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Cutting Edge |
* Division of Immunology, University of Connecticut Health Center, Farmington, CT 06030;
Committee on Immunology, University of Chicago, Chicago, IL 60637; and
Department of Medicine, Division of Immunology, Harvard Medical School, Boston, MA 02215
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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are required for generation of
memory-phenotype CD8 T cells in unimmunized mice. However, the role of
IL-15 in primary expansion and generation of Ag-specific memory CD8 T
cells in vivo has not been investigated. We characterized the CD8 T
cell response against vesicular stomatitis virus (VSV) in
IL-15-/- and IL-15R-/- mice.
Surprisingly, IL-15 was required for primary expansion of VSV-specific
CD8 T cells. The generation of VSV-specific memory CD8 T cells was also
impaired without IL-15 signaling, and this defect correlated with a
decrease in memory CD8 T cell turnover. Despite minimal proliferation
without IL-15, a subset of memory cells survived long-term. IL-15R
expression was low on naive CD8 T cells, up-regulated on Ag-specific
effector cells, and sustained on memory cells. Thus, IL-15 was
important for the generation and the subsequent maintenance of
antiviral memory CD8 T cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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subunit (CD122)
and the common 
-chain (CD132), but each receptor complex combines
with a private -chain conferring high-affinity binding for either
IL-2 or IL-15 (3, 4, 5). The expression patterns of IL-2R
and IL-15R are quite distinct and this may contribute to
differential functions mediated by these cytokines (1).
Whereas IL-2R is expressed by immature T and B lineage cells and
mature T cells, IL-15R mRNA is expressed in many cell types
including lymphocytes (6). IL-15R protein
expression has yet to be characterized in detail. Despite the fact that
IL-15R mRNA is widely expressed outside the immune system, the
majority of data indicate that one of the major roles of IL-15 is in
regulating development of NK cells and CD8 T cells
(7, 8, 9).
The precise mechanisms by which memory CD8 T cells survive are unknown
but survival is due in part to their ability to undergo continuous low
level proliferation (10) in which IL-15 may participate
(11). Memory-phenotype CD8 T cells express elevated levels
of IL-2/15R compared with naive CD8 T cells (7) and
this correlates with their ability to proliferate in response to IL-15
(7). Studies by Ku et al. (11) also show that
proliferation of memory-phenotype CD8 T cells is blocked by in vivo
treatment with an anti-IL-2/IL-15R receptor Ab. Furthermore,
mice lacking IL-15 or IL-15R expression are deficient in memory
phenotype CD8 T cells. Thus, there is evidence that IL-15 is involved
in the generation and/or the maintenance of memory phenotype CD8 T
cells. However, whether the requirements for the production of these
cells are the same as those for production of Ag-specific antimicrobial
CD8 memory T cells has not been tested. Moreover, whether the
importance of IL-15 is manifest during a primary response is unknown.
In this study, we characterize the primary and memory CD8 T cell
response to vesicular stomatitis virus
(VSV)3 infection in
IL-15-/- and
IL-15R-/- mice and analyze IL-15R
expression during the response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C57BL/6J (Ly5.1) mice were purchased from The Jackson Laboratory
(Bar Harbor, ME). C57BL/6-IL-15-/- mice were
provided by Dr. J. Peschon (Immunex, Seattle, WA) (9).
IL-15R-/- mice (8) were used
after five backcross generations to C57BL/6J.
Infections, isolation of lymphocytes, and immunofluorescence analysis
Mice were infected i.v. with 1 x 106
PFU of VSV-Indiana (12). At the indicated times,
lymphocytes from spleen, peripheral lymph nodes (PLN), mesenteric lymph
nodes (MLN), lung, and liver, and small intestinal lamina propria (LP)
were isolated as previously described (13, 14).
VSV-N-specific CD8 T cells were detected using
H-2Kb tetramers containing the N protein-derived
peptide RGYVYQGL (14) and were generated as previously
described (15, 16). To identify VSV-N-specific CD8 T
cells, cells were incubated with 100 µl of a properly diluted mixture
of N-tetramer-APC and anti-CD8 PerCP mAb (clone 53.6.72; BD
Biosciences, San Jose, CA) at 25°C for 1 h as previously
described (14). To detect IL-15 binding, cells were
incubated with IL-15 mutant Fc2a fusion protein (5 µg/ml)
(17) for 20 min at 4°C and the bound IL-15/Fc fusion
protein was detected using goat anti-mouse IgG2a-PE (2.5 µg/ml;
Southern Biotechnology Associates, Birmingham, AL). Relative
fluorescence intensities were measured with a FACSCalibur (BD
Biosciences). Data were analyzed using WinMDI software (J. Trotter, The
Scripps Clinic, La Jolla, CA). Statistics were performed using
Student’s t test.
Analysis of proliferation in vivo
VSV-infected mice were given water daily containing 5-bromo-2'-deoxyuridine (BrdU, 0.8 mg/ml; Sigma-Aldrich, St. Louis, MO) for 4 wk. Spleen cells were stained with N-tetramer and anti-CD8 mAb and then treated according to the BrdU flow kit protocol (BD Biosciences). For transfer studies, B cell-depleted spleen cells labeled with CFSE (0.01 mM; Molecular Probes, Eugene, OR) (18) were transferred into control and IL-15-/- hosts by i.v. injection. The percentage of cells of the original population that had divided (the "responding" population, R) was calculated as described elsewhere (19).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Whereas both IL-15 and IL-15R are required for the generation
of CD44highCD8 T cells (8, 9), we
asked whether there was a similar requirement for generation of primary
Ag-specific CD44highCD8 T cells in response to an
infection. To examine the dynamics of an antiviral CD8 T cell response
in the absence of IL-15, IL-15-/- and control
mice were infected i.v. with VSV, and VSV-specific CD8 T cells were
tracked by reactivity with an H-2Kb tetramer
containing the immunodominant VSV-derived nucleoprotein peptide
(14). Lymphocytes from spleen, PLN, MLN, lung, liver, and
LP were isolated and tested for tetramer reactivity. We extended this
observation to extralymphoid tissues as we have previously demonstrated
that virus-specific primary and memory CD8 T cells populate many
nonlymphoid tissues (14). At the peak of the response, 7
days after infection (14), the percentage of
tetramer-positive cells among CD8 T cells was decreased 40–50% in
secondary lymphoid and tertiary tissues of
IL-15-/- mice compared with wild-type mice
(Fig. 1
, A and B).
In IL-15-/- and
IL-15R-/- mice, the overall CD8 T cell pool
is decreased by 
50% (8, 9). Therefore, we expressed
our results as a percentage of the total CD8 T cell population to
provide a valid comparison to controls since the total number of
tetramer-positive cells will be decreased in IL-15/IL-15R-deficient
mice due to the reduced starting population.
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A), indicating that
IL-15-/- CD8 T cells do not have a defect in
CD44 up-regulation. Interestingly, a population of tetramer-negative
CD44high CD8 T cells was also induced after
infection of control or IL-15-/- mice
(Fig. 1A, lower right quadrant). It is
possible that some of these cells were specific for VSV epitopes other
than the N-peptide used in our tetramer, although no others have been
described. This population may also be the result of bystander
activation induced by the inflammation associated with virus infections
(20).
To determine whether the defect in IL-15-/-
mice was due to an abnormal precursor frequency or due to decreased
expansion of activated T cells, the percentage of tetramer-positive
cells from the peripheral blood was measured before the peak of the
response. At 4 and 5 days after infection, there was no deficiency in
tetramer-positive cells in the IL-15 -/- mice
compared with controls (Fig. 1C). However, 6 days after
infection, a slight decrease in tetramer-positive cells became apparent
and this decrease was dramatic after 7 days (Fig. 1C). These
data indicated that IL-15 was important in determining the amplitude of
the VSV-specific primary response and that the initial precursor
frequency in IL-15-/- mice was likely normal.
The burst size of the primary antiviral CD8 T cell response is thought
to correlate with the size of the resulting memory population
(21). Therefore, the defective primary CD8 T cell
expansion noted in VSV-infected IL15-/- mice
might be expected to yield a reduced memory population (see below).
Given our results using IL-15-/- mice, we
wished to determine the requirement for IL-15R in the same response.
To this end, IL-15R-/- and control mice were
VSV-infected and 7 days later the percentage of tetramer-positive cells
was determined. IL-15R-/- mice had an
10–20% decrease in the percentage of tetramer-positive cells among
CD8 T cells in the spleen but this difference was not statistically
significant (Fig. 2) in this or several
other experiments. There was no difference in the percentage of
tetramer-positive cells in the PLN or MLN but, interestingly, the
response in the intestine was decreased 50% in
IL-15R-/- mice (Fig. 2). In contrast, the
lung and liver contained normal percentages of VSV-specific CD8 T cells
(Fig. 2). These results demonstrated a minimal requirement for
IL-15R in the primary expansion of antiviral CD8 T cells except in
the intestinal mucosa.
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in generation of CD44high
virus-specific memory CD8 T cells
Considering the deficiency in memory-phenotype
CD44highCD8 T cells in
IL-15-/- and
IL-15R-/- mice, we investigated whether the
absence of IL-15R or IL-15 affected the generation of Ag-specific
memory CD8 T cells. The percentage of tetramer-positive memory cells
was quantitated 38 days after VSV infection of
IL-15-/- and control mice. Compared with memory
levels in lymphoid and nonlymphoid tissues of control mice, memory
populations were decreased 60–80% in the tissues of
IL-15-/- mice and all differences were
statistically significant (Fig. 3A). The response was also
measured over time in the peripheral blood of a cohort of mice (Fig. 3B). At 15 days after infection, the percentage of
Ag-specific cells in IL-15-/- mice was only
38% of control levels (Fig. 3B) and at 77 days was 23% of
control levels, and this difference was maintained until at least 105
days after infection (Fig. 3B). These results suggested that
although the generation of a substantial portion of antiviral memory
CD8 T cells required IL-15, a subset of long-lived IL-15-independent
CD8 memory T cells existed.
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-/- and control mice 75 days after
infection (Fig. 3C). The percentage of tetramer-positive
memory cells in the spleen, LP, lung, and liver of
IL-15R-/- mice was decreased 50–75% as
compared with controls (Fig. 3C). To determine the point in
the immune response when IL-15R became important for CD8 memory
generation, the level of tetramer-positive cells was tracked over time.
Whereas there was no difference in the percentage of tetramer-positive
cells between the lL-15R-/- mice and control
mice 7 days after infection, differences emerged 14 days after
infection and became progressively greater over time (Fig. 3D). These data indicated that IL-15R participates in the
generation of memory CD8 T cells during the contraction phase and
effects memory maintenance.
Turnover of memory CD8 T cells requires IL-15 and IL-15R
Previous studies have demonstrated that IL-15 has a role in the
low level proliferation of memory-phenotype CD8 T cells
(11). Therefore, we determined whether IL-15 regulated
proliferation of Ag-specific memory CD8 T cells.
IL-15-/-, IL-15R-/-,
and control mice that were infected with VSV at least 30 days earlier
were administered BrdU for 4 wk. At that time, incorporation of BrdU
into tetramer-positive CD8 T cells from the spleen was measured as an
indicator of cell division. Among
CD8+tetramer+ gated cells,
45% of the cells from control mice had incorporated BrdU (Fig. 4A). In contrast, only 17 and
14% of the tetramer-positive CD8 cells were BrdU positive from
IL-15-/- and
IL-15R-/- mice, respectively (Fig. 4A). In addition, the BrdU+ T cells in
the IL-15 and IL-15R-deficient mice exhibited only low levels of
incorporation as compared with controls.
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B). Similarly, N-tetramer-positive CD8 T cells divided in
control mice but not in IL-15-/- mice (Fig. 4C). In contrast to CD8 T cells, CD4 T cell division was
similar in IL-15-/- and control mice (data not
shown). Thus, IL-15/IL-15R is critical for maintaining proliferation
of virus-specific CD8 memory cells. Expression of IL-15R by naive and memory CD8 T cells
Whether the differential effects of IL-15 on naive, primary
effectors, or memory CD8 T cells was due to differences in IL-15R
expression are unknown and thus far the expression of the IL-15R
subunit on CD8 T cell subsets has not been examined. Therefore, we
measured IL-15R expression by using an IL-15 mutant/Fc2a fusion
protein (17) (Fig. 5). In
unimmunized mice, the highest level of IL-15/Fc binding was detected on
CD44highCD8 T cells which also correlates with
high expression of CD122 (IL-2/15R) on memory-phenotype CD8 T cells
(7, 11). Interestingly, naive
CD44lowCD8 T cells also expressed IL-15R,
albeit at lower levels than memory-phenotype CD8 T cells. The binding
of IL-15/Fc was attributed to reactivity with the IL-15R chain,
since naive IL-15R-/-CD8 T cells did not
bind the IL-15/Fc protein (Fig. 5, left panel). IL-15/Fc
binding was also analyzed on Ag-specific CD8 T cells from normal and
IL-15R-/-mice. Six days after VSV infection,
tetramer-positive CD8 T cells from normal mice displayed high IL-15/Fc
binding (Fig. 5). Although some low level binding of IL-15/Fc to
tetramer-positive IL-15R-/- cells was
detected, this binding was not blocked by preincubation with IL-15,
while IL-15/Fc binding to normal naive CD8 T cells and to activated
normal tetramer-positive cells was inhibited by IL-15 (data not shown).
Similar to memory-phenotype CD8 T cells from unimmunized mice,
tetramer-positive memory cells from normal mice 75 days after infection
displayed high levels of IL-15/Fc binding. Tetramer-positive memory
cells from IL-15R-/- mice exhibited no
detectable binding of IL-15/Fc (Fig. 5). Therefore, IL-15/Fc binding to
CD8 T cells is dependent on the expression of the IL-15R molecule
and thus our data show for the first time the expression of IL-15R
throughout an antiviral immune response.
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and thus may be targets of IL-15 action. Therefore, the
deficiency of naive CD8 T cells in IL-15-/- and
IL-15R-/- mice may be due to effects
on naive CD8 T cells, although thymic defects could also contribute.
Nevertheless, our examination of the early CD8 T cell response to VSV
infection indicated that a proportionately normal frequency of
Ag-specific cells was present in IL-15-/- mice
since the percentage of tetramer-positive cells was similar in
IL-15-/- and normal mice 4 days after infection
(Fig. 1).
The increased levels of IL-15R expressed by activated and memory CD8
T cells were likely responsible for the observed IL-15 augmentation of
the primary response and the induction of memory cell proliferation by
IL-15. Although we observed that the defect in the primary response in
IL-15-/- mice was more severe than that in
IL-15R-/- mice, it is possible that IL-15
delivers signals via the intermediate affinity IL-15R
(5) and that the up-regulation of IL-15 during infection
could augment this signaling. In addition, a second receptor for IL-15
has been described but is apparently expressed only in mast cells and
has not been further characterized (22). In any case, the
overall requirement for IL-15 during the antiviral response is
exemplified by the defects observed in IL-15-/-
mice in both the primary and memory phases of the response. It should
also be noted that IL-15 was important for the generation of both
central and effector memory cells, in that establishment of memory
cells in lymphoid and nonlymphoid tissues was IL-15 dependent
(Fig. 3).
Despite the fact that IL-15 was critical for the generation and
maintenance of memory CD8 T cells, a subset of memory cells survived
for several months in the absence of IL-15 signaling and with minimal
proliferation. This is in contrast to CD44highCD8
T cells which are deficient in 5-wk-old
IL-15-/- mice. This finding suggests that the
generation and/or survival of memory-phenotype CD8 T cells is more
critically dependent on IL-15 than are virus-specific memory CD8 T
cells. Furthermore, the presence of an IL-15-independent memory CD8 T
cell population suggests that other factors may be involved in memory
CD8 T cell maintenance. Since IL-7R is highly expressed by memory
CD8 T cells and is involved in T cell survival (23), it is
possible that the IL-15-independent memory population is being
maintained by IL-7 survival signals. Thus, growth-promoting effects of
IL-15 in combination with the survival signals induced by IL-7 are
likely to be in large part responsible for induction and maintenance of
memory CD8 T cells.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Leo Lefrançois, Department of Medicine, Division of Immunology, University of Connecticut Health Center, M/C 1319, 263 Farmington Avenue, Farmington, CT 06030. E-mail address: llefranc{at}neuron.uchc.edu
3 Abbreviations used in this paper: VSV, vesicular stomatitis virus; BrdU, 5-bromo-2'-deoxyuridine; PLN, peripheral lymph node; MLN, mesenteric lymph node; LP, lamina propria.
Received for publication February 19, 2002. Accepted for publication March 18, 2002.
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H. Shin, S. D. Blackburn, J. N. Blattman, and E. J. Wherry Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection J. Exp. Med., April 16, 2007; 204(4): 941 - 949. [Abstract] [Full Text] [PDF]
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R. B. Smeltz Profound Enhancement of the IL-12/IL-18 Pathway of IFN-{gamma} Secretion in Human CD8+ Memory T Cell Subsets via IL-15 J. Immunol., April 15, 2007; 178(8): 4786 - 4792. [Abstract] [Full Text] [PDF]
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L. C. Osborne, S. Dhanji, J. W. Snow, J. J. Priatel, M. C. Ma, M. J. Miners, H.-S. Teh, M. A. Goldsmith, and N. Abraham Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R{alpha} mutant mice J. Exp. Med., March 19, 2007; 204(3): 619 - 631. [Abstract] [Full Text] [PDF]
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B. S. Sheridan, K. M. Khanna, G. M. Frank, and R. L. Hendricks Latent Virus Influences the Generation and Maintenance of CD8+ T Cell Memory J. Immunol., December 15, 2006; 177(12): 8356 - 8364. [Abstract] [Full Text] [PDF]
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Q. Li, C. Eppolito, K. Odunsi, and P. A. Shrikant IL-12-Programmed Long-Term CD8+ T Cell Responses Require STAT4 J. Immunol., December 1, 2006; 177(11): 7618 - 7625. [Abstract] [Full Text] [PDF]
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X. Zhang, H. Dong, W. Lin, S. Voss, L. Hinkley, M. Westergren, G. Tian, D. Berry, D. Lewellen, R. G. Vile, et al. Human Bone Marrow: A Reservoir for "Enhanced Effector Memory" CD8+ T Cells with Potent Recall Function J. Immunol., November 15, 2006; 177(10): 6730 - 6737. [Abstract] [Full Text] [PDF]
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K. D. Klonowski, A. L. Marzo, K. J. Williams, S.-J. Lee, Q.-M. Pham, and L. Lefrancois CD8 T Cell Recall Responses Are Regulated by the Tissue Tropism of the Memory Cell and Pathogen J. Immunol., November 15, 2006; 177(10): 6738 - 6746. [Abstract] [Full Text] [PDF]
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T. A. Stoklasek, K. S. Schluns, and L. Lefrancois Combined IL-15/IL-15R{alpha} Immunotherapy Maximizes IL-15 Activity In Vivo J. Immunol., November 1, 2006; 177(9): 6072 - 6080. [Abstract] [Full Text] [PDF]
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T. Ohteki, H. Tada, K. Ishida, T. Sato, C. Maki, T. Yamada, J. Hamuro, and S. Koyasu Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo J. Exp. Med., October 2, 2006; 203(10): 2329 - 2338. [Abstract] [Full Text] [PDF]
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K. D. Klonowski, K. J. Williams, A. L. Marzo, and L. Lefrancois Cutting Edge: IL-7-Independent Regulation of IL-7 Receptor {alpha} Expression and Memory CD8 T Cell Development J. Immunol., October 1, 2006; 177(7): 4247 - 4251. [Abstract] [Full Text] [PDF]
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M. Prlic, G. Hernandez-Hoyos, and M. J. Bevan Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response J. Exp. Med., September 4, 2006; 203(9): 2135 - 2143. [Abstract] [Full Text] [PDF]
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J. J. Obar, S. Fuse, E. K. Leung, S. C. Bellfy, and E. J. Usherwood Gammaherpesvirus persistence alters key CD8 T-cell memory characteristics and enhances antiviral protection. J. Virol., September 1, 2006; 80(17): 8303 - 8315. [Abstract] [Full Text] [PDF]
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J. M. Grayson, A. E. Weant, B. C. Holbrook, and D. Hildeman Role of Bim in Regulating CD8+ T-Cell Responses during Chronic Viral Infection. J. Virol., September 1, 2006; 80(17): 8627 - 8638. [Abstract] [Full Text] [PDF]
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D. K. Taylor, P. T. Walsh, D. F. LaRosa, J. Zhang, M. A. Burchill, M. A. Farrar, and L. A. Turka Constitutive Activation of STAT5 Supersedes the Requirement for Cytokine and TCR Engagement of CD4+ T Cells in Steady-State Homeostasis J. Immunol., August 15, 2006; 177(4): 2216 - 2223. [Abstract] [Full Text] [PDF]
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S. Dubois, T. A. Waldmann, and J. R. Muller ITK and IL-15 support two distinct subsets of CD8+ T cells PNAS, August 8, 2006; 103(32): 12075 - 12080. [Abstract] [Full Text] [PDF]
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E. Bolesta, A. Kowalczyk, A. Wierzbicki, C. Eppolito, Y. Kaneko, M. Takiguchi, L. Stamatatos, P. A. Shrikant, and D. Kozbor Increased Level and Longevity of Protective Immune Responses Induced by DNA Vaccine Expressing the HIV-1 Env Glycoprotein when Combined with IL-21 and IL-15 Gene Delivery J. Immunol., July 1, 2006; 177(1): 177 - 191. [Abstract] [Full Text] [PDF]
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D. Sauce, M. Larsen, S. J. Curnow, A. M. Leese, P. A. H. Moss, A. D. Hislop, M. Salmon, and A. B. Rickinson EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15 Blood, July 1, 2006; 108(1): 11 - 18. [Abstract] [Full Text] [PDF]
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M. Shi and J. Xiang CD4+ T cell-independent maintenance and expansion of memory CD8+ T cells derived from in vitro dendritic cell activation Int. Immunol., June 1, 2006; 18(6): 887 - 895. [Abstract] [Full Text] [PDF]
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A. M. Byers, N. P. Andrews, and A. E. Lukacher CD94/NKG2A Expression Is Associated with Proliferative Potential of CD8 T Cells during Persistent Polyoma Virus Infection J. Immunol., May 15, 2006; 176(10): 6121 - 6129. [Abstract] [Full Text] [PDF]
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T. Bianchi, S. Gasser, A. Trumpp, and H. R. MacDonald c-Myc acts downstream of IL-15 in the regulation of memory CD8 T-cell homeostasis Blood, May 15, 2006; 107(10): 3992 - 3999. [Abstract] [Full Text] [PDF]
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C. L. Combe, M. M. Moretto, J. D. Schwartzman, J. P. Gigley, D. J. Bzik, and I. A. Khan Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite PNAS, April 25, 2006; 103(17): 6635 - 6640. [Abstract] [Full Text] [PDF]
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A. Le Bon, V. Durand, E. Kamphuis, C. Thompson, S. Bulfone-Paus, C. Rossmann, U. Kalinke, and D. F. Tough Direct Stimulation of T Cells by Type I IFN Enhances the CD8+ T Cell Response during Cross-Priming. J. Immunol., April 15, 2006; 176(8): 4682 - 4689. [Abstract] [Full Text] [PDF]
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H. Su, D. S. Chang, S. S. Gambhir, and J. Braun Monitoring the Antitumor Response of Naive and Memory CD8 T Cells in RAG1-/- Mice by Positron-Emission Tomography J. Immunol., April 1, 2006; 176(7): 4459 - 4467. [Abstract] [Full Text] [PDF]
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G. Pulle, M. Vidric, and T. H. Watts IL-15-Dependent Induction of 4-1BB Promotes Antigen-Independent CD8 Memory T Cell Survival. J. Immunol., March 1, 2006; 176(5): 2739 - 2748. [Abstract] [Full Text] [PDF]
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S. A. Fadel, L. G. Cowell, S. Cao, D. A. Ozaki, T. B. Kepler, D. A. Steeber, and M. Sarzotti Neonate-primed CD8+ memory cells rival adult-primed memory cells in antigen-driven expansion and anti-viral protection Int. Immunol., February 1, 2006; 18(2): 249 - 257. [Abstract] [Full Text] [PDF]
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T. Yajima, K. Yoshihara, K. Nakazato, S. Kumabe, S. Koyasu, S. Sad, H. Shen, H. Kuwano, and Y. Yoshikai IL-15 Regulates CD8+ T Cell Contraction during Primary Infection J. Immunol., January 1, 2006; 176(1): 507 - 515. [Abstract] [Full Text] [PDF]
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C. Hsu, M. S. Hughes, Z. Zheng, R. B. Bray, S. A. Rosenberg, and R. A. Morgan Primary Human T Lymphocytes Engineered with a Codon-Optimized IL-15 Gene Resist Cytokine Withdrawal-Induced Apoptosis and Persist Long-Term in the Absence of Exogenous Cytokine J. Immunol., December 1, 2005; 175(11): 7226 - 7234. [Abstract] [Full Text] [PDF]
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A. Muthukumar, D. Zhou, M. Paiardini, A. P. Barry, K. S. Cole, H. M. McClure, S. I. Staprans, G. Silvestri, and D. L. Sodora Timely triggering of homeostatic mechanisms involved in the regulation of T-cell levels in SIVsm-infected sooty mangabeys Blood, December 1, 2005; 106(12): 3839 - 3845. [Abstract] [Full Text] [PDF]
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M.-H. Lacombe, M.-P. Hardy, J. Rooney, and N. Labrecque IL-7 Receptor Expression Levels Do Not Identify CD8+ Memory T Lymphocyte Precursors following Peptide Immunization J. Immunol., October 1, 2005; 175(7): 4400 - 4407. [Abstract] [Full Text] [PDF]
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A. M. Marleau and N. Sarvetnick T cell homeostasis in tolerance and immunity J. Leukoc. Biol., September 1, 2005; 78(3): 575 - 584. [Abstract] [Full Text] [PDF]
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F. N. Toka and B. T. Rouse Mucosal application of plasmid-encoded IL-15 sustains a highly protective anti-Herpes simplex virus immunity J. Leukoc. Biol., July 1, 2005; 78(1): 178 - 186. [Abstract] [Full Text] [PDF]
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M. A. Kutzler, T. M. Robinson, M. A. Chattergoon, D. K. Choo, A. Y. Choo, P. Y. Choe, M. P. Ramanathan, R. Parkinson, S. Kudchodkar, Y. Tamura, et al. Coimmunization with an Optimized IL-15 Plasmid Results in Enhanced Function and Longevity of CD8 T Cells That Are Partially Independent of CD4 T Cell Help J. Immunol., July 1, 2005; 175(1): 112 - 123. [Abstract] [Full Text] [PDF]
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E. Parretta, G. Cassese, P. Barba, A. Santoni, J. Guardiola, and F. Di Rosa CD8 Cell Division Maintaining Cytotoxic Memory Occurs Predominantly in the Bone Marrow J. Immunol., June 15, 2005; 174(12): 7654 - 7664. [Abstract] [Full Text] [PDF]
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S. P. Dubois, T. A. Waldmann, and J. R. Muller Survival adjustment of mature dendritic cells by IL-15 PNAS, June 14, 2005; 102(24): 8662 - 8667. [Abstract] [Full Text] [PDF]
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 V. Lazarevic, D. J. Yankura, S. J. Divito, and J. L. Flynn Induction of Mycobacterium tuberculosis-Specific Primary and Secondary T-Cell Responses in Interleukin-15-Deficient Mice Infect. Immun., May 1, 2005; 73(5): 2910 - 2922. [Abstract] [Full Text] [PDF]
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N. N. Meissner, S. Swain, M. Tighe, A. Harmsen, and A. Harmsen Role of Type I IFNs in Pulmonary Complications of Pneumocystis murina Infection J. Immunol., May 1, 2005; 174(9): 5462 - 5471. [Abstract] [Full Text] [PDF]
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T. C. Becker, S. M. Coley, E. J. Wherry, and R. Ahmed Bone Marrow Is a Preferred Site for Homeostatic Proliferation of Memory CD8 T Cells J. Immunol., February 1, 2005; 174(3): 1269 - 1273. [Abstract] [Full Text] [PDF]
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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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O. Alpdogan, J. M. Eng, S. J. Muriglan, L. M. Willis, V. M. Hubbard, K. H. Tjoe, T. H. Terwey, A. Kochman, and M. R. M. van den Brink Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation Blood, January 15, 2005; 105(2): 865 - 873. [Abstract] [Full Text] [PDF]
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D. J. Powell Jr, M. E. Dudley, P. F. Robbins, and S. A. Rosenberg Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy Blood, January 1, 2005; 105(1): 241 - 250. [Abstract] [Full Text] [PDF]
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M. M. Sandau, K. S. Schluns, L. Lefrancois, and S. C. Jameson Cutting Edge: Transpresentation of IL-15 by Bone Marrow-Derived Cells Necessitates Expression of IL-15 and IL-15R{alpha} by the Same Cells J. Immunol., December 1, 2004; 173(11): 6537 - 6541. [Abstract] [Full Text] [PDF]
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D. Kamimura, N. Ueda, Y. Sawa, S. Hachida, T. Atsumi, T. Nakagawa, S.-i. Sawa, G.-H. Jin, H. Suzuki, K. Ishihara, et al. Evidence of a Novel IL-2/15R{beta}-Targeted Cytokine Involved in Homeostatic Proliferation of Memory CD8+ T Cells J. Immunol., November 15, 2004; 173(10): 6041 - 6049. [Abstract] [Full Text] [PDF]
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E. J. Wherry, D. L. Barber, S. M. Kaech, J. N. Blattman, and R. Ahmed Antigen-independent memory CD8 T cells do not develop during chronic viral infection PNAS, November 9, 2004; 101(45): 16004 - 16009. [Abstract] [Full Text] [PDF]
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 J J O'Shea Targeting the Jak/STAT pathway for immunosuppression Ann Rheum Dis, November 1, 2004; 63(suppl_2): ii67 - ii71. [Full Text] [PDF]
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D. R. Latner, S. M. Kaech, and R. Ahmed Enhanced Expression of Cell Cycle Regulatory Genes in Virus-Specific Memory CD8+ T Cells J. Virol., October 15, 2004; 78(20): 10953 - 10959. [Abstract] [Full Text] [PDF]
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R. M. Teague, R. M. Tempero, S. Thomas, K. Murali-Krishna, and B. H. Nelson Proliferation and Differentiation of CD8+ T Cells in the Absence of IL-2/15 Receptor {beta}-Chain Expression or STAT5 Activation J. Immunol., September 1, 2004; 173(5): 3131 - 3139. [Abstract] [Full Text] [PDF]
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J. J. Obar, S. G. Crist, E. K. Leung, and E. J. Usherwood IL-15-Independent Proliferative Renewal of Memory CD8+ T Cells in Latent Gammaherpesvirus Infection J. Immunol., August 15, 2004; 173(4): 2705 - 2714. [Abstract] [Full Text] [PDF]
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G. Ratzinger, J. Baggers, M. A. de Cos, J. Yuan, T. Dao, J. L. Reagan, C. Munz, G. Heller, and J. W. Young Mature Human Langerhans Cells Derived from CD34+ Hematopoietic Progenitors Stimulate Greater Cytolytic T Lymphocyte Activity in the Absence of Bioactive IL-12p70, by Either Single Peptide Presentation or Cross-Priming, Than Do Dermal-Interstitial or Monocyte-Derived Dendritic Cells J. Immunol., August 15, 2004; 173(4): 2780 - 2791. [Abstract] [Full Text] [PDF]
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G. C. Hildebrandt, L. A. Corrion, K. M. Olkiewicz, B. Lu, K. Lowler, U. A. Duffner, B. B. Moore, W. A. Kuziel, C. Liu, and K. R. Cooke Blockade of CXCR3 Receptor:Ligand Interactions Reduces Leukocyte Recruitment to the Lung and the Severity of Experimental Idiopathic Pneumonia Syndrome J. Immunol., August 1, 2004; 173(3): 2050 - 2059. [Abstract] [Full Text] [PDF]
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D. C. Lenz, S. K. Kurz, E. Lemmens, S. P. Schoenberger, J. Sprent, M. B. A. Oldstone, and D. Homann IL-7 regulates basal homeostatic proliferation of antiviral CD4+T cell memory PNAS, June 22, 2004; 101(25): 9357 - 9362. [Abstract] [Full Text] [PDF]
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E. J. Wherry and R. Ahmed Memory CD8 T-Cell Differentiation during Viral Infection J. Virol., June 1, 2004; 78(11): 5535 - 5545. [Full Text] [PDF]
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J. J. Lum, D. J. Schnepple, Z. Nie, J. Sanchez-Dardon, G. L. Mbisa, J. Mihowich, N. Hawley, S. Narayan, J. E. Kim, D. H. Lynch, et al. Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity J. Virol., June 1, 2004; 78(11): 6033 - 6042. [Abstract] [Full Text] [PDF]
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Z. Wu, M. Roberts, M. Porter, F. Walker, E. J. Wherry, J. Kelly, M. Gadina, E. M. Silva, G. A. DosReis, M. F. Lopes, et al. Viral FLIP Impairs Survival of Activated T Cells and Generation of CD8+ T Cell Memory J. Immunol., May 15, 2004; 172(10): 6313 - 6323. [Abstract] [Full Text] [PDF]
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K. S. Schluns, E. C. Nowak, A. Cabrera-Hernandez, L. Puddington, L. Lefrancois, and H. L. Aguila Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor {alpha} expression PNAS, April 13, 2004; 101(15): 5616 - 5621. [Abstract] [Full Text] [PDF]
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J. Castelli, E. K. Thomas, M. Gilliet, Y.-J. Liu, and J. A. Levy Mature dendritic cells can enhance CD8+ cell noncytotoxic anti-HIV responses: the role of IL-15 Blood, April 1, 2004; 103(7): 2699 - 2704. [Abstract] [Full Text] [PDF]
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J. Chang, J.-H. Cho, S.-W. Lee, S.-Y. Choi, S.-J. Ha, and Y.-C. Sung IL-12 Priming during In Vitro Antigenic Stimulation Changes Properties of CD8 T Cells and Increases Generation of Effector and Memory Cells J. Immunol., March 1, 2004; 172(5): 2818 - 2826. [Abstract] [Full Text] [PDF]
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S.-K. Kim and R. M. Welsh Comprehensive Early and Lasting Loss of Memory CD8 T Cells and Functional Memory during Acute and Persistent Viral Infections J. Immunol., March 1, 2004; 172(5): 3139 - 3150. [Abstract] [Full Text] [PDF]
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K. S. Schluns, K. D. Klonowski, and L. Lefrancois Transregulation of memory CD8 T-cell proliferation by IL-15R{alpha}+ bone marrow-derived cells Blood, February 1, 2004; 103(3): 988 - 994. [Abstract] [Full Text] [PDF]
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J. J. Obar, S. G. Crist, D. C. Gondek, and E. J. Usherwood Different Functional Capacities of Latent and Lytic Antigen-Specific CD8 T Cells in Murine Gammaherpesvirus Infection J. Immunol., January 15, 2004; 172(2): 1213 - 1219. [Abstract] [Full Text] [PDF]
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R. Vankayalapati, P. Klucar, B. Wizel, S. E. Weis, B. Samten, H. Safi, H. Shams, and P. F. Barnes NK Cells Regulate CD8+ T Cell Effector Function in Response to an Intracellular Pathogen J. Immunol., January 1, 2004; 172(1): 130 - 137. [Abstract] [Full Text] [PDF]
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W. N. D'Souza and L. Lefrancois IL-2 Is Not Required for the Initiation of CD8 T Cell Cycling but Sustains Expansion J. Immunol., December 1, 2003; 171(11): 5727 - 5735. [Abstract] [Full Text] [PDF]
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M. A. Burchill, C. A. Goetz, M. Prlic, J. J. O'Neil, I. R. Harmon, S. J. Bensinger, L. A. Turka, P. Brennan, S. C. Jameson, and M. A. Farrar Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells versus CD8+ Memory T Cells J. Immunol., December 1, 2003; 171(11): 5853 - 5864. [Abstract] [Full Text] [PDF]
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M. Jinushi, T. Takehara, T. Tatsumi, T. Kanto, V. Groh, T. Spies, T. Suzuki, T. Miyagi, and N. Hayashi Autocrine/Paracrine IL-15 That Is Required for Type I IFN-Mediated Dendritic Cell Expression of MHC Class I-Related Chain A and B Is Impaired in Hepatitis C Virus Infection J. Immunol., November 15, 2003; 171(10): 5423 - 5429. [Abstract] [Full Text] [PDF]
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K. H. Ely, A. D. Roberts, and D. L. Woodland Cutting Edge: Effector Memory CD8+ T Cells in the Lung Airways Retain the Potential to Mediate Recall Responses J. Immunol., October 1, 2003; 171(7): 3338 - 3342. [Abstract] [Full Text] [PDF]
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N. L. Alves, B. Hooibrink, F. A. Arosa, and R. A. W. van Lier IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro Blood, October 1, 2003; 102(7): 2541 - 2546. [Abstract] [Full Text] [PDF]
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L. Lefrancois, A. Marzo, and K. Williams Sustained Response Initiation Is Required for T Cell Clonal Expansion But Not for Effector or Memory Development In Vivo J. Immunol., September 15, 2003; 171(6): 2832 - 2839. [Abstract] [Full Text] [PDF]
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 F. G. Lakkis and M. H. Sayegh Memory T Cells: A Hurdle to Immunologic Tolerance J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2402 - 2410. [Full Text] [PDF]
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