| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan;
CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corp., Chiyoda-ku, Tokyo, Japan;
Department of First Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan;
§
Department of Pathogenic Biochemistry, Research Institute of Wakan-yaku, Toyama Medical and Pharmaceutical University, Toyama, Japan; and
¶
Central Institute for Experimental Animals, Nogawa, Miyamae, Kawasaki, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production of freshly isolated
NK cells and enhanced the proliferation and IFN- production of
anti-NK1.1-sutimulated NK cells. Although NK cell cytotoxicity was
not triggered by anti-CD27 mAb or against CD70 transfectants,
prestimulation via CD27 enhanced the cytotoxic activity of NK cells in
an IFN--dependent manner. These results suggest that CD27-mediated
activation may be involved in the NK cell-mediated innate immunity
against virus-infected or transformed cells expressing
CD70. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
With respect to NK cells, it has been recently revealed that many activating or inhibitory NK cell receptors (KIR, NKR-P1 family, and CD94-NKG2, etc.) and other molecules (CD2, CD16, etc.) regulate NK cell activation (7). It has been also reported that CD28 was also involved in NK cell activation (7, 8, 9, 10, 11). However, there has been little information about the expression and function of TNF receptor superfamily members on NK cells.
In the present study we examined the expression and function of some
TNF receptor superfamily members on murine NK cells. We found that
murine NK cells constitutively express CD27, and the stimulation with
anti-CD27 mAb or CD27 ligand (CD70) enhances NK cell proliferation
and IFN- production. The physiological relevance of the findings is
discussed.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Male C57BL/6 (B6) mice, 6 wk of age, were purchased from Clear Japan (Tokyo, Japan). B6 RAG-2-/- mice were bred in Central Institute for Experimental Animals (Kawasaki, Japan) and used at 6–8 wk of age (12). All mice were maintained under specific pathogen-free conditions.
Abs and reagents
Purified anti-CD16/32 mAb (2.4 G2), FITC-conjugated or no
azide/low endotoxin anti-mouse NK1.1 mAb (PK 136),
biotin-conjugated or no azide/low endotoxin anti-mouse CD27 mAb
(LG.3A10), peridinin chlorophyl protein
(PerCP)3-conjugated
anti-mouse CD3
mAb (145-2C11), biotin-conjugated anti-mouse
CD30 mAb (mCD30.1), biotin-conjugated anti-mouse CD40 mAb (3/23),
biotin-conjugated anti-mouse 4-1 BB mAb (1AH2), no azide/low
endotoxin anti-mouse CD70 mAb (FR-70), isotype control for hamster
IgG (G235-2356), rat IgG1(R3-34), rat IgG2a (R35-95) and rat
IgG2b(R95-1), and PE-conjugated streptavidin were purchased from
PharMingen (San Diego, CA). The hybridoma-producing anti-mouse
OX-40 mAb (OX-86) was obtained from European Cell Culture Collection
(Wilshire, U.K.), and the hybridomas producing anti-mouse
IFN--neutralizing mAb (R4-6A2), anti-mouse MHC class II mAb
(M5/114), anti-mouse B220 mAb (RA3-3A1), anti-mouse CD8 mAb
(3.155), and anti-mouse CD4 mAb (RL172.4) were obtained from
American Type Culture Collection (Manassas, VA). The mAbs were prepared
and biotinylated in our laboratory followings described standard method
(13). Human rIL-2 was provided by Shionogi Pharmaceutical
(Osaka, Japan). Recombinant murine IL-12 (4.9 x
106 U/mg) was provided by Genetic Institute
(Andover, MA).
Cell preparation
Splenic mononuclear cells were prepared by pressing spleens through a stainless steel mesh followed by treatment with RBC lysis solution as previously described (14). NK cells were purified as previously described (8). In brief, B and T cells were depleted from splenocytes by passage through a nylon wool column (Wako, Osaka, Japan) and then by treatment with a mixture of hybridoma supernatants (anti-MHC class II, anti-B220, anti-CD4, and anti-CD8) and low toxic rabbit complement (Cedarlane, Hornby, Canada). After Percoll (Pharmacia Biotech) gradient centrifugation, the purity of NK (NK1.1+ CD3-) cells was >95% as determined by flow cytometry.
Cell lines
NK-susceptible YAC-1 target cells and NK-resistant P815 target cells were maintained in RPMI 1640 medium supplemented with 10% heat-inactivated FCS, 2 mM L-glutamine, and 25 mM NaHCO3 in humidified 5% CO2 at 37°C. P815 cells stably transfected with mouse CD70cDNA (P815-CD70) were prepared as previously described (15).
Flow cytometry
Expression of respective molecules on NK cells was analyzed by
three-color flow cytometry as described previously (14, 16). To avoid the nonspecific binding of Abs to FcR on NK
cells, the cells were preincubated with anti-mouse CD16/32 (2.4G2)
mAb before staining, which diminished the binding of isotype controls
to NK cells. Then the cells were incubated with a saturating amount of
biotinylated mAbs. After washing with PBS twice, the cells were
incubated with FITC-conjugated anti-mouse NK1.1 mAb,
PerCP-conjugated anti-CD3 mAb, and PE-conjugated streptavidin.
After washing with PBS twice, the stained cells were analyzed on a
FACScan (Becton Dickinson, San Jose, CA), and data were processed using
the CellQuest program (Becton Dickinson).
Cell culture
Spleen cells from B6 RAG-2-/- mice were incubated in a tissue culture grade polystyrene dish at 37°C for 1 h to deplete adherent cells. Harvested cells were routinely >95% NK1.1+ CD3- as estimated by flow cytometry. Purified NK cells were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated FCS, 2 mM L-glutamine, and 25 mM NaHCO3 in humidified 5% CO2 at 37°C as previously reported (17). NK cell (3 x 105) were stimulated with immobilized anti-NK1.1 mAb (10 µg/ml) and/or anti-mouse CD27 mAb (10 µg/ml) in the presence or the absence of IL-2 (25 U/ml) and/or IL-12 (5 U/ml) on a 96-well flat-bottom culture plate (Costar, Cambridge, MA). Abs in PBS were immobilized by overnight incubation at 4°C. In the coculture experiments, purified NK cells (3 x 105/well) were cocultured with irradiated (15,000 rad) P815 or P815-CD70 cells (3 x 104/well) in 96-well round-bottomed culture plate in the presence of 25 U/ml IL-2. In some experiments, coculture was performed in the presence of anti-NK1.1 mAb (10 µg/ml) and/or anti-CD70 mAb (5 µg/ml). The cultures were incubated for 2 days and pulsed with 0.5 µCi/well of [3H]thymidine (Amersham, Aylesbury, U.K.) for the last 16 h. Incorporated radioactivity was measured in a Microbeta counter (Microbeta Plus, Wallac, Turku, Finland). Cell-free culture supernatants were harvested after incubation for 3 days and subjected to cytokine assay.
ELISA
IFN- levels in the culture supernatants were evaluated by
using a mouse IFN--specific ELISA kit (OptEIA) purchased from
PharMingen according to the manufacturer’s instruction.
Cytotoxicity assay
Cytotoxic activity was assessed by a standard 51Cr release assay (14). Briefly, 51Cr-labeled target cells (5 x 103) were added to serial dilutions of effector cells. For assessing redirected lysis, anti-NK1.1 mAb or anti-CD27 mAb were added at 10 µg/ml. After 4-h incubation, supernatants were harvested and counted with a gamma counter. Specific cytotoxicity was calculated as previously described (14).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To examine the expression of TNF receptor family molecules on NK
cells, freshly isolated splenic NK cells from B6 mice and
IL-2-activated NK cells were subjected to three-color staining with
FITC-conjugated anti-NK1.1 mAb, Per-CP-conjugated anti-CD3
mAb, and biotin-conjugated mAb against CD27, CD30, CD40, OX40(CD134),
or 4-1BB(CD137) followed by PE-conjugated streptavidin. Expression of
the respective TNF receptor family molecule was analyzed on gated
NK1.1+ CD3- cells. While
CD30, CD40, OX40, and CD134 were not detectable on either fresh or
IL-2-activated NK cells, CD27 was constitutively expressed on both
fresh and IL-2-activated NK cells (Fig. 1
). As recently reported
(18), CD137 was expressed on IL-2-activated NK cells, but
not on fresh NK cells. These results indicated that CD27 is unique
among the TNF receptor family molecules tested in that it is
constitutively expressed on freshly isolated NK cells.
|
Since CD27 has been reported to provide a costimulatory signal for
T cell proliferation (15, 19, 20, 21, 22, 23, 24), the effect of CD27
cross-linking by immobilized anti-CD27 mAb on the proliferation of
NK cells was first examined. To exclude the possible contribution of
contaminated T cells, NK cells were purified from B6
RAG-2-/- splenocytes, which lack T cells and
NKT cell (12). RAG-2-/- NK cells
expressed CD27 at the same level as the B6 NK cells shown in Fig. 1
(data not shown). The cross-linking of CD27 induced a low, but
significant, level of proliferation, which was comparable to that
induced by NKR-P1 cross-linking by immobilized anti-NK1.1 mAb (Fig. 2A). Co-cross-linking of CD-27
and NKR-P1 showed an additive effect. In the presence of a submitogenic
concentration of IL-2, anti-CD27 mAb also induced a substantial
level of proliferation, albeit to a lesser extent than anti-NK1.1
mAb, and enhanced the proliferation induced by anti-NK1.1 mAb (Fig. 2B). These results suggested that CD27 expressed on freshly
isolated NK cells is functional in inducing NK cell proliferation.
|
production by NK cells upon cross-linking of CD27
We next examined the IFN- induction by NK cells upon CD27
cross-linking with anti-CD27 mAb. When NK cells were incubated with
immobilized anti-CD27 mAb in the presence of 25 U/ml IL-2 for 3
days, a substantial level of IFN- was detected in the culture
supernatant, which was comparable to that induced by anti-NK1.1 mAb
(Fig. 3A). The combination of
anti-CD27 and anti-NK1.1 mAbs showed an additive effect. In the
presence of a suboptimal concentration of IL-12, anti-CD27 mAb
induced a considerable level of IFN- production, which was again
comparable to that induced by anti-NK1.1 mAb, and enhanced the
IFN- production induced by anti-NK1.1 mAb (Fig. 3B).
These results indicated that CD27 cross-linking by anti-CD27 mAb
can induce IFN- production by NK cells as potently as NKR-P1
cross-linking by anti-NK1.1 mAb.
|
To exclude the possible contribution of Fc receptors on NK cells
to the NK cell activation by immobilized mAb, we determined whether the
natural ligand for CD27 (CD70) could induce the proliferation and
IFN- production of NK cells. Purified NK cells from
RAG-2-/- mice were
cocultured with irradiated P815 or CD70-transfected P815 (P815-CD70)
cells in the presence of IL-2. When NK cells were cocultured with
P815-CD70 cells, substantial levels of proliferation and IFN-
production were observed, which were abrogated by anti-CD70
mAb (Fig. 4). Moreover, CD70
enhanced the proliferation and IFN- production induced by
anti-NK1.1 mAb, which were again abrogated by anti-CD70 mAb.
These results indicated that CD27 on NK cells can induce proliferation
and IFN- production of NK cells upon interaction with its
ligand, CD70.
|
It has been reported that cross-linking of NK1.1 could trigger NK
cell cytotoxicity (25, 26, 27). We then examined whether CD27
could trigger NK cell cytotoxicity by using anti-CD27
mAb-redirected cytotoxic assay against FcR-bearing P815 target cells or
by using CD70-transfected P815 cells as the target cells. Freshly
isolated NK cells lysed the classical NK target YAC-1 cells efficiently
(data not shown), but not P815 cells. Although anti-NK1.1 mAb
efficiently directed NK cell cytotoxicity against P815, anti-CD27
mAb did not (Fig. 5). Moreover, P815-CD70
cells did not show increased susceptibility to NK cells in the presence
or the absence of anti-NK1.1 mAb (Fig. 5). These results indicated
that CD27 cannot trigger cytotoxic activity to NK cells, unlike
NK1.1.
|
-mediated enhancement of NK cell cytotoxicity by
prestimulation via CD27
Since IFN- has been known to enhance the NK cell cytotoxicity
(28, 29), it would be possible that NK cell cytotoxicity
could be augmented by prestimulation via CD27, which induce IFN-
production by NK cells as shown in Fig. 3. To address this possibility,
purified NK cells were stimulated with immobilized anti-CD27 mAb
for 3 days in the presence of a suboptimal dose of IL-2, and then
cytotoxic activity was tested against YAC-1 and P815 target cells. As
shown in Fig. 6, the prestimulation with
anti-CD27 mAb significantly augmented the cytotoxic activities
against both target cells to levels comparable to those induced by
anti-NK1.1 prestimulation and further enhanced the
anti-NK1.1-induced cytotoxicity. The enhancement by anti-CD27
prestimulation was completely abrogated by neutralizing
anti-IFN- mAb. These results indicated that CD27-mediated
stimulation can augment NK cell cytotoxicity indirectly by inducing
IFN- production.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production of freshly isolated NK cells as potently as
stimulation of the NK1.1 (NKR-P1) molecule, which has been implicated
in murine NK cell activation in previous studies (7, 17, 25, 26, 27). Although CD27 stimulation does not directly trigger
cytolytic function of NK cells, unlike NKR-P1, it can augment NK cell
cytotoxicity indirectly by inducing autocrine IFN- production. These
results suggest the involvement of CD27 in the regulation of NK cell
expansion and functions.
Expression and function of CD27 on T cells have been well characterized
in both human and murine systems (5, 6, 15, 19, 20, 21, 22, 23, 24). CD27
is expressed on the majority of human peripheral blood T cells, and its
engagement by anti-CD27 mAb or CD70 induced proliferation of naive
T cells in the presence of a suboptimal dose of PMA, PHA, or
anti-CD3 mAb (5, 6, 19, 20, 21, 22, 23, 24). Also in the murine
system, CD27 is expressed on the vast majority of mature T cells, and
its engagement by anti-CD27 mAb or murine CD70 costimulated
proliferation of Con A- or anti-CD3-stimulated T cells (15, 20). In contrast, the expression and function of CD27 on NK
cells have not been well characterized. In the human system, it has
been reported that CD27 was expressed at low levels by 
30–40% of
peripheral blood NK cells and was up-regulated on IL-2-activated NK
cells (30). In the present study we showed that the great
majority of murine NK cells express CD27 before and after IL-2
stimulation. Expression of CD27 on freshly isolated NK cells was unique
among the TNF receptor family molecules tested, while CD137 was
expressed on IL-2-activated NK cells as previously reported
(18). Moreover, we demonstrated that CD27 on murine NK
cells is functional in inducing proliferation and IFN- production,
while such functions have not been explored in previous studies with
human NK cells. Our present observation of the failure to trigger
cytolytic function of murine NK cells by anti-CD27 mAb or against
CD70 transfectants is consistent with previous observations, which
reported that human NK cells did not show enhanced cytotoxicity
against CD70 transfectants in a 4-h 51Cr release
assay (31). Furthermore, we clarified that the enhanced
cytotoxic activity of murine NK cells after prestimulation with
immobilized anti-CD27 mAb is mediated by autocrine IFN-,
suggesting that the increased NK cell activity after coculture with
CD70 transfectans in the human system might be also mediated by IFN-
(31). These results imply that CD27 plays a similar role
on murine and human NK cells.
The signaling mechanism by which CD27 activates NK cells remains to be
determined in the future study. It has been shown that cross-linking of
CD27 induced tyrosine phosphorylation of cytoplasmic proteins,
including ZAP-70, in human T cells, might enhance the TCR/CD3-mediated
signaling (22). It remains to be determined whether CD27
stimulation may also induce protein tyrosine phosphorylation of NK
cells. In this respect, it may be interesting to compare the signaling
via CD27 with that via the NKR-P1 molecule, which not only induces
IFN- production but also triggers NK cell lytic function. It has
been shown that NKR-P1 is associated with the FcR -chain, which
activates ZAP-70 and/or Syk and induces an increase in intracellular
Ca2+ that is requisite for triggering NK cell
lytic function (32, 33, 34). In contrast, it has been shown
that CD27 ligation affected calcium mobilization in NK cells only in
the induction mediated by CD2 (30), which might be
responsible for the failure to trigger the cytolytic function of NK
cells. In addition to the tyrosine phosphorylation events, we recently
revealed that CD27 recruits TNF receptor-associated factor-2 (TRAF2)
and TRAF5, which activate NF-
B and c-Jun N-terminal kinase and have
been implicated in cellular proliferation and cytokine production
(35). An important role for TRAF-mediated signaling in T
cells has been substantiated by the impaired proliferation of
TRAF5-deficient T cell in response to CD27-mediated costimulation
(36). Further studies are underway to characterize the
signaling pathway responsible for the CD27-mediated activation of NK
cells.
It has been established that NK cells play important roles in the
innate immunity against infection and tumor development (29, 37, 38). NK cells preferentially lyse virus-infected cells and
transformed cells by their cytotoxic function. IFN- produced by NK
cells not only exerts anti-viral and proinflammatory effects, but
also induces Th1-and CTL-mediated acquired immunity. In the present
study we showed that CD27-mediated stimulation by anti-CD27 mAb or
CD70 enhanced IFN- production and the cytotoxic activity of NK
cells. CD70 was originally characterized as a marker of Reed-Sternberg
cells in Hodgkin’s disease and non-Hodgkin’s lymphomas
(39). It has also been found that CD70 is highly expressed
on EBV-transformed lymphoblastoid cells and human immunodeficiency
virus-infected T cells (39, 40). Therefore, the
CD27-mediated activation of NK cells may be involved in the innate
immune surveillance against these virus-infected or transformed cells
expressing CD70. Consistent with this idea, CD70-transfected murine
tumor cells exhibited a reduced ability of lung or hepatic metastasis,
which was predominantly mediated by NK cells (K. Takeda, unpublished
observations). Further studies are underway to elucidate the
physiological role of CD27 in the regulation of NK cell functions
in vivo.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Kazuyoshi Takeda, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bukyou-ku, Tokyo 113-8421, Japan.
3 Abbreviations used in this paper: PerCP, peridinin chlorophyl protein; TRAF, TNF receptor-associated factor.
Received for publication October 22, 1999. Accepted for publication December 1, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
ß T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis. J. Immunol. 156:3366.[Abstract]
production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking. J. Exp. Med. 183:2391. (IFN-). J. Immunol. 134:3124.[Abstract]
is essential for activation signal through NKR-P1 (CD161) in natural killer (NK) cells and NK1.1+ T cells. J. Exp. Med. 186:1957. receptor-initiated activation of natural killer cells. J. Biol. Chem. 270:16415.B and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-B-inducing kinase. J. Biol. Chem. 273:13353.This article has been cited by other articles:
|
|
 |
|
  M. Manocha, R. Svend, A. Laouar, G. Liao, A. Bhan, J. Borst, C. Terhorst, and N. Manjunath Blocking CD27-CD70 Costimulatory Pathway Suppresses Experimental Colitis J. Immunol., July 1, 2009; 183(1): 270 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-W. Lee, Z.-Z. Yang, G. Li, C. M. Weyand, and J. J. Goronzy Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis J. Immunol., August 15, 2007; 179(4): 2609 - 2615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. D. Huntington, H. Tabarias, K. Fairfax, J. Brady, Y. Hayakawa, M. A. Degli-Esposti, M. J. Smyth, D. M. Tarlinton, and S. L. Nutt NK Cell Maturation and Peripheral Homeostasis Is Associated with KLRG1 Up-Regulation J. Immunol., April 15, 2007; 178(8): 4764 - 4770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Wieland, M. E. Kerver, S. Florquin, M. A. Nolte, J. Borst, R. van Lier, M. H. J. van Oers, and T. van der Poll CD27 contributes to the early systemic immune response to Mycobacterium tuberculosis infection but does not affect outcome Int. Immunol., November 1, 2006; 18(11): 1531 - 1539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hayakawa and M. J. Smyth CD27 Dissects Mature NK Cells into Two Subsets with Distinct Responsiveness and Migratory Capacity J. Immunol., February 1, 2006; 176(3): 1517 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Iwamoto, M. Ishida, K. Takahashi, K. Takeda, and A. Miyazaki Lipopolysaccharide stimulation converts vigorously washed dendritic cells (DCs) to nonexhausted DCs expressing CD70 and evoking long-lasting type 1 T cell responses J. Leukoc. Biol., August 1, 2005; 78(2): 383 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Takeda, E. Cretney, Y. Hayakawa, T. Ota, H. Akiba, K. Ogasawara, H. Yagita, K. Kinoshita, K. Okumura, and M. J. Smyth TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver Blood, March 1, 2005; 105(5): 2082 - 2089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yamada, A. D. Salama, M. Sho, N. Najafian, T. Ito, J. P. Forman, R. Kewalramani, S. Sandner, H. Harada, M. R. Clarkson, et al. CD70 Signaling Is Critical for CD28-Independent CD8+ T Cell-Mediated Alloimmune Responses In Vivo J. Immunol., February 1, 2005; 174(3): 1357 - 1364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. T. van den Broeke, E. Daschbach, E. K. Thomas, G. Andringa, and J. A. Berzofsky Dendritic Cell-Induced Activation of Adaptive and Innate Antitumor Immunity J. Immunol., December 1, 2003; 171(11): 5842 - 5852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Douin-Echinard, J.-M. Peron, V. Lauwers-Cances, G. Favre, and B. Couderc Involvement of CD70 and CD80 intracytoplasmic domains in the co-stimulatory signal required to provide an antitumor immune response Int. Immunol., March 1, 2003; 15(3): 359 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Wilcox, K. Tamada, S. E. Strome, and L. Chen Signaling Through NK Cell-Associated CD137 Promotes Both Helper Function for CD8+ Cytolytic T Cells and Responsiveness to IL-2 But Not Cytolytic Activity J. Immunol., October 15, 2002; 169(8): 4230 - 4236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ohyama, S. Kanto, K. Kato, O. Nakano, Y. Arai, T. Kato, S. Chen, M. N. Fukuda, and M. Fukuda Natural killer cells attack tumor cells expressing high levels of sialyl Lewis x oligosaccharides PNAS, October 15, 2002; 99(21): 13789 - 13794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Kelly, K. Takeda, P. K. Darcy, H. Yagita, and M. J. Smyth A Role for IFN-{gamma} in Primary and Secondary Immunity Generated by NK Cell-Sensitive Tumor-Expressing CD80 In Vivo J. Immunol., May 1, 2002; 168(9): 4472 - 4479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Shimozato, J. R. Ortaldo, K. L. Komschlies, and H. A. Young Impaired NK Cell Development in an IFN-{gamma} Transgenic Mouse: Aberrantly Expressed IFN-{gamma} Enhances Hematopoietic Stem Cell Apoptosis and Affects NK Cell Differentiation J. Immunol., February 15, 2002; 168(4): 1746 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Yamada, A. D. Salama, and M. H. Sayegh The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation J. Am. Soc. Nephrol., February 1, 2002; 13(2): 559 - 575. [Full Text] [PDF]
|
|
|
|
|
|
Y. Hayakawa, K. Takeda, H. Yagita, L. Van Kaer, I. Saiki, and K. Okumura Differential Regulation of Th1 and Th2 Functions of NKT Cells by CD28 and CD40 Costimulatory Pathways J. Immunol., May 15, 2001; 166(10): 6012 - 6018. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
