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Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14 J281; Refs
14, 15, 16) and therefore cannot be the source of the
polyclonal T cell response typically seen during viral infection
(17, 18, 19). DX5 is a marker that is used extensively to
identify NK cells in mouse strains that do not express NK1.1 (e.g.,
BALB/c), and the expression of this NK marker has been observed on only
a small number of splenic T cells (20). These published
studies have identified only small populations of
NK-marker+ T cells and have not directly
quantitated the extent of NK marker expression. Moreover, they have
focused only on CD8+ T cells, and the expression
of NK markers on CD4+ T cells has not been
explored. Here, we used flow cytometry to quantitate the expression of all three prototypical NK markers on virus-specific and nonspecific CD8+ T cells and CD4+ T cells at each stage of the antiviral immune response. Our study demonstrates that these "NK markers" are found on a remarkably high number of virus-specific CD8+ and CD4+ T cells. In addition, these T cells are depleted in vivo by administration of anti-ASGM1 Ab, a procedure commonly believed to specifically remove NK cells. Based on these results, the present definition of NKT cells will require considerable restructuring to include Ag-specific T cells that express the NK markers DX5, NK1.1, and ASGM1.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice (5–15 wk of age) were injected i.p. with 2 x 105 PFU of lymphocytic choriomeningitis virus (LCMV)-Armstrong (Arm-53b) and were used at the indicated time points. C57BL/6 mice were either purchased from The Jackson Laboratory (Bar Harbor, ME) or obtained from The Scripps Research Institute breeding facility.
Peptides and in vitro stimulation
HPLC-purified (>95% pure) MHC class I epitope peptides,
GP33–41 (KAVYNFATM),
NP396–404 (FQPQNGQFI),
GP276–286 (SGVENPGGYCL), and
NP205–212 (YTVKYPNL), and MHC class II epitope
peptides NP309–328 (SGEGWPYIACRTSIVGRAWE), and
GP61–80 (GLKGPDIYKGVYQFKSVEFD) were
purchased from Peptidogenic (Livermore, CA), or synthesized at The
Scripps Research Institute Core Facility and stored at -80°C until
use. Peptides were pooled and used at the following concentrations:
1 x 10-7 M (of each peptide) to stimulate
CD8+ T cells or 1 x
10-5 M (of each peptide) to stimulate
CD4+ T cells. Spleen cells (2 x
106/well) from LCMV-infected or naive mice were
cultured at 37°C, 6% CO2 for 6 h in the
presence or absence of pooled peptide in RPMI 1640 containing 10% FBS,
20 mM HEPES, L-glutamine, and antibiotics. Brefeldin A
(Sigma, St. Louis, MO) was added at a final concentration of 2
µg/ml. No IFN-
production was observed after stimulation
ofvirus-specific T cells with an irrelevant peptide restricted by
MHC class I (SMIKNLEYM; Ref. 21) or by MHC class II
(VSV415–433, SSKAQVFEHPHIQDAASQL; Ref.
22).
Intracellular cytokine staining and flow cytometry
After in vitro stimulation, cells were immediately placed on
ice, washed, and stained overnight at 4°C with Ab combinations of
CD8-cychrome, CD4-cychrome, NK1.1-PE, and/or DX5-biotin (followed by
streptavidin-PE) (PharMingen, San Diego, CA). Some samples were also
stained with rabbit anti-ASGM1 (Cedarlane, Ontario, Canada)
followed by polyclonal anti-rabbit-PE (PharMingen). The cells were
washed and permeabilized using a Cytofix/Cytoperm kit (PharMingen)
according to the manufacturer’s directions and stained with
FITC-conjugated anti-IFN- (PharMingen). Samples were resuspended
in PBS containing 2% formaldehyde and acquired on a FACScan flow
cytometer (100,000–500,000 events acquired per sample) and analyzed
using Cellquest software (Becton Dickinson, San Jose, CA). An
irrelevant PE-conjugated Ab (Rat IgG1 PE isotype control, PharMingen,)
or streptavidin PE alone (the secondary reagent for DX5 staining) was
used to determine the quadrant line settings, and nonspecific staining
with these negative controls was subtracted from the numbers described
in the figures.
In vivo depletion of ASGM1+ cells
C57BL/6 mice were infected with LCMV at 8 days or 105 days before the assay and were injected i.v. with 30 µL of rabbit polyclonal anti-ASGM1 (Cedarlane) or PBS in a total volume of 300 µl at 36 h and again at 24 h before harvest.
51Cr release assays
At 8 days postinfection, direct ex vivo cytolytic activity against peptide-coated (1 x 10-7 M NP396–404 and 1 x 10-7 M GP33–41) MC57 target cells was performed as previously described (23). Lytic units were defined as the number of splenocytes required to exhibit 30% lysis of peptide-coated targets.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LCMV infection of adult mice is typically resolved within 1–2 wk
postinfection, and it is well established that viral clearance is
mediated by CD8+ T cells (24, 25, 26, 27, 28, 29, 30).
The peak of the cellular immune response against LCMV occurs at about 8
days postinfection, and, consistent with previous results
(31, 32, 33), we found that 
60% of
CD8+ T cells produced IFN- after direct ex
vivo stimulation with the four major CD8 epitope peptides
(GP33, GP276,
NP205, and NP396) (Fig. 1
). IFN- production was not observed
in the absence of peptide, indicating that cytokine synthesis is not
constitutive in virus-specific T cells and requires direct contact with
specific Ag to be induced and maintained (33). No IFN-
production was observed after stimulation of virus-specific T cells
with irrelevant MHC class I or class II peptides (data not shown). In
addition, IFN- production was not observed after peptide stimulation
of naive T cells, indicating that only virus-specific T cells are
detected by this assay (Fig. 1 and Refs. 32, 34, 35).
Expression of the three most commonly used NK markers (DX5, NK1.1, and
ASGM1) was determined using flow cytometry. Approximately 6–8% of
naive CD8+ T cells expressed DX5, 1–3%
expressed NK1.1, and nearly 30% expressed ASGM1. In contrast, 30–40%
of virus-specific (IFN-+)
CD8+ T cells were positive for DX5 or NK1.1
and 
90% expressed ASGM1 at 8 days postinfection. The
proportion of nonspecific (IFN--)
CD8+ T cells expressing NK markers also
increased, although not to the degree observed with Ag-specific T cells
(described in detail below). The addition of brefeldin A during the in
vitro stimulation period not only blocked cytokine secretion but also
inhibited the transport of new molecules to the surface of the cells
(data not shown). Consistent with this, the total percentage of
CD8+ T cells expressing each NK marker remained
essentially the same, both in the presence or absence of peptide
stimulation. Thus, the high percentage of virus-specific T cells
expressing NK markers is not the result of in vitro peptide
stimulation, but is instead a reflection of the in vivo
NK-marker+ status of these cells.
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). About 20% of memory
CD8+ T cells expressed DX5, whereas NK1.1 was
expressed on 50%, and ASGM1 was expressed on 98% of the
virus-specific memory T cells. This shows that, compared with activated
T cells at 8 days postinfection, the percentage of virus-specific
memory T cells expressing DX5 declined, whereas NK1.1 expression
increased and ASGM-1 expression remained nearly unchanged.
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Similar to naive CD8+ T cells, 6–8% of
naive CD4+ T cells expressed DX5, 1–3%
expressed NK1.1, and 20% expressed ASGM1 (Fig. 3). By 8 days postinfection with LCMV,
between 15–20% of the CD4+ T cells in the
spleen respond to LCMV-specific MHC class II peptides (Fig. 3; Refs.
34, 35). At this time point, DX5 and NK1.1 were
expressed on 40–60% of the peptide-specific
CD4+ T cells, and nearly 90% of the Ag-specific
CD4+ T cells expressed ASGM1. By 50 days
postinfection, DX5 was still expressed on 35–50% of memory
CD4+ T cells whereas NK1.1 was expressed on only
15–25% of the memory cells (Fig. 4).
Almost 90% of the Ag-specific CD4+ T cells
continued to express ASGM1. Together, these results indicate that
virus-specific CD4+ T cells express prototypical
NK markers at frequencies similar to those observed on virus-specific
CD8+ T cells.
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To further characterize the kinetics of NK marker expression on
T cells during the course of acute viral infection, we determined
the percentage of virus-specific T cells and nonspecific T cells
expressing NK Ags at time points ranging from 5 days to 580 days
postinfection (Fig. 5). Following acute
LCMV infection, there was a rapid expansion of virus-specific
CD8+ and CD4+ T cells that
peaked at 8 days postinfection. In accord with previous studies
(32, 35), virus-specific CD8+ T
cells numbers declined 10- to 20-fold by 15 days postinfection, and
virus-specific CD4+ T cell numbers dropped by 4-
to 5-fold (Fig. 5, A and E). By 30–40 days
postinfection, each virus-specific T cell population had declined to a
plateau that was maintained essentially for the life of the immune
animal. Fig. 5, B–D, and Fig. 5, F–H, show the
percentage of virus-specific and nonspecific CD8+
and CD4+ T cells that express NK markers during
each stage of the immune response. Compared with naive T cells, the
percentage of virus-specific CD8+ T cells
expressing DX5 increased 14-fold and peaked by 5 days postinfection
before declining to a stable, but smaller, population of
DX5+ cells by day 15. Nonspecific
CD8+ T cells exhibited only a 4-fold increase in
DX5 expression by day 5 before returning to near normal levels by about
15 days postinfection. In contrast to DX5, NK1.1 expression on
Ag-specific CD8+ T cells increased by 40-fold at
15 days postinfection and then declined slowly over the following
month. NK1.1 expression increased about 7-fold on nonspecific
CD8+ T cells by 15 days postinfection and
remained elevated in comparison with naive CD8+ T
cells. Similar to previous observations (7), we found that
30% of naive CD8+ T cells expressed ASGM1
(Fig. 1
). In contrast, by 5 days postinfection and at all later time
points examined, nearly 100% of virus-specific
CD8+ T cells expressed this marker, whereas only
40–60% of the nonspecific CD8+ T cells in
LCMV-infected mice expressed the ASGM1 Ag.
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, F–H) followed kinetics similar to those observed on
virus-specific CD8+ T cells. Compared with naive
CD4+ T cells, the percentage of virus-specific
CD4+ T cells expressing DX5 increased 7-fold by 5
days postinfection, and the DX5 Ag was maintained on over half of the
antiviral CD4+ T cells for >500 days. The
percentage of virus-specific CD4+ T cells
expressing NK1.1 increased by 18-fold at 8 days postinfection before
declining slowly over the next several months. ASGM1 expression on
virus-specific CD4+ T cells was maximal by day 5
and was then maintained on 85–90% of antiviral
CD4+ T cells at all other time points examined.
In contrast to Ag-specific CD4+ T cells, NK
marker expression on nonspecific CD4+ T cells was
not greatly altered. On average, there was less than a 2- to 3-fold
increase in NK marker expression on nonspecific
CD4+ T cells. In vivo depletion of NK cells also depletes virus-specific T cells
Since a surprisingly high percentage of virus-specific T cells
expressed ASGM1, we determined whether these lymphocytes could be
depleted in vivo with the same anti-ASGM1 Ab that is commonly used
to deplete NK cells. Using the criterion of in vitro cytotoxicity,
others have addressed this issue, but with conflicting results. One
study found reduced CTL activity following anti-ASGM1 depletion of
normal mice (10), whereas a second investigation suggested
that such depletion is of concern only in previously immunosuppressed
animals (9). Furthermore, these studies focused solely on
CD8+ T cells. We chose to determine the effects
of anti-ASGM1 depletion on both virus-specific
CD4+ and CD8+ T cells; and
we used flow cytometry to directly quantitate the frequency of NK
marker expression in both groups, as well as evaluating the cytolytic
activity of the latter population. LCMV-specific T cell responses were
analyzed at either 8 days postinfection or 105 days postinfection to
compare the susceptibility of activated and memory T cells to in vivo
depletion. Based on flow cytometry, anti-ASGM1 treatment was
reasonably effective at depleting NK cells; on average, about 75% of
the NK1.1+CD3- NK cells
were removed by this procedure (data from representative mice are shown
in Fig. 6A). However,
NK1.1+CD3+ T cells also
were severely depleted by this procedure, indicating that
NK1.1+ T cells in LCMV-infected mice coexpress
the ASGM1 Ag. We next evaluated the effects of anti-ASGM1 treatment
on virus-specific T cells (Fig. 6, B–D). In mice infected 8
days previously, CD8+ T cell-mediated CTL
activity against peptide-coated targets was greatly diminished after in
vivo administration of anti-ASGM1 (Fig. 6B), and lytic
units per 106 spleen cells were reduced by
approximately 8-fold. In addition, we used intracellular cytokine
staining to directly quantitate the efficiency of anti-ASGM1
depletion of Ag-specific T cells, and found that about 90% of
virus-specific CD8+ T cells and 50–80% of
virus-specific CD4+ T cells were depleted by this
treatment (Fig. 6, C and D). Both activated and
memory T cells were enumerated, and both populations were greatly
depleted in vivo using Abs to this NK marker.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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75% of
NK1.1+CD3- NK cells and
also resulted in a similar loss of virus-specific
CD8+ and CD4+ T cells.
Together, these results demonstrate that the majority of virus-specific
T cells express one or more of the three most commonly used NK markers.
In light of our observations and others (9, 10, 36), the
results of in vivo NK cell depletion studies should be viewed
conservatively unless the appropriate T cell controls have been
included. Our results show that a high proportion of LCMV-specific and nonspecific T cells in C57BL/6 mice express NK markers following LCMV infection. The high-frequency expression of NK markers on Ag-specific T cells was not limited to the specific mouse strain or the virus used in this particular study. We examined DX5 and ASGM1 expression on virus-specific T cells in BALB/c mice following acute LCMV infection (the NK1.1 marker is not expressed in this mouse strain). DX5 was expressed on >80% of LCMV-specific CD8+ T cells by 5 days postinfection in BALB/c mice, and on >20% of the virus-specific memory T cells analyzed at >100 days postinfection (data not shown). ASGM1 was expressed on 80–100% of virus-specific CD8+ T cells in BALB/c mice at all time points examined. Furthermore, NK marker expression was not restricted to LCMV-specific T cells; recombinant vaccinia virus (rVV-NP) infection of BALB/c mice also resulted in high-level DX5 and ASGM1 expression on virus-specific CD8+ T cells (M. K. Slifka and J. L. Whitton, unpublished results). This suggests that the high expression of NK markers on virus-specific T cells, especially during the early stages of infection, may be much more common than previously believed.
Following acute LCMV infection, NK markers were
preferentially expressed on virus-specific T cells (Fig. 5), although a
substantial number of nonspecific CD8+ and
CD4+ T cells also showed an increase in NK
marker expression. Up-regulation of NK markers was more
pronounced on nonspecific CD8+ T cells than on
nonspecific CD4+ T cells. One explanation for
this result may be the differences in the overall expansion of these
two T cell subsets. CD8+ T cells undergo a
massive expansion during the course of LCMV infection in which 50%
of the CD8+ T cells are specific for viral
peptide Ags by 8 days postinfection (Fig. 1 and Refs.
31, 32, 33). In contrast, CD4+ T cells
undergo a more modest expansion, resulting in 15–20% of the
CD4+ T cell population becoming virus-specific by
8 days postinfection (Fig. 3 and Refs. 34, 35). At the
peak of the antiviral immune response, the total number of
virus-specific CD4+ T cells per spleen is roughly
10-fold lower than the number of CD8+ T cells
(Fig. 5). We speculate that the more extensive expansion of a
particular T cell subset may correlate with an increase in NK marker
expression. This may be due, in part, to bystander activation
(37). Studies are underway to determine whether the number
of cell divisions and/or the cytokine milieu play a role in the
induction of NK marker expression on CD8+ and
CD4+ T cells.
NKT cells have been considered a novel lymphoid lineage that is
distinct from T cells and NK cells. In mice, NKT cells have been
characterized as NK1.1+ cells that express an
invariant Ag receptor encoded by V14 and J281 (15, 16) in association with a variety of Vß genes, but mainly
Vß8.2 (38, 39). These cells can be stimulated with
anti-CD3 or the CD1-restricted Ag, -galactosylceramide
(40). In contrast, the virus-specific "NKT cells"
described in this study have polymorphic TCR, express either the CD8 or
CD4 coreceptors, and have specificity for several distinct viral
peptide Ags that are either MHC class I or MHC class II restricted. For
these reasons, it is unlikely that the "NKT cells" generated after
LCMV infection are similar to V14 NKT cells. It will be important to
determine the functional and phenotypic characteristics of each of
these subsets of NKT cells and clarify their role in the immune
response to a variety of Ags. Moreover, the "NKT cell" nomenclature
will require extensive revision to distinguish between these different
lymphocyte populations.
This study demonstrates that the great majority of virus-specific
CD8+ and CD4+ T cells
express one or more prototypical NK markers at every stage of the
antiviral immune response. Although ß T cells and NK cells are
quite distantly related in terms of lineage commitment, our results
suggest that, at least phenotypically, these two cell types have a
great deal in common. Other NK receptors such as KIRs (killer
inhibitory receptors) have also been identified on T cells
(41), and it will be interesting to learn what role these
receptors play in T cell-mediated immunity. In addition to expanding
our phenotypic analysis, we are currently investigating whether
virus-specific T cells that express NK markers also respond to signals
known to regulate NK cell activity. Together, these studies will help
clarify the important functional roles of T cells, NK cells, and NKT
cells in providing protective anti-microbial immunity.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mark K. Slifka, Department of Neuropharmacology, CVN-9, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address:
3 Abbreviations used in this paper: ASGM1, asialo-GM1; LCMV, lymphocytic choriomeningitis virus.
Received for publication October 15, 1999. Accepted for publication December 1, 1999.
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14 NKT cells in IL-12-mediated rejection of tumors. Science 278:1623.14+ TCR chain in NK1.1+ T cell populations. Int. Immunol. 7:1157. chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J. Exp. Med. 180:1097.ß-bearing thymocytes which predominantly expresses a single Vß gene family. Nature 329:251.[Medline]
14 natural killer T cells. J. Exp. Med. 190:783.This article has been cited by other articles:
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H. Kobayashi, S. Dubois, N. Sato, H. Sabzevari, Y. Sakai, T. A. Waldmann, and Y. Tagaya Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance Blood, January 15, 2005; 105(2): 721 - 727. [Abstract] [Full Text] [PDF]
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T. A. Baldwin, K. A. Hogquist, and S. C. Jameson The Fourth Way? Harnessing Aggressive Tendencies in the Thymus J. Immunol., December 1, 2004; 173(11): 6515 - 6520. [Abstract] [Full Text] [PDF]
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H.-P. Raue, J. D. Brien, E. Hammarlund, and M. K. Slifka Activation of Virus-Specific CD8+ T Cells by Lipopolysaccharide-Induced IL-12 and IL-18 J. Immunol., December 1, 2004; 173(11): 6873 - 6881. [Abstract] [Full Text] [PDF]
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 M. Amado, Q. Yan, E. M. Comelli, B. E. Collins, and J. C. Paulson Peanut Agglutinin High Phenotype of Activated CD8+ T Cells Results from de Novo Synthesis of CD45 Glycans J. Biol. Chem., August 27, 2004; 279(35): 36689 - 36697. [Abstract] [Full Text] [PDF]
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 J. E. Gumperz CD1d-restricted "NKT" cells and myeloid IL-12 production: an immunological crossroads leading to promotion or suppression of effective anti-tumor immune responses? J. Leukoc. Biol., August 1, 2004; 76(2): 307 - 313. [Abstract] [Full Text] [PDF]
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 D. Yuan, R. Bibi, and T. Dang The role of adjuvant on the regulatory effects of NK cells on B cell responses as revealed by a new model of NK cell deficiency Int. Immunol., May 1, 2004; 16(5): 707 - 716. [Abstract] [Full Text] [PDF]
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 D. Atanackovic, A. Block, A. de Weerth, C. Faltz, D. K. Hossfeld, and S. Hegewisch-Becker Characterization of Effusion-Infiltrating T Cells: Benign versus Malignant Effusions Clin. Cancer Res., April 15, 2004; 10(8): 2600 - 2608. [Abstract] [Full Text] [PDF]
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L. Saurer, I. Seibold, C. Vallan, W. Held, and C. Mueller Cutting Edge: Stimulation with the Cognate Self-Antigen Induces Expression of the Ly49A Receptor on Self-Reactive T Cells Which Modulates Their Responsiveness J. Immunol., December 15, 2003; 171(12): 6334 - 6338. [Abstract] [Full Text] [PDF]
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 K. U. Saikh, B. Dyas, T. Kissner, and R. G. Ulrich CD56+-T-Cell Responses to Bacterial Superantigens and Immune Recognition of Attenuated Vaccines Clin. Vaccine Immunol., November 1, 2003; 10(6): 1065 - 1073. [Abstract] [Full Text] [PDF]
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M. Skold and S. M. Behar Role of CD1d-Restricted NKT Cells in Microbial Immunity Infect. Immun., October 1, 2003; 71(10): 5447 - 5455. [Full Text] [PDF]
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S. O. Andreasen, A. R. Thomsen, V. E. Koteliansky, T. I. Novobrantseva, A. G. Sprague, A. R. de Fougerolles, and J. P. Christensen Expression and Functional Importance of Collagen-Binding Integrins, {alpha}1{beta}1 and {alpha}2{beta}1, on Virus-Activated T Cells J. Immunol., September 15, 2003; 171(6): 2804 - 2811. [Abstract] [Full Text] [PDF]
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C. N. Baxevanis, A. D. Gritzapis, and M. Papamichail In Vivo Antitumor Activity of NKT Cells Activated by the Combination of IL-12 and IL-18 J. Immunol., September 15, 2003; 171(6): 2953 - 2959. [Abstract] [Full Text] [PDF]
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 V. Sivakumar, K. J.L. Hammond, N. Howells, K. Pfeffer, and F. Weih Differential Requirement for Rel/Nuclear Factor {kappa}B Family Members in Natural Killer T Cell Development J. Exp. Med., June 16, 2003; 197(12): 1613 - 1621. [Abstract] [Full Text] [PDF]
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S. H. Robbins, S. C. Terrizzi, B. C. Sydora, T. Mikayama, and L. Brossay Differential Regulation of Killer Cell Lectin-Like Receptor G1 Expression on T Cells J. Immunol., June 15, 2003; 170(12): 5876 - 5885. [Abstract] [Full Text] [PDF]
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X. Gu, A. Laouar, J. Wan, M. Daheshia, J. Lieberman, W. M. Yokoyama, H. R. Katz, and N. Manjunath The gp49B1 Inhibitory Receptor Regulates the IFN-{gamma} Responses of T Cells and NK Cells J. Immunol., April 15, 2003; 170(8): 4095 - 4101. [Abstract] [Full Text] [PDF]
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V. J. Cavanaugh, Y. Deng, M. P. Birkenbach, J. S. Slater, and A. E. Campbell Vigorous Innate and Virus-Specific Cytotoxic T-Lymphocyte Responses to Murine Cytomegalovirus in the Submaxillary Salivary Gland J. Virol., February 1, 2003; 77(3): 1703 - 1717. [Abstract] [Full Text] [PDF]
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J. H. Meyers, A. Ryu, L. Monney, K. Nguyen, E. A. Greenfield, G. J. Freeman, and V. K. Kuchroo Cutting Edge: CD94/NKG2 Is Expressed on Th1 But Not Th2 Cells and Costimulates Th1 Effector Functions J. Immunol., November 15, 2002; 169(10): 5382 - 5386. [Abstract] [Full Text] [PDF]
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Y.-J. Kim, R. R. Brutkiewicz, and H. E. Broxmeyer Role of 4-1BB (CD137) in the functional activation of cord blood CD28-CD8+ T cells Blood, October 16, 2002; 100(9): 3253 - 3260. [Abstract] [Full Text] [PDF]
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C. W. McMahon, A. J. Zajac, A. M. Jamieson, L. Corral, G. E. Hammer, R. Ahmed, and D. H. Raulet Viral and Bacterial Infections Induce Expression of Multiple NK Cell Receptors in Responding CD8+ T Cells J. Immunol., August 1, 2002; 169(3): 1444 - 1452. [Abstract] [Full Text] [PDF]
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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]
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N. Ohta, T. Hiroi, M.-N. Kweon, N. Kinoshita, M. H. Jang, T. Mashimo, J.-I. Miyazaki, and H. Kiyono IL-15-Dependent Activation-Induced Cell Death-Resistant Th1 Type CD8{alpha}{beta}+NK1.1+ T Cells for the Development of Small Intestinal Inflammation J. Immunol., July 1, 2002; 169(1): 460 - 468. [Abstract] [Full Text] [PDF]
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E. N. Kersh, S. M. Kaech, T. M. Onami, M. Moran, E. J. Wherry, M. C. Miceli, and R. Ahmed TCR Signal Transduction in Antigen-Specific Memory CD8 T Cells J. Immunol., June 1, 2002; 170(11): 5455 - 5463. [Abstract] [Full Text] [PDF]
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S. Korten, L. Volkmann, M. Saeftel, K. Fischer, M. Taniguchi, B. Fleischer, and A. Hoerauf Expansion of NK Cells with Reduction of Their Inhibitory Ly-49A, Ly-49C, and Ly-49G2 Receptor-Expressing Subsets in a Murine Helminth Infection: Contribution to Parasite Control J. Immunol., May 15, 2002; 168(10): 5199 - 5206. [Abstract] [Full Text] [PDF]
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J. E. Gumperz, S. Miyake, T. Yamamura, and M. B. Brenner Functionally Distinct Subsets of CD1d-restricted Natural Killer T Cells Revealed by CD1d Tetramer Staining J. Exp. Med., March 4, 2002; 195(5): 625 - 636. [Abstract] [Full Text] [PDF]
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M. J. Skeen, E. P. Rix, M. M. Freeman, and H. K. Ziegler Exaggerated Proinflammatory and Th1 Responses in the Absence of gamma /delta T Cells after Infection with Listeria monocytogenes Infect. Immun., December 1, 2001; 69(12): 7213 - 7223. [Abstract] [Full Text] [PDF]
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J. A. Hobbs, S. Cho, T. J. Roberts, V. Sriram, J. Zhang, M. Xu, and R. R. Brutkiewicz Selective Loss of Natural Killer T Cells by Apoptosis following Infection with Lymphocytic Choriomeningitis Virus J. Virol., November 15, 2001; 75(22): 10746 - 10754. [Abstract] [Full Text] [PDF]
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D. Voehringer, C. Blaser, P. Brawand, D. H. Raulet, T. Hanke, and H. Pircher Viral Infections Induce Abundant Numbers of Senescent CD8 T Cells J. Immunol., November 1, 2001; 167(9): 4838 - 4843. [Abstract] [Full Text] [PDF]
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 M. Villalba, K. Bi, F. Rodriguez, Y. Tanaka, S. Schoenberger, and A. Altman Vav1/Rac-dependent actin cytoskeleton reorganization is required for lipid raft clustering in T cells J. Cell Biol., October 29, 2001; 155(3): 331 - 338. [Abstract] [Full Text] [PDF]
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C. Karnbach, M. R. Daws, E. C. Niemi, and M. C. Nakamura Immune Rejection of a Large Sarcoma Following Cyclophosphamide and IL-12 Treatment Requires Both NK and NK T Cells and Is Associated with the Induction of a Novel NK T Cell Population J. Immunol., September 1, 2001; 167(5): 2569 - 2576. [Abstract] [Full Text] [PDF]
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K. J. L. Hammond, D. G. Pellicci, L. D. Poulton, O. V. Naidenko, A. A. Scalzo, A. G. Baxter, and D. I. Godfrey CD1d-Restricted NKT Cells: An Interstrain Comparison J. Immunol., August 1, 2001; 167(3): 1164 - 1173. [Abstract] [Full Text] [PDF]
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M. Umemura, H. Nishimura, K. Hirose, T. Matsuguchi, and Y. Yoshikai Overexpression of IL-15 In Vivo Enhances Protection Against Mycobacterium bovis Bacillus Calmette-Guerin Infection Via Augmentation of NK and T Cytotoxic 1 Responses J. Immunol., July 15, 2001; 167(2): 946 - 956. [Abstract] [Full Text] [PDF]
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K. A. Daniels, G. Devora, W. C. Lai, C. L. O'Donnell, M. Bennett, and R. M. Welsh Murine Cytomegalovirus Is Regulated by a Discrete Subset of Natural Killer Cells Reactive with Monoclonal Antibody to Ly49h J. Exp. Med., July 2, 2001; 194(1): 29 - 44. [Abstract] [Full Text] [PDF]
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R. Nishikomori, S. Gurunathan, K. Nishikomori, and W. Strober BALB/c Mice Bearing a Transgenic IL-12 Receptor {{beta}}2 Gene Exhibit a Nonhealing Phenotype to Leishmania major Infection Despite Intact IL-12 Signaling J. Immunol., June 1, 2001; 166(11): 6776 - 6783. [Abstract] [Full Text] [PDF]
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Y. Peng, E. Falck-Pedersen, and K. B. Elkon Variation in Adenovirus Transgene Expression between BALB/c and C57BL/6 Mice Is Associated with Differences in Interleukin-12 and Gamma Interferon Production and NK Cell Activation J. Virol., May 15, 2001; 75(10): 4540 - 4550. [Abstract] [Full Text]
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J. Baker, M. R. Verneris, M. Ito, J. A. Shizuru, and R. S. Negrin Expansion of cytolytic CD8+ natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon {gamma} production Blood, May 15, 2001; 97(10): 2923 - 2931. [Abstract] [Full Text] [PDF]
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N. L. O'Sullivan, C. A. Skandera, and P. C. Montgomery Lymphocyte Lineages at Mucosal Effector Sites: Rat Salivary Glands J. Immunol., May 1, 2001; 166(9): 5522 - 5529. [Abstract] [Full Text] [PDF]
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N. Iwanami, A. Niwa, Y. Yasutomi, N. Tabata, and M. Miyazawa Role of Natural Killer Cells in Resistance against Friend Retrovirus-Induced Leukemia J. Virol., April 1, 2001; 75(7): 3152 - 3163. [Abstract] [Full Text]
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 A. Gati, N. Guerra, J. Giron-Michel, B. Azzarone, E. Angevin, A. Moretta, S. Chouaib, and A. Caignard Tumor Cells Regulate the Lytic Activity of Tumor-specific Cytotoxic T Lymphocytes by Modulating the Inhibitory Natural Killer Receptor Function Cancer Res., April 1, 2001; 61(8): 3240 - 3244. [Abstract] [Full Text]
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Z. Trobonjaca, F. Leithauser, P. Moller, H. Bluethmann, Y. Koezuka, H. R. MacDonald, and J. Reimann MHC-II-Independent CD4+ T Cells Induce Colitis in Immunodeficient RAG-/- Hosts J. Immunol., March 15, 2001; 166(6): 3804 - 3812. [Abstract] [Full Text] [PDF]
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T. Kambayashi, E. Assarsson, J. Michaelsson, P. Berglund, A. D. Diehl, B. J. Chambers, and H.-G. Ljunggren Emergence of CD8+ T Cells Expressing NK Cell Receptors in Influenza A Virus-Infected Mice J. Immunol., November 1, 2000; 165(9): 4964 - 4969. [Abstract] [Full Text] [PDF]
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S. Riffault, C. Carrat, G. Milon, B. Charley, and J. H. Colle Transient IFN-{gamma} synthesis in the lymph node draining a dermal site loaded with UV-irradiated herpes simplex virus type 1: an NK- and CD3-dependent process regulated by IL-12 but not by IFN-{alpha}/{beta} J. Gen. Virol., October 1, 2000; 81(10): 2365 - 2373. [Abstract] [Full Text]
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E. Assarsson, T. Kambayashi, J. K. Sandberg, S. Hong, M. Taniguchi, L. Van Kaer, H.-G. Ljunggren, and B. J. Chambers CD8+ T Cells Rapidly Acquire NK1.1 and NK Cell-Associated Molecules Upon Stimulation In Vitro and In Vivo J. Immunol., October 1, 2000; 165(7): 3673 - 3679. [Abstract] [Full Text] [PDF]
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J. L. Matsuda, O. V. Naidenko, L. Gapin, T. Nakayama, M. Taniguchi, C.-R. Wang, Y. Koezuka, and M. Kronenberg Tracking the Response of Natural Killer T Cells to a Glycolipid Antigen Using Cd1d Tetramers J. Exp. Med., September 5, 2000; 192(5): 741 - 754. [Abstract] [Full Text] [PDF]
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D. G. Pellicci, K. J.L. Hammond, A. P. Uldrich, A. G. Baxter, M. J. Smyth, and D. I. Godfrey A Natural Killer T (NKT) Cell Developmental Pathway Involving a Thymus-dependent NK1.1-CD4+ CD1d-dependent Precursor Stage J. Exp. Med., March 25, 2002; 195(7): 835 - 844. [Abstract] [Full Text] [PDF]
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