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Trudeau Institute, Saranac Lake, NY 12983
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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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may not be sufficient to eliminate
the virus, it may help to reduce the viral load encountered by the
memory T cells recruited from secondary lymphoid sites later in the
response. More recently, it has emerged that pools of memory T cells
also persist in other peripheral tissues, such as the kidney, fat pads,
salivary glands, and liver (9, 10, 11, 12). One study estimated
that at least half of all memory CD8+ T cells
reside in nonlymphoid peripheral tissues, consistent with the idea that
peripheral memory T cells play a major role in combating mucosal
infections (12, 13, 14, 15).
Although effector memory cells from peripheral tissues have been well
characterized, we have very little understanding of the mechanisms that
regulate these cell populations. We have previously shown that the
absolute numbers of T cells in the lung airways after influenza or
Sendai virus infections are initially high and then decline over the
course of about 6 mo with a t1/2 of 
40
days (5). The cell numbers then stabilize at a relatively
low basal level. Interestingly, the decline and subsequent
stabilization in the numbers of memory cells in the lung airways
correlate with the loss of protective cellular immunity
(1). Consistent with this concept, intratracheal transfer
studies have confirmed that memory T cells in the lung airways can
mediate substantial control of secondary viral infections in the
absence of Abs (6).
Since the numbers of peripheral memory T cells show a strong correlation with protective cellular immunity, it is essential that we understand the mechanisms that maintain memory T cells at peripheral sites such as the lung. In the current manuscript, we have analyzed the persistence of memory CD8+ T cells in the lung airways following recovery from a Sendai virus infection. Initially, we assumed that since the lung airways interface with the external environment, memory T cells at this site would be very short-lived. However, the data show that a large bolus of memory CD8+ T cells remains in the lung tissue for several months after the resolution of the acute response. These cells persist in the lung airways without proliferating, although their absolute numbers decline steadily over time. There is also a minor population of memory CD8+ T cells in the lung airways that proliferates after the resolution of the acute response. These cells may account for the stabilization of memory T cell numbers in the lung airways over the longer term. These data represent an important step forward in our understanding of peripheral memory T cell populations and have significant implications for vaccine development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Enders strain of Sendai virus was grown, stored, and titrated as previously described (4). Female C57BL/6, B6.PL-Thy1a/Cy (Thy1.1+), and B6.SJL-Ptprca Pep3b/BoyJ (Ly5.1+) mice were purchased from the Animal Breeding Facility at the Trudeau Institute (Saranac Lake, NY). Mice (6–12 wk) were anesthetized by i.p. injection with 2,2,2-tribromoethanol and infected intranasally with either 125 or 500 50% egg infectious doses (EID50)4 of Sendai virus.
Peptides
Sendai virus peptides (nucleoprotein (NP) 324–332) and influenza virus (NP366–374) peptides were purchased from New England Peptide (Fitchburg, MA). Peptide purity was evaluated using reversed-phase HPLC analysis.
In vivo 5-bromo-2-deoxyuridine (BrdU) labeling
BrdU (Sigma-Aldrich, St. Louis, MO) was administered either in sterile drinking water (0.8 mg/ml) or by i.p. injection of 0.2 ml of PBS/BrdU solution (4 mg/ml) at the indicated times during infection. In experiments where mice were fed water containing BrdU, the solution was replaced daily. For pulse-chase experiments, animals were given normal drinking water at the end of the pulse period.
Tissue preparation
Single-cell suspensions were prepared from spleens and mediastinal lymph nodes (MLN) by passage through cell strainers. Spleen cells were depleted of erythrocytes by treatment with buffered ammonium chloride solution. Bronchoalveolar lavage (BAL) cells were collected by lavage of the lungs three to four times with 1 ml of HBSS. T cells were isolated from the remaining lung tissue by mechanical disruption through cell strainers. The cells were subsequently resuspended in 80% isotonic percoll and layered with 40% isotonic percoll. After centrifugation at 400 x g for 25 min, the cells at the 80%/40% interface were collected, washed, and counted.
Intratracheal cell transfers and in situ labeling of cells in the lung airways
BAL cells were collected from C57BL/6 mice at >30 days after Sendai virus infection. Where indicated, donor cells were labeled with CFSE (Molecular Probes, Eugene, OR) by incubation in HBSS containing 0.5–0.7 µM CSFE for 10 min in the dark. The cells were then washed and resuspended in PBS at a concentration of 0.5–2 x 107 cells/ml before transfer. Thy1.1+ C57BL/6 recipient mice were anesthetized and 100 µl (0.5–2 x 106 cells) of the cell suspension or PBS were instilled into the lungs (via the trachea) using a 1-ml syringe fitted with a blunted 20-gauge needle. In some experiments, CFSE-labeled cells were subsequently isolated from the lung airways and restimulated for 4–5 days in vitro, using either the Sendai (Sen) NP324–332 or influenza (Flu)-NP366–374 peptides (2 µg/ml final concentration), human rIL-2 (10 U/ml final concentration) (R&D Systems, Minneapolis, MN), and a cell density of 1 x 106/well in 24-well plates. All wells received 1 x 106 gamma-irradiated (4000 rad) Ly5.1+ naive spleen cells as APCs. For in situ labeling of cells in the lung airways, 80 µl of PBS containing CFSE (0.2 mM) was instilled into the trachea using a blunted 20-gauge needle.
MHC tetrameric reagents, staining, and analysis
MHC class I peptide tetramers were generated by the Molecular Biology Core Facility at the Trudeau Institute as described previously (16). The Sen-NP324–332/Kb tetramer is highly specific for CD8+ T cells that recognize the Sendai virus NP324–332/Kb epitope (2, 17). Staining with tetrameric reagents was performed for 1 h at room temperature. After washing, the cells were stained with anti-CD8 Tricolor (Caltag Laboratories, Burlingame, CA) or anti-CD8-CyChrome and biotinylated, FITC-conjugated, or APC-conjugated Abs specific for Ly5.1 (CD45.1) or Thy1.2 (BD PharMingen, San Diego, CA) on ice for 20 min. Stained samples were run on either a BD Biosciences FACScan or FACSCalibur flow cytometer and data were analyzed using CellQuest software (BD Immunocytometry Systems, San Jose, CA). In some experiments, B cells were depleted before staining by panning on anti-Ig-coated flasks.
BrdU staining was performed as previously described (18). Briefly, 1–2 x 106 cells were surface stained as indicated above and treated with 0.9 ml of FACS Lysing Solution (BD Biosciences) for 15 min at room temperature. The cells were then fixed overnight at 4°C in 1 ml of 1% paraformaldehyde/PBS containing 0.05% Nonidet P-40. After washing, cellular DNA was denatured with 50 Kunitz units of DNase I (bovine pancreas; Sigma-Aldrich) for 30 min at 37°C. The cells were then washed with PBS containing 5% FCS and 0.5% Nonidet P-40 and incubated with 5 µl of anti-BrdU/FITC (BD Biosciences) for 45 min on ice. The cells were washed twice before analysis by flow cytometry.
The percentage of tetramer-positive cells among total live cells was calculated by dividing the number of tetramer+/CD8+ events by the total number of events in a live cell gate.
Cell cycle analysis
T cells were isolated from the lung airways and surface stained as indicated above. After washing, the cells were resuspended in 1 ml of PBS containing 2% FCS, 0.1% NaN3, 0.5% saponin, and 10 µg of Hoechst 33342 for 30–60 min on ice. Data were acquired using a FACSVantage SE cell sorter fitted with an argon laser emitting at 488 nm and a krypton laser with UV optics. The data were analyzed using FlowJo software (Treestar, San Carlos, CA), and doublets were excluded by width and area analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Substantial numbers of
NP324–332/Kb-specific
CD8+ T cells persist in the lung airways of
C57BL/6 mice following recovery from an intranasal Sendai virus
infection (5, 6). These cells are located primarily in the
airway epithelium and the lamina propria (data not shown) and express
markers that are generally associated with acute activation
(CD25+ and CD69+)
(3). The absolute numbers of Ag-specific memory
CD8+ T cells in the airways decline slowly over
the first 6 mo postinfection (with a t1/2
of 40 days) and then stabilize thereafter (5). To
identify the mechanisms that control this biphasic decline in numbers
of memory T cells in the lung airways, we first asked whether the cells
were proliferating. Mice were given BrdU in the drinking water for a
period of 8 days during either the acute phase of infection (days 0–8)
or after a stable memory population had been established (days 25–32,
Sendai virus is cleared by day 10). T cells were then isolated from the
lung airways and tissues on day 33 and
NP324–332/Kb-specific T cells were
analyzed for the incorporation of BrdU. As shown in Fig. 1
, when BrdU was administered between 0
and 8 days of the infection, 90% of the
NP324–332/Kb-specific
memory T cells in the lung airways were BrdU positive on day 33. This
indicates that virus-specific CD8+ T cells had
divided during the acute infection and incorporated BrdU, but the
majority had not divided substantially after that time. However, at
least 10% of the cells were BrdU negative, indicating that some cells
had continued to divide after the virus had been cleared. To confirm
this, we analyzed BrdU incorporation later in the response after
infectious virus was cleared (days 25–32 postinfection). As shown in
Fig. 1, 14% of the
NP324–332/Kb-specific T
cells in the lung airways on day 33 were BrdU positive, indicating that
some cell division at this late time point. Similar data were
obtained for cells isolated from the lung tissues (Fig. 1). The
reciprocal nature of the BrdU profiles in these experiments suggested
that there were two populations of
NP324–332/Kb-specific
memory T cells in the lung airways. One was a large static population
of nonproliferating cells (90%) that persisted in the lung airways
following the acute infection. The other was a smaller population of
cells that continued to divide after resolution of the primary
infection (10%).
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, memory T cells that had been labeled
during days 1–8 declined from 90% of the recovered cells at day 33 to
0% by day 368 (Table I). This decline in the frequency of BrdU-labeled
NP324–332/Kb-specific
memory cells paralleled the early decline (over the first 6 mo) in
absolute numbers of cells in the lung airways that has been reported
previously (5). Similarly, when mice were given BrdU in
the drinking water at late time points postinfection, such as 1 year,
there was a steady accumulation of BrdU-labeled
NP324–332/Kb-specific
memory T cells in the lung airways over 21 days (Fig. 2B). This rate of accumulation
was identical to that observed at 1 mo after infection (Fig. 2A) and was also very similar to that observed in the
spleen. These observations are consistent with the idea that a
subpopulation of memory CD8+ T cells in the lung
airways are maintained over the long term by homeostatic proliferation
of the memory T cell pool. Together, the data support the hypothesis
that memory CD8+ T cells in the lung are
comprised of a pool of nondividing cells that remain static in the lung
after the resolution of the infection and a pool of slowly dividing
cells that may be recruited from the lymphoid organs.
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The BrdU data suggested that the biphasic kinetics of
NP324–332/Kb-specific
memory T cell persistence in the lungs may be attributable to the
deposition of a large bolus of nondividing memory cells during the
acute response, which slowly declined over time, and a parallel slow
continual recruitment of recently divided cells from secondary lymphoid
organs. To distinguish between persistence vs continual recruitment,
memory T cells were labeled in situ in the lung airways by
intratracheal administration of CFSE (day 16 after Sendai virus
infection). Flow cytometry was then used to follow the survival of the
labeled cells over the succeeding 2 wk. Analysis 1 day after labeling
indicated that 30% of the total cells in the airways became labeled
with CFSE (Fig. 3A). Although
the range of staining intensity was quite broad, it was possible to
specifically gate on CFSE-positive cells and demonstrate that they
included a substantial fraction of
NP324–332/Kb-specific T
cells (Fig. 3, A and B). Further analysis on days
4 and 15 postlabeling (Fig. 3, C and D,
representing days 20 and 31 postinfection), demonstrated that
CFSE-positive,
NP324–332/Kb-specific T
cells could be readily recovered 2 wk after labeling. The absolute
percentage of CFSE-positive cells in the airways declined over time
from 30% at day 1 postlabeling to <5% at day 15 postlabeling (data
not shown). However, the percentage of
NP324–332/Kb-specific T
cells remained stable within this CFSE-labeled population. These data
confirmed that a substantial number of Ag-specific memory
CD8+ T cells are able to persist in the lung
airways for at least 2 wk. These recovered cells expressed CD69 and
CD25 markers, consistent with the activated phenotype found in previous
studies on memory CD8+ T cells recovered from the
lung airways (data not shown).
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A, 17% of
NP324–332/Kb-specific
CD8+ T cells in the lung airways were in the
G2-M or S phase of the cell cycle at the peak of
the infection (day 8 postinfection). However, this percentage decreased
to <1% by day 15 postinfection and then persisted at this level for
>24 days (Fig. 4A). A similar pattern of cell cycle
kinetics was observed in tetramer-negative CD8+ T
cells, except that a lower percentage of the cells were in cycle at day
8 (Fig. 4B). Together these data confirm that the effector
memory CD8+ T cells that persist in the lung
following recovery from a Sendai virus infection are not in the cell
cycle.
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The BrdU and CFSE studies suggested that large numbers of
nonproliferating memory CD8+ T cells persisted in
the lung airways after recovery from a Sendai virus infection. We
further investigated the longevity of memory T cells in the airways
using an intratracheal transfer system. BAL cells were isolated from
Thy1.2+ mice that had recovered from a Sendai
virus infection and CFSE labeled in vitro. The labeled cells were then
transferred to the airways of naive Thy1.1+ mice.
After 8 days, the BAL, lung tissue, MLN, and spleens were recovered
from recipient mice and donor cells were identified by Thy1.2 staining.
As shown in Fig. 5 (left
panels), substantial numbers of Thy1.2+
donor cells could be recovered from the airways, but not the lung
tissue, spleens, or MLN, indicating that the donor cells had not
colonized other sites. Analysis of the CFSE levels on
NP324–332/Kb
tetramer-positive cells at various days (days 1–8) posttransfer
further demonstrated that the cells did not proliferate over this time
frame (Fig. 5, right panels). Similar results were obtained
when memory T cells were transferred into the lungs of mice that had
previously recovered from a Sendai virus infection (data not shown). In
this case, the host and donor
NP324–332/Kb-specific
CD8+ T cells were distinguished using the Thy1
marker. Although the memory cells from the lung airways did not
proliferate in situ, they had not lost their capacity to respond to Ag.
Thus, cells that had been reisolated from the lung airways 8 days after
transfer proliferated in vitro in response to the
NP324–332 peptide and IL-2 (Fig. 6). These cells were also able to produce
IFN- and mediate cytolytic activity in response to target cells
coated with the NP324–332 peptide (data not
shown). Taken together, the data demonstrate that memory
CD8+ T cells can survive in the lung airways for
substantial periods of time without proliferating and still retain the
capacity to respond to Ag.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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40
days and their numbers decline with increasing months after infection.
The steady attrition of cells probably reflects their migration out of
the epithelial layer and removal via the mucociliary escalator. The
second population of cells is characterized by cell division at late
time points after viral clearance. Although these cells initially
represent a small percentage of the memory CD8+ T
cell pool in the lung airways, their relative proportion increases over
time, as the nondividing cells disappear. The presence of two separate
populations of memory CD8+ T cells in the lung
provide an explanation for the kinetics of memory cell persistence
described previously (5). Thus, the initial waning of cell
numbers may represent the steady loss of a large bolus of cells
deposited after the initial infection. The subsequent stabilization of
cell numbers after 6 mo may represent steady-state recruitment and loss
of memory cells, possibly driven by homeostatic proliferation of memory
T cell populations in the secondary lymphoid organs followed by
recruitment to the lung (19, 20). The observation that T
cells can persist in an environment such as the lung airway lumina is
novel and has significant implications for understanding protective
cellular immune responses. Although the BrdU data demonstrate that a subpopulation of memory CD8+ T cells continues to proliferate after resolution of the infection, it is not clear where this proliferation occurs. The cells may divide in the lung airway lumen or at other distal sites before being recruited to the lung. We believe that the latter possibility is most likely for a number of reasons. First, there is substantial evidence that surfactants in the lung specifically interfere with T cell proliferation (21). Second, it seems unlikely that there are appropriate signals to drive T cell proliferation in a nonlymphoid site such as the airways of an uninfected lung. Third, we have shown that memory cells are recruited to the lung even after peritoneal infection or distal vaccination (5) (K. H. Ely, L. S. Cauley, A. D. Roberts, J. W. Brennan, T. Cookenham, and D. L. Woodland, manuscript in preparation). Fourth, the idea that cells have divided at a distal site before recruitment to the lung is consistent with the fact that memory populations in secondary lymphoid organs undergo a continual slow homeostatic turnover (19, 22, 23, 24, 25). Thus, the memory cells in the lung appear to represent a nondividing population of cells that persists in the airways after viral clearance and a smaller population of cells that continue to divide in secondary lymphoid organs after viral clearance.
It is unclear why such large numbers of cells persist in the lung
airways following recovery from respiratory virus infections. One
possible explanation is that the apoptotic mechanisms that normally
eliminate effector T cells in the lung may be arrested when Ag is
cleared from the lung. Recent studies have suggested that IFN- plays
a key role in regulating effector T cell numbers by potentiating
apoptosis or cell removal by macrophages (26, 27). Thus,
the cessation of IFN- production in the lung following Ag clearance
may result in the accumulation and persistence of memory T cells at
this site. We are currently testing this hypothesis.
Memory CD8+ T cells were recovered from both the
lung interstitium (including the bronchus-associated lymphoid tissue)
and the lung airway lumina several weeks after infection. Since the
lung airways are directly exposed to the external environment, it seems
remarkable that memory cells can persist in a functionally stable state
for several weeks at this site. The presence of effector memory T cells
in the lung airways likely represents an early defense mechanism
against a secondary viral infection. Although the absolute numbers of
cells are not large, early production of IFN- and other antiviral
cytokines may reduce the level of viral replication and reduce the
viral load to be cleared by the memory response that develops in local
draining lymph nodes. In this regard, localization of the cells in the
airways and nasal mucosa represents an optimal location for responding
to the early phase of an infection (7, 13, 14, 15). Indeed, we
have previously shown that memory CD4+ T cells in
the lung airways can provide a substantial degree of protective
immunity against a subsequent virus infection (6). In
addition, previous studies have shown that cellular control of
influenza virus infections wanes substantially over the course of about
6 mo, which correlates with the loss of memory
CD8+ T cells in the lung airways
(1). This basic observation mirrors the situation in
humans where cellular immunity to influenza virus appears to wane
between yearly epidemics (28, 29, 30, 31, 32). The data in the current
report argue that protective cellular immunity against this class of
infection depends on a bolus of cells that is established in the lungs
by the primary infection. The recruitment of new memory T cells
generated by homeostatic turnover mechanisms in secondary lymphoid
organs is apparently insufficient to replenish this lung population
which then steadily declines over time. This observation has
significant implications for the design and development of vaccines
that promote cellular immunity in the lung. In this regard, we have
shown that relatively long-term protective immunity can be established
following some vaccination strategies, such as DNA vaccination
(33). This type of vaccine may induce lymphoid memory T
cell pools that exhibit increased rates of homeostatic turnover,
resulting in enhanced maintenance of peripheral memory T cell pools.
Thus, it is possible that the best strategy for inducing mucosal
immunity may involve a combination of vaccines that optimally induce a
local pool of peripheral memory cells and a rapidly turning over pool
of lymphoid memory T cells. We are currently investigating this
possibility.
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Acknowledgments |
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Footnotes |
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2 Current address: Division of Virology, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702.
3 Address correspondence and reprint requests to Dr. David L. Woodland, Trudeau Institute, P.O. Box 59, Saranac Lake, NY 12983. E-mail address: dwoodland{at}trudeauinstitute.org
4 Abbreviations used in this paper: EID50, 50% egg infectious dose; NP, nucleoprotein; BrdU, 5-bromo-2-deoxyuridine; MLN, mediastinal lymph node; BAL, bronchoalveolar lavage; Flu, influenza; Sen, Sendai.
Received for publication June 4, 2002. Accepted for publication August 29, 2002.
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eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J. Exp. Med. 192:117.. J. Immunol. 165:6056.This article has been cited by other articles:
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  M. Jeyanathan, J. Mu, K. Kugathasan, X. Zhang, D. Damjanovic, C. Small, M. Divangahi, B. J. Petrof, C. M. Hogaboam, and Z. Xing Airway Delivery of Soluble Mycobacterial Antigens Restores Protective Mucosal Immunity by Single Intramuscular Plasmid DNA Tuberculosis Vaccination: Role of Proinflammatory Signals in the Lung J. Immunol., October 15, 2008; 181(8): 5618 - 5626. [Abstract] [Full Text] [PDF]
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J. E. Kohlmeier, S. C. Miller, and D. L. Woodland Cutting Edge: Antigen Is Not Required for the Activation and Maintenance of Virus-Specific Memory CD8+ T Cells in the Lung Airways J. Immunol., April 15, 2007; 178(8): 4721 - 4725. [Abstract] [Full Text] [PDF]
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C.-H. Wei, R. Trenney, M. Sanchez-Alavez, K. Marquardt, D. L. Woodland, S. J. Henriksen, and L. A. Sherman Tissue-Resident Memory CD8+ T Cells Can Be Deleted by Soluble, but Not Cross-Presented Antigen J. Immunol., November 15, 2005; 175(10): 6615 - 6623. [Abstract] [Full Text] [PDF]
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M. F. Bachmann, P. Wolint, K. Schwarz, and A. Oxenius Recall Proliferation Potential of Memory CD8+ T Cells and Antiviral Protection J. Immunol., October 1, 2005; 175(7): 4677 - 4685. [Abstract] [Full Text] [PDF]
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D. L. Woodland and I. Scott T Cell Memory in the Lung Airways Proceedings of the ATS, August 1, 2005; 2(2): 126 - 131. [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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M. Santosuosso, X. Zhang, S. McCormick, J. Wang, M. Hitt, and Z. Xing Mechanisms of Mucosal and Parenteral Tuberculosis Vaccinations: Adenoviral-Based Mucosal Immunization Preferentially Elicits Sustained Accumulation of Immune Protective CD4 and CD8 T Cells within the Airway Lumen J. Immunol., June 15, 2005; 174(12): 7986 - 7994. [Abstract] [Full Text] [PDF]
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H. Unsoeld and H. Pircher Complex Memory T-Cell Phenotypes Revealed by Coexpression of CD62L and CCR7 J. Virol., April 1, 2005; 79(7): 4510 - 4513. [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. F. Debes, K. Bonhagen, T. Wolff, U. Kretschmer, S. Krautwald, T. Kamradt, and A. Hamann CC Chemokine Receptor 7 Expression by Effector/Memory CD4+ T Cells Depends on Antigen Specificity and Tissue Localization during Influenza A Virus Infection J. Virol., July 15, 2004; 78(14): 7528 - 7535. [Abstract] [Full Text] [PDF]
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C. J. Workman, L. S. Cauley, I.-J. Kim, M. A. Blackman, D. L. Woodland, and D. A. A. Vignali Lymphocyte Activation Gene-3 (CD223) Regulates the Size of the Expanding T Cell Population Following Antigen Activation In Vivo J. Immunol., May 1, 2004; 172(9): 5450 - 5455. [Abstract] [Full Text] [PDF]
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 J. Skitzki, R. A. Craig, R. Okuyama, R. N. Knibbs, K. McDonagh, A. E. Chang, and L. M. Stoolman Donor Cell Cycling, Trafficking, and Accumulation during Adoptive Immunotherapy for Murine Lung Metastases Cancer Res., March 15, 2004; 64(6): 2183 - 2191. [Abstract] [Full Text] [PDF]
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 W. W. Hancock, F. M. Szaba, K. N. Berggren, M. A. Parent, I. K. Mullarky, J. Pearl, A. M. Cooper, K. H. Ely, D. L. Woodland, I.-J. Kim, et al. Intact type 1 immunity and immune-associated coagulative responses in mice lacking IFN{gamma}-inducible fibrinogen-like protein 2 PNAS, March 2, 2004; 101(9): 3005 - 3010. [Abstract] [Full Text] [PDF]
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E. Flano, C. L. Hardy, I.-J. Kim, C. Frankling, M. A. Coppola, P. Nguyen, D. L. Woodland, and M. A. Blackman T Cell Reactivity during Infectious Mononucleosis and Persistent Gammaherpesvirus Infection in Mice J. Immunol., March 1, 2004; 172(5): 3078 - 3085. [Abstract] [Full Text] [PDF]
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J. Chang, S. Y. Choi, H. T. Jin, Y. C. Sung, and T. J. Braciale Improved Effector Activity and Memory CD8 T Cell Development by IL-2 Expression during Experimental Respiratory Syncytial Virus Infection J. Immunol., January 1, 2004; 172(1): 503 - 508. [Abstract] [Full Text] [PDF]
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D. Berenzon, R. J. Schwenk, L. Letellier, M. Guebre-Xabier, J. Williams, and U. Krzych Protracted Protection to Plasmodium berghei Malaria Is Linked to Functionally and Phenotypically Heterogeneous Liver Memory CD8+ T Cells J. Immunol., August 15, 2003; 171(4): 2024 - 2034. [Abstract] [Full Text] [PDF]
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L. S. Cauley, T. Cookenham, R. J. Hogan, S. R. Crowe, and D. L. Woodland Renewal of Peripheral CD8+ Memory T Cells During Secondary Viral Infection of Antibody-Sufficient Mice J. Immunol., June 1, 2003; 170(11): 5597 - 5606. [Abstract] [Full Text] [PDF]
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K. H. Ely, L. S. Cauley, A. D. Roberts, J. W. Brennan, T. Cookenham, and D. L. Woodland Nonspecific Recruitment of Memory CD8+ T Cells to the Lung Airways During Respiratory Virus Infections J. Immunol., February 1, 2003; 170(3): 1423 - 1429. [Abstract] [Full Text] [PDF]
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) or spleen (
) and stained with
Sen-NP324–332/Kb tetramer-PE,
anti-CD8-Tricolor, and anti-BrdU-FITC Abs. The data are shown
as BrdU incorporation among CD8+/tetramer+
gated T cells and the error bars indicate the SD of three individual
mice. The full time course was done once, but the day 6 and day 21 time
points were repeated several times with similar results.
