by human NK cells (31, 32), T
cells (31), and V2+ T
cells (30). Our data show that IL-12 also is an inducer of
CD94 and NKG2-A, two genes located in the same gene locus as
NKRP1-A, the NK gene complex (33). Our data show that the
transcription of at least three genes from this locus coding for these
C-type lectin receptors is regulated by the same cytokine.
The present and previous studies (2, 23, 24) therefore
show that several cytokines, TGF-, IL-15, and IL-12, produced by
APCs and B cells, can induce the expression of the CD94/NKG2-A
inhibitory receptor by CD8+ T cells.
Interestingly, IL-10 and TGF- modulate the expression of the IL-12R
(34) and could therefore affect IL-12-induced expression
of CD94. Whether this induction contributes to the normal T cell
homeostasis remains to be established. It has been reported that
oligoclonal T cells that express killer cell Ig-like receptors in
normal individuals could be autoreactive T cells, and that expression
of these inhibitory receptors would contribute to tolerance by these
cells (35). Therefore, IL-12 and IL-10 produced by
dendritic cells could contribute to the expression of the CD94/NKG2-A
receptor during T cell cross-priming.
While in vivo treatment by IL-12 has been essentially stopped, IL-12 is still used in vitro for the production of Ag-specific T cells for research or clinical purposes. Our results suggest that using this cytokine might compromise the function of Ag-specific T cells obtained as far as a majority of them will express the inhibitory CD94/NKG2-A receptor. It might thus be better to avoid using IL-12, inasmuch as other cytokines can support the optimal induction of Ag-specific T cells in vitro (28).
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Nadine Gervois, Institut National de la Santé et de la Recherche Médicale Unité 463, 9 Quai Moncousu, 44093 Nantes Cedex 01, France. E-mail address: ngervois{at}nantes.inserm.fr
3 Abbreviations used in this paper: NKR, NK cell receptor; MART-1, melanoma Ag recognized by T cells-1; TIL, tumor-infiltrating lymphocyte.
Received for publication September 19, 2001. Accepted for publication March 6, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
T cells, and antigen-specific CTL. J. Immunol. 160:5239.-induced expression of CD94/NKG2A inhibitory receptors in human T lymphocytes. Eur. J. Immunol. 29:23.[Medline]
on NK receptor expression by allostimulated CD8+ T lymphocytes. Eur. Cytokine Network 10:357.[Medline]
production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J. Exp. Med. 173:869.2+ TCR + T lymphocytes from healthy donors and multiple sclerosis patients. J. Immunol. 162:4349.This article has been cited by other articles:
|
|
 |
|
  A. Saez-Borderias, N. Romo, G. Magri, M. Guma, A. Angulo, and M. Lopez-Botet IL-12-Dependent Inducible Expression of the CD94/NKG2A Inhibitory Receptor Regulates CD94/NKG2C+ NK Cell Function J. Immunol., January 15, 2009; 182(2): 829 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Iizuka, T. Kaifu, A. Nakamura, M. Obinata, and T. Takai Establishment and Functional Characterization of Novel Natural Killer Cell Lines Derived from a Temperature-Sensitive SV40 Large T Antigen Transgenic Mouse J. Biochem., August 1, 2006; 140(2): 255 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Warren, P. M. Rana, D. T. Rieger, K. A. Hewitt, J. E. Dahlstrom, and A. L. Kent CD8 T cells expressing killer Ig-like receptors and NKG2A are present in cord blood and express a more naive phenotype than their counterparts in adult blood J. Leukoc. Biol., June 1, 2006; 79(6): 1252 - 1259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-C. Sheu, S.-H. Chiou, H.-H. Lin, S.-N. Chow, S.-C. Huang, H.-N. Ho, and S.-M. Hsu Up-regulation of Inhibitory Natural Killer Receptors CD94/NKG2A with Suppressed Intracellular Perforin Expression of Tumor-Infiltrating CD8+ T Lymphocytes in Human Cervical Carcinoma Cancer Res., April 1, 2005; 65(7): 2921 - 2929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Draghi, N. Yawata, M. Gleimer, M. Yawata, N. M. Valiante, and P. Parham Single-cell analysis of the human NK cell response to missing self and its inhibition by HLA class I Blood, March 1, 2005; 105(5): 2028 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. Marusina, D.-K. Kim, L. D. Lieto, F. Borrego, and J. E. Coligan GATA-3 Is an Important Transcription Factor for Regulating Human NKG2A Gene Expression J. Immunol., February 15, 2005; 174(4): 2152 - 2159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tanaka, T. Toubai, Y. Tsutsumi, Y. Miura, N. Kato, S. Umehara, K. Kahata, A. Mori, N. Toyoshima, S. Ota, et al. Cytolytic activity and regulatory functions of inhibitory NK cell receptor-expressing T cells expanded from granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells Blood, August 1, 2004; 104(3): 768 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Saruhan-Direskeneli, F. A. Uyar, A. Cefle, S. C. Onder, E. Eksioglu-Demiralp, S. Kamali, M. Inanc, L. Ocal, and A. Gul Expression of KIR and C-type lectin receptors in Behcet's disease Rheumatology, April 1, 2004; 43(4): 423 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. T. Wilhelm, J.-R. Landry, F. Takei, and D. L. Mager Transcriptional Control of Murine CD94 Gene: Differential Usage of Dual Promoters by Lymphoid Cell Types J. Immunol., October 15, 2003; 171(8): 4219 - 4226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gunturi, R. E. Berg, and J. Forman Preferential Survival of CD8 T and NK Cells Expressing High Levels of CD94 J. Immunol., February 15, 2003; 170(4): 1737 - 1745. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
