| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
T Cells, and Antigen-Specific CTL1
*
Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304; and
Department of Tumor Immunology, University Hospital Nijmegen, Nijmegen, The Netherlands
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and Methods ResultsDiscussionReferences |
|---|
T cell
clones. Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes
resulted in inhibition of cytotoxicity against HLA-B*4403-transfected
melanomas as well as against melanomas endogenously expressing HLA-Bw4
allotypes. Similarly, interactions of KIR2DL2 or KIR2DL3 (KIR2DL2/3)
with HLA-Cw3-related allotypes on melanomas resulted in decreased tumor
cell lysis. We also investigated whether signaling via KIR affected
melanoma recognition by CTL. Introduction of KIR3DL1 molecules into
HLA-A*0201-restricted gp100-specific CTL resulted in inhibition of
lysis of gp100+ melanomas co-expressing HLA-A*0201
and HLA-Bw4 allotypes. These results suggest that disrupting
interactions of KIR with their ligands on tumor cells in vivo may
enhance antitumor responses mediated by both innate and adaptive immune
effector cells. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and Methods ResultsDiscussionReferences |
|---|
Recently, genes encoding the NK receptors for MHC class I molecules have been cloned (7, 8, 9). The killer cell inhibitory receptors (KIR)3 are expressed on subsets of human NK and T lymphocytes and are type I membrane glycoproteins with homology to the Ig superfamily (10). These receptors recognize defined groups of polymorphic HLA class I glycoproteins. This interaction is responsible for the inhibition of NK cell-mediated lysis of target cells bearing the appropriate HLA class I allotypes (11, 12). Ligation of KIR results in tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibition motifs in their cytoplasmic domain, leading to the recruitment of SH2-containing tyrosine phosphatase 1 (SHP-1) and inhibition of cell-mediated cytotoxicity (13, 14). In addition to KIR, human NK cells can express inhibitory receptors belonging to the C-type lectin glycoprotein superfamily that also recognize MHC class I molecules. Heterodimers composed of CD94 glycoproteins disulfide bonded with immunoreceptor tyrosine-based inhibition motif-bearing NKG2A glycoproteins transmit negative signals resulting in inhibition of target cell lysis upon recognizing HLA-E (15, 16, 17, 54).
While KIR and CD94/NKG2 receptors have been implicated in regulation of
NK cell recognition of normal and transformed hematopoietic cells,
their role in NK cell and T cell recognition of solid tumors is
controversial. In the present report, we investigated whether
interactions of KIR with MHC class I molecules on melanoma tumor cells
could inhibit tumor cell lysis by NK cells and T lymphocytes.
Furthermore, we examined whether introduction of a KIR into
melanoma-reactive CTL could interfere with Ag-specific tumor cell
recognition.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and Methods ResultsDiscussionReferences |
|---|
KIR-expressing NK and T cells were selected by flow
cytometry using mAbs DX9 (IgG1,
anti-KIR3DL1)4 (12)
and DX27 (IgG1, anti-KIR2DL2/3) (18) and were cloned and expanded
as described (19). KIR3DL1+ NK and T cell clones and
KIR2DL2/3+ NK clones were selected that lysed the MHC class
I-negative 721.221 B lymphoblasts but not 721.221-HLA-B*5801 and
721.221-HLA-C*0301 transfectants, respectively. TIL 1200 CTL and the
melanomas Mel 397 and Mel 624 were a kind gift from Dr. Y. Kawakami
(National Cancer Institute, National Institutes of Health, Bethesda,
MD) and were cultured as reported previously (20). Melanomas Mel 513D,
Mel 530, MZ 2, and MZ 7.4; FM 81 and FM 88; LB 373 and SK 29.1; and
FO-1 (21) were kindly provided by Dr. N. Brouwenstijn (Leiden
University Hospital, Department of Clinical Oncology, Leiden, The
Netherlands), Dr. J. Zeuthen (Danish Cancer Society, Department of
Tumor Cell Biology, Copenhagen, Denmark), Dr. P. Van der Bruggen
(Ludwig Institute for Cancer Research, Brussels, Belgium), and Dr. S.
Ferrone (New York Medical College, Department of Microbiology and
Immunology, Valhalla, NY), respectively. All melanomas were maintained
in DMEM (JRH Biosciences, Lenexa, KS) supplemented with 10% FCS
(HyClone, Logan, UT). The melanoma lines BLM and Mel 624 were
transfected with plasmid pCr3Uni-HLA-B*4403, as described previously
(22). The HLA-B*4403 cDNA was a kind gift from Dr. H. Dolstra
(University Hospital Nijmegen, Department of Hematology, Nijmegen, the
Netherlands). HLA-B*4403-expressing transfectants were selected by flow
cytometry using the human IgM anti-HLA-B12 mAb 13E12, a kind gift
from Dr. A. Mulder (Leiden University Hospital, Department of
Immuno-hematology and Blood Bank, Leiden, the Netherlands).
Recombinant vaccinia viruses and CTL infection
Recombinant vaccinia viruses encoding human KIR3DL1 and mouse LY49A were generated and purified as described (23). Briefly, both cDNAs were subcloned as SalI-NotI fragments into pSC66 (kindly provided by Dr. N. Wagtmann, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD). Subsequently, they were inserted into the WR strain of vaccinia virus by homologous recombination, and blue recombinant plaques were isolated using thymidine kinase and X-gal selection. Viral plaques were amplified and purified. The titer of each recombinant virus was determined using standard viral plaque assays. Before infection, TIL 1200 CTL were washed three times with infection medium (Iscove’s modified Dulbecco’s medium, 0.5% BSA, nonessential amino acids, 2 mM L-glutamine) and were resuspended at 1 x 106/ml in infection medium supplemented with 100 U/ml of rIL-2. The cells were infected with recombinant vaccinia virus at 30 plaque-forming units/cell for 4 h at 37°C on a rotator. After infection, the cells were washed once and directly used as effector cells in chromium release assays. Samples of infected cells were analyzed for expression of KIR3DL1 or LY49A by flow cytometry using the mAbs DX9 and JR9-318 (IgG1, anti-LY49A) (24), respectively.
Chromium release assay
Chromium release assays were performed as described previously
(22). Briefly, 106 target cells were incubated with
100 µCi of Na251CrO4 (Amersham,
Bucks, U.K.) for 1 h. Effector cells were then added to the target
cells in triplicate wells of U-bottomed microtiter plates (Costar,
Cambridge, MA) in a final vol of 150 µl. mAbs used for blocking
studies were: Leu 19 (IgG1, anti-CD56, isotype-matched control),
DX15 (IgG1, anti-HLA-B,-C) (25), DX16 (IgG1, anti-HLA-B,-C)
(25), DX17 (IgG1, anti-HLA-A, B, C) (26), DX9, and DX27. All mAbs
were used at a final concentration of 5 µg/ml. After 4 h of
incubation, part of the supernatant was harvested and its radioactive
content was measured. The mean percentage specific lysis of triplicate
wells was calculated using the formula: % specific lysis =
((experimental release - spontaneous release) ÷ (maximal
release - spontaneous release)) x 100. Before their use as
targets in chromium release assays, all melanomas were treated with 200
U/ml of IFN- (R & D Systems, Minneapolis, MN) for 48 h unless
otherwise indicated. The HLA class I expression of the target cells was
analyzed by flow cytometry using mAbs DX15, DX17, and FH0007 (IgG2a,
anti-HLA-Bw4) (One Lambda, Canoga Park, CA), as previously
described (27).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and Methods ResultsDiscussionReferences |
|---|
The KIR3DL1 is a receptor for HLA-B allotypes that bear the Bw4
public epitope (27) (Table I
). To investigate whether solid tumors were
protected from lysis by KIR3DL1+ NK clones, we used a
panel of HLA-typed melanoma tumor cell lines in cytotoxicity assays
(Table II). HLA-Bw4-
melanomas BLM and Mel 624 were transfected with the HLA-B*4403 (Bw4)
cDNA. Bw4-expressing transfectants were selected by flow cytometry and
were tested in cytotoxicity assays for lysis by KIR3DL1+ NK
clones. Before their use as target cells, all melanomas were treated
with IFN- and examined by flow cytometry to ensure substantial
expression of cell surface MHC class I molecules (data not shown).
Representative data obtained with a KIR3DL1+ NK clone are
shown in Figure 1A. NK clone
LB44.3 killed the nontransfected melanoma target cells, but displayed
diminished cytotoxicity toward the HLA-B*4403-BLM and -Mel 624
transfectants. Addition of either anti-HLA class I or
anti-KIR3DL1 mAb restored cytotoxicity to levels comparable to
killing of the nontransfected melanomas, demonstrating that the
KIR3DL1-HLA-B*4403 interaction was responsible for the observed
inhibition of lysis. We also investigated whether HLA-Bw4 allotypes
endogenously expressed on melanomas could protect these tumors from
killing by KIR3DL1+ NK clones (Fig. 1B).
All HLA-Bw4-expressing melanomas tested were either lysed to a low
extent or were resistant to lysis by NK clone LB44.1, whereas the MHC
class I-deficient FO-1 cells were efficiently lysed. The addition of
mAb against MHC class I or KIR3DL1 resulted in significant augmentation
of cytotoxicity against the Bw4-bearing melanomas.
|
|
|
, the NK clone
LB70.18 efficiently lysed Mel 397 melanoma cells expressing HLA-Cw4
molecules (asparagine at residue 77 and lysine at residue 80), while
melanomas expressing the Cw3-related allotypes Cw1 and/or Cw7 were
protected from lysis. Addition of mAb against either MHC class I or
KIR2DL2/3 reversed this protection, demonstrating that signaling via
the KIR2DL2/3 was responsible for the observed inhibition. Thus, both
HLA-B and -C molecules expressed by melanomas can abrogate lysis by NK
cells via ligation of KIR.
|
Down-regulation of HLA-B allotypes occurs frequently in cultured
melanoma cell lines (29). In line with this, we observed that melanoma
lines Mel 513D, FM 88, and LB 373 displayed very low levels of HLA-Bw4
expression. Consequently, these melanomas were lysed by
KIR3DL1+ NK and T cell clones in the absence of
IFN- treatment (data not shown). To determine the level of HLA-Bw4
expression necessary to protect FM 88 cells from lysis by
KIR3DL1+ NK clones, FM 88 cells were treated with
increasing amounts of IFN- before their use in cytotoxicity assays.
As shown in Figure 3, the level of lysis
mediated by KIR3DL1+ NK clone LB44.3 inversely correlated
with the amount of HLA-Bw4 molecules expressed at the cell surface of
the FM 88 cells. Addition of mAb against MHC class I or KIR3DL1
restored the level of cytotoxicity to that of the untreated FM 88
cells.
|
T cell-mediated lysis of melanomas
Activated human T lymphocytes have been shown to display
MHC nonrestricted cytotoxicity against a variety of tumor cells (30).
To determine whether the lytic activity of T cells against
melanoma tumor cells could be influenced by signaling via KIR, we
generated a panel of KIR3DL1+ T cell clones.
All KIR3DL1+ T cell clones obtained expressed a TCR
composed of V9 and V2 chains (data not shown). As shown in Figure 4A, T cell clone
LB44.11 efficiently lysed the HLA-Bw4- melanomas BLM and
Mel 624. This lytic activity involved the TCR-CD3 complex, since the
addition of mAb against the TCR diminished lysis by 40 to 60%
(data not shown). Both transfected and endogenously expressed HLA-Bw4
allotypes could protect melanoma tumor cells from being lysed by
KIR3DL1+ T cell clones LB44.11 and LB44.19 (Fig. 4, A and B), while anti-HLA class I and
anti-KIR3DL1 mAb reversed this protection. Interestingly,
anti-KIR3DL1 mAb only partially restored the lytic activity of
T cell clone LB44.19 against MZ 7.4 melanoma cells, when
compared with the level of killing reached in the presence of
anti-HLA class I mAb. This indicates that apart from the
KIR3DL1-HLA-B38 (Bw4) interaction, other HLA allotypes on MZ 7.4 cells
might be engaged by another MHC class I inhibitory receptor expressed
on the LB44.19 T cell clone, a phenomenon that was also observed
in the lysis pattern of Mel 530 cells when using LB70.18 NK cells (Fig. 2
), and that has previously been described for other NK clones (31).
The presence of other inhibitory receptors for MHC class I molecules
such as CD94/NKG2A (32) or ILT-2 (33, 34) may explain the partial
protection of MZ 7.4 cells from lysis by LB44.19 T cells.
|
To test whether signaling via MHC class I inhibitory receptors
could also affect tumor cell recognition by Ag-specific CTL, we
introduced the KIR3DL1 into TIL 1200 CTL. This antimelanoma
CD8+ CTL line is HLA-A*0201-restricted and recognizes
epitopes derived from the gp100 Ag (22). TIL 1200 CTL neither express
KIR nor CD94 complexes at their cell surfaces. KIR3DL1 expression was
accomplished by means of recombinant vaccinia virus infection. The
vaccinia virus expression system had previously been used to deliver
KIR molecules into NK cell clones (23). Infection of the gp100-specific
TIL 1200 CTL with vaccinia viruses encoding the murine LY49A protein
(LY49A-Vac, control) or the KIR3DL1 (KIR3DL1-Vac) showed that the
majority of the cells can be productively infected (Fig. 5A). Although infection
with the vaccinia viruses causes a moderate reduction in the lytic
capacity of TIL 1200 CTL (data not shown), their specific recognition
of gp100 peptides in the context of HLA-A*0201 molecules was clearly
retained. HLA-A*0201+ BLM cells that lack gp100 expression
were not lysed, while Mel 624 cells expressing both HLA-A*0201 and
gp100 were clearly recognized (Fig. 5B). Whereas TIL
1200 CTL infected with LY49A-Vac lysed the HLA-A*0201+
gp100+ targets, infection with KIR3DL1-Vac strongly
inhibited the lysis of HLA-Bw4-expressing Mel 624 B4403 and Mel 513D
cells, but not the lysis of the nontransfected HLA-Bw4-
Mel 624 cells (Fig. 5B). The addition of mAb against
HLA-B or KIR3DL1 restored the levels of cytotoxicity, demonstrating
that the KIR3DL1-HLA-Bw4 interaction was responsible for the observed
inhibition. Thus, when transferred into Ag-specific CTL, KIR can
transmit negative signals upon engaging its HLA class I ligand on a
solid tumor cell that effectively suppresses the activating signal that
is generated via TCR-MHC class I/peptide interactions.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and Methods ResultsDiscussionReferences |
|---|
T lymphocytes bearing MHC class I inhibitory receptors, consistent with
other recent findings (37). Furthermore, we observed a direct
relationship between the level of protection induced and the amount of
HLA molecules present on the melanoma targets, confirming a
stochiometric relationship of KIR-ligand interactions (38).
The role of IFN- in the induction of resistance to NK cell killing
has been controversial. Some studies have claimed that IFN-
treatment rendered tumor cells resistant to NK cell lysis irrespective
of the level of target cell MHC class I expression, while others showed
that IFN- treatment increased MHC class I expression without
affecting NK susceptibility (39, 40). Our results clearly show a direct
correlation between IFN--induced MHC class I surface expression and
tumor cell protection from NK cell killing (Fig. 3). Furthermore,
experiments using the IFN--treated nontransfected and
HLA-B*4403-transfected melanomas (Fig. 1) exclude that parameters other
than HLA class I affected the observed protection.
At present, it is unclear whether the repertoire of MHC class I inhibitory receptors is biased toward the recognition of self-HLA allotypes. Examination of the KIR3DL1 receptor in a large panel of donors revealed no correlation between KIR3DL1 expression patterns and the presence or absence of HLA-Bw+ allotypes in the individual (41). However, since NK cells can express multiple KIR and/or CD94/NKG2 complexes, selection of NK cells may be based on the total set of receptors expressed, requiring the expression of at least one receptor recognizing a self-HLA class I allotype (42). Consequently, NK cells may target tumor cells that have preferentially lost the expression of some HLA class I molecules, in addition to cells that totally lack HLA class I expression.
The degree of MHC class I expression in solid tumors varies extensively. Total loss of expression of HLA class I Ags has been described, resulting from mutations in ß2-microglobulin genes (21), as well as from mutations in peptide transporter genes (43, 44). Furthermore, specific HLA-B locus down-regulation has been reported (29, 45). While MHC class I expression is vital for CD8+ T cell recognition, loss of HLA class I molecules may permit lysis of tumor cells by NK cells. Since HLA expression within solid tumors is very heterogeneous, both innate and acquired immune effector cells may need to join their efforts to accomplish complete tumor eradication. At present, the role and timing of NK cells in antitumor immunity is not clear. In antiviral immune responses, NK cells may provide a first line of defense by eliminating virus-infected cells that have down-modulated their MHC class I molecules as a consequence of the viral infection (46, 47). In tumors, however, loss of HLA class I expression may result from selection by antitumor T cell responses. Therefore, antitumor NK cell activity may follow the classical CTL response.
While initially discovered on NK cells, MHC class I inhibitory receptors are also expressed on T cells (26, 48, 49). Previously, it has been demonstrated that KIR can inhibit the lytic function of CTL activated by superantigens (26). The results described in this report extend these findings to Ag-specific CTL, demonstrating that negative signaling via KIR also interferes with CTL effector function upon TCR engagement by MHC-peptide complexes. KIR are expressed by a minor population of T lymphocytes, and are thought to raise the threshold needed to activate cells via the TCR (26). Since KIR are expressed predominantly on CD28-negative "memory" T cells, they may function to prevent inadvertent activation of primed T cells bearing TCR against self-Ags. This may provide a mechanism of peripheral tolerance to prevent autoimmunity against normal tissues in the case of chronic stimulation of the immune system. A recent report describing a KIR2DL2/3+ CTL clone obtained from PBL of a patient with metastatic melanoma exemplifies this hypothesis (50). An HLA-A24-restricted CTL clone was shown to recognize a peptide derived from a normal human gene (PRAME) expressed by melanomas and other tumors and at a lower level in some normal tissues (44). The CTL lysed an in vivo-selected melanoma variant that had lost the expression of an HLA-C allele, while it failed to lyse a melanoma line expressing all HLA class I allotypes obtained from the same patient 5 yr before the recurrence of the disease. This CTL may represent a category of antitumor T lymphocytes recognizing self-Ags that specifically recognize tumor cells that have lost some, but not all, HLA class I molecules. Detailed analysis of CTL clones that are obtained from T lymphocytes that are cocultured with tumor cells in the presence of anti-KIR Abs may reveal whether such CTL are common and thus potentially play an important role in antitumor immune responses.
Manipulation of MHC class I inhibitory receptors in vivo may enhance
antitumor immunity. In murine cancer models, infusion of Abs to CTLA4,
a negative regulator of T cell activation, resulted in the rejection of
tumors, while no overt toxicity was observed (51). Similarly, a
blockade of MHC class I inhibitory receptors may release the brake on
NK and T cells and KIR+ tumor-reactive CTL,
resulting in enhanced antitumor activity. Since the window between
development of an antitumor response and autoimmunity may be narrow,
the success of this approach may depend on a preferential activation of
the immune effector cells at the tumor site.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. L. L. Lanier, Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA 94304-1104. E-mail address:
3 Abbreviations used in this paper: KIR, killer cell inhibitory receptor.
4 Nomenclature for KIR proteins is as proposed by Dr. E. Long (National Institutes of Health, Bethesda, MD) in consultation with Drs. L. L. Lanier and M. Colonna (Basel Institute, Basel, Switzerland) (Table I and Refs. 52 and 53).
Received for publication November 14, 1997. Accepted for publication January 29, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and Methods ResultsDiscussionReferences |
|---|
ß TCR population in i-IEL with an extrathymic maturation. Int. Immunol. 4:699.9V2 T lymphocytes. J. Immunol. 159:6009.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  M. Lagadari, K. Truta-Feles, K. Lehmann, L. Berod, M. Ziemer, M. Idzko, D. Barz, T. Kamradt, A. A. Maghazachi, and J. Norgauer Lysophosphatidic acid inhibits the cytotoxic activity of NK cells: involvement of Gs protein-mediated signaling Int. Immunol., June 1, 2009; 21(6): 667 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. La Rocca, M. Fulciniti, T. Lakshmikanth, M. Mesuraca, T. H. Ali, V. Mazzei, N. Amodio, L. Catalano, B. Rotoli, O. Ouerfelli, et al. Early Hematopoietic Zinc Finger Protein Prevents Tumor Cell Recognition by Natural Killer Cells J. Immunol., April 15, 2009; 182(8): 4529 - 4537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. T. van der Veken, M. Diez Campelo, M. A. W. G. van der Hoorn, R. S. Hagedoorn, H. M. E. van Egmond, J. van Bergen, R. Willemze, J. H. F. Falkenburg, and M. H. M. Heemskerk Functional Analysis of Killer Ig-Like Receptor-Expressing Cytomegalovirus-Specific CD8+ T Cells J. Immunol., January 1, 2009; 182(1): 92 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fourmentraux-Neves, A. Jalil, S. Da Rocha, C. Pichon, S. Chouaib, G. Bismuth, and A. Caignard Two opposite signaling outputs are driven by the KIR2DL1 receptor in human CD4+ T cells Blood, September 15, 2008; 112(6): 2381 - 2389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Binyamin, R. K. Alpaugh, T. L. Hughes, C. T. Lutz, K. S. Campbell, and L. M. Weiner Blocking NK Cell Inhibitory Self-Recognition Promotes Antibody-Dependent Cellular Cytotoxicity in a Model of Anti-Lymphoma Therapy J. Immunol., May 1, 2008; 180(9): 6392 - 6401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shi, G. J. Tricot, T. K. Garg, P. A. Malaviarachchi, S. M. Szmania, R. E. Kellum, B. Storrie, A. Mulder, J. D. Shaughnessy Jr, B. Barlogie, et al. Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma Blood, February 1, 2008; 111(3): 1309 - 1317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Campillo, J. A. Martinez-Escribano, M. R. Moya-Quiles, L. A. Marin, M. Muro, N. Guerra, A. Parrado, M. Campos, J. F. Frias, A. Minguela, et al. Natural Killer Receptors on CD8 T Cells and Natural Killer Cells from Different HLA-C Phenotypes in Melanoma Patients. Clin. Cancer Res., August 15, 2006; 12(16): 4822 - 4831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lundqvist, S. I. Abrams, D. S. Schrump, G. Alvarez, D. Suffredini, M. Berg, and R. Childs Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res., July 15, 2006; 66(14): 7317 - 7325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Williams, A. R. Bateman, and S. I. Khakoo HANGING IN THE BALANCE: KIR and Their Role in Disease Mol. Interv., August 1, 2005; 5(4): 226 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Xu, A. N. Vallejo, Y. Jiang, C. M. Weyand, and J. J. Goronzy Distinct Transcriptional Control Mechanisms of Killer Immunoglobulin-like Receptors in Natural Killer (NK) and in T Cells J. Biol. Chem., June 24, 2005; 280(25): 24277 - 24285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. van Bergen, A. Thompson, A. van der Slik, T. H. M. Ottenhoff, J. Gussekloo, and F. Koning Phenotypic and Functional Characterization of CD4 T Cells Expressing Killer Ig-Like Receptors J. Immunol., December 1, 2004; 173(11): 6719 - 6726. [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]
|
|
|
|
|
|
K. Tajima, N. Matsumoto, K. Ohmori, H. Wada, M. Ito, K. Suzuki, and K. Yamamoto Augmentation of NK cell-mediated cytotoxicity to tumor cells by inhibitory NK cell receptor blockers Int. Immunol., March 1, 2004; 16(3): 385 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zoller Tumor Vaccination after Allogeneic Bone Marrow Cell Reconstitution of the Nonmyeloablatively Conditioned Tumor-Bearing Murine Host J. Immunol., December 15, 2003; 171(12): 6941 - 6953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hummel, D. Wilms, M. Vitacolonna, and M. Zoller Donor T cell and host NK depletion improve the therapeutic efficacy of allogeneic bone marrow cell reconstitution in the nonmyeloablatively conditioned tumor-bearing host J. Leukoc. Biol., November 1, 2002; 72(5): 898 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Chwae, M. J. Chang, S. M. Park, H. Yoon, H.-J. Park, S. J. Kim, and J. Kim Molecular Mechanism of the Activation-Induced Cell Death Inhibition Mediated by a p70 Inhibitory Killer Cell Ig-Like Receptor in Jurkat T Cells J. Immunol., October 1, 2002; 169(7): 3726 - 3735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Guerra, F. Michel, A. Gati, C. Gaudin, Z. Mishal, B. Escudier, O. Acuto, S. Chouaib, and A. Caignard Engagement of the inhibitory receptor CD158a interrupts TCR signaling, preventing dynamic membrane reorganization in CTL/tumor cell interaction Blood, September 26, 2002; 100(8): 2874 - 2881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. VanLith, K. G. Kohlgraf, C. L. Sivinski, R. M. Tempero, and M. A. Hollingsworth MUC1-specific anti-tumor responses: molecular requirements for CD4-mediated responses Int. Immunol., August 1, 2002; 14(8): 873 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Miller, M. Peters, A. E. Oran, G. W. Beresford, L. Harrington, J. M. Boss, and J. D. Altman CD94/NKG2 Expression Does Not Inhibit Cytotoxic Function of Lymphocytic Choriomeningitis Virus-Specific CD8+ T Cells J. Immunol., July 15, 2002; 169(2): 693 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Derre, M. Corvaisier, M.-C. Pandolfino, E. Diez, F. Jotereau, and N. Gervois Expression of CD94/NKG2-A on Human T Lymphocytes Is Induced by IL-12: Implications for Adoptive Immunotherapy J. Immunol., May 15, 2002; 168(10): 4864 - 4870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Spies Induction of T cell alertness by bacterial colonization of intestinal epithelium PNAS, March 5, 2002; 99(5): 2584 - 2586. [Full Text] [PDF]
|
|
|
|
|
|
J. Y. Djeu, K. Jiang, and S. Wei A View to a Kill: Signals Triggering Cytotoxicity Clin. Cancer Res., March 1, 2002; 8(3): 636 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Uhrberg, N. M. Valiante, N. T. Young, L. L. Lanier, J. H. Phillips, and P. Parham The Repertoire of Killer Cell Ig-Like Receptor and CD94:NKG2A Receptors in T Cells: Clones Sharing Identical {{alpha}}{{beta}} TCR Rearrangement Express Highly Diverse Killer Cell Ig-Like Receptor Patterns J. Immunol., March 15, 2001; 166(6): 3923 - 3932. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lohwasser, A. Kubota, M. Salcedo, R. H. Lian, and F. Takei1 The non-classical MHC class I molecule Qa-1b inhibits classical MHC class I-restricted cytotoxicity of cytotoxic T lymphocytes Int. Immunol., March 1, 2001; 13(3): 321 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Vely, M.-A. Peyrat, C. Couedel, J.-F. Morcet, F. Halary, F. Davodeau, F. Romagne, E. Scotet, X. Saulquin, E. Houssaint, et al. Regulation of Inhibitory and Activating Killer-Cell Ig-Like Receptor Expression Occurs in T Cells After Termination of TCR Rearrangements J. Immunol., February 15, 2001; 166(4): 2487 - 2494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Baars, L. M. Ribeiro do Couto, J. H. W. Leusen, B. Hooibrink, T. W. Kuijpers, S. M. A. Lens, and R. A. W. van Lier Cytolytic Mechanisms and Expression of Activation-Regulating Receptors on Effector-Type CD8+CD45RA+CD27- Human T Cells J. Immunol., August 15, 2000; 165(4): 1910 - 1917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Guerra, M. Guillard, E. Angevin, H. Echchakir, B. Escudier, A. Moretta, S. Chouaib, and A. Caignard Killer inhibitory receptor (CD158b) modulates the lytic activity of tumor-specific T lymphocytes infiltrating renal cell carcinomas Blood, May 1, 2000; 95(9): 2883 - 2889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Ortaldo, R. Winkler-Pickett, J. Willette-Brown, R. L. Wange, S. K. Anderson, G. J. Palumbo, L. H. Mason, and D. W. McVicar Structure/Function Relationship of Activating Ly-49D and Inhibitory Ly-49G2 NK Receptors ,2 J. Immunol., November 15, 1999; 163(10): 5269 - 5277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Lutz and Z. B. Kurago Human Leukocyte Antigen Class I Expression on Squamous Cell Carcinoma Cells Regulates Natural Killer Cell Activity Cancer Res., November 1, 1999; 59(22): 5793 - 5799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Cambiaggi, S. Darche, S. Guia, P. Kourilsky, J.-P. Abastado, and E. Vivier Modulation of T-Cell Functions in KIR2DL3 (CD158b) Transgenic Mice Blood, October 1, 1999; 94(7): 2396 - 2402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Speiser, M. J. Pittet, D. Valmori, R. Dunbar, D. Rimoldi, D. Lienard, H. R. MacDonald, J.-C. Cerottini, V. Cerundolo, and P. Romero In Vivo Expression of Natural Killer Cell Inhibitory Receptors by Human Melanoma-Specific Cytolytic T Lymphocytes J. Exp. Med., September 20, 1999; 190(6): 775 - 782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F.-A. Le Gal, B. Riteau, C. Sedlik, I. Khalil-Daher, C. Menier, J. Dausset, J.-G. Guillet, E. D. Carosella, and N. Rouas-Freiss HLA-G-mediated inhibition of antigen-specific cytotoxic T lymphocytes Int. Immunol., August 1, 1999; 11(8): 1351 - 1356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Meyaard, J. Hurenkamp, H. Clevers, L. L. Lanier, and J. H. Phillips Leukocyte-Associated Ig-Like Receptor-1 Functions as an Inhibitory Receptor on Cytotoxic T Cells J. Immunol., May 15, 1999; 162(10): 5800 - 5804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Paul, F. A. Cabestre, F.-A. Le Gal, I. Khalil-Daher, C. Le Danff, M. Schmid, S. Mercier, M.-F. Avril, J. Dausset, J.-G. Guillet, et al. Heterogeneity of HLA-G Gene Transcription and Protein Expression in Malignant Melanoma Biopsies Cancer Res., April 1, 1999; 59(8): 1954 - 1960. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
1000 arbitrary units.
One representative experiment of three is shown.
