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*
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester, Rochester, NY 14642;
Istituto Superiore di Sanita, Rome, Italy;
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and
Division of Immunology, Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Melbourne, Victoria, Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-herpesvirus-68 Ag. Interestingly, the primary host
response to the immunodominant influenza nucleoprotein epitope was not
affected by the presence of memory or recently activated OT-I T cells.
Thus, although Ag is required to activate the T cells, the subsequent
localization of T cells to the lung during a virus infection is a
property of recently activated and memory T cells and is not
necessarily driven by Ag in the lung. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Early studies comparing active and passive CD8+ T cell recruitment to sites of virus-induced inflammatory pathology depended on cell transfer protocols using immune Thy-1 congenic donors and naive virus-infected recipients (1), and limiting dilution analysis (LDA) to determine the relative prevalence of acutely stimulated vs memory T cells (1, 11, 12). Although primed, donor Thy 1.1+CD8+ T cells were very much the minority population in naive Thy1.2+ recipients (13), the frequencies of acutely stimulated and memory virus-specific T cells determined by LDA were similar between the host and donor T cells (12). Evidence was found for the non-Ag-specific recruitment of CD8 T cells during the infection (11, 12). Two limitations of these earlier studies were the inefficiency of the in vitro assays used to enumerate the Ag-specific cells and the inability to assess the effects on naive T cells with a defined specificity. Thus the experiments may have underestimated the actual numbers of T cells nonspecifically recruited, and the recruitment of naive T cells to the site of infection could not be studied. Both problems were solved by combining a more efficient method to detect the virus-specific T cells (MHC class I tetramers) and naive CD8 T cells with a defined Ag specificity (TCR-transgenic). The present experiments dissect the role of Ag in the localization profiles of naive, acutely activated, and memory Ag-specific CD8+ T cells during respiratory infection with influenza virus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J (B6) Thy1.2+ and congenic B6.PL Thy1.1+ mice were purchased from The Jackson Laboratory (Bar Harbor, ME). A colony of the OT-I transgenic mouse strain that expresses a TCR specific for the OVA SIINFEKL (OVA257–264) peptide presented in the context of H-2Kb (14) was established at St. Jude Children’s Research Hospital (Memphis, TN) from breeding pairs provided by Dr. M. Bevan (University of Washington, Seattle, WA). All mice were first exposed to virus at 6–8 wk of age and were otherwise held under specific pathogen-free conditions.
Recombinant influenza viruses
The influenza A/WSN/33 (WSN)-OVAI and
WSN-PEPII influenza viruses containing the
OVA257–264 (siinfekl) peptide and a peptide
PEPII (khylfrnl) derived from the EL4 tumor cell line (15)
in the neuraminidase (NA) stalk were generated by reverse genetics
(16) using the plasmids pT3WSN-OVAI
and pT3WSNPepII, with the NA gene flanked by an upstream T3 RNA
polymerase promoter and a downstream Ksp6321 site. The in vitro
transcripts were complexed with purified nucleoprotein (NP) and
polymerase proteins to obtain reconstituted NA ribonucleoprotein
complexes and transfected into 70–90% confluent Madin-Darby bovine
kidney-cells infected 1 h before transfection with the helper
virus WSN/HK (H1N2). Eighteen hours after transfection, virus
recombinants in the supernatant were assayed for plaque formation on
MDBK cells. The inserted sequence was confirmed by sequencing
PCR-amplified cDNA. The WSN-p56 virus-expressing and
H-2Db-restricted epitope from the murine
-herpesvirus-68 (HV-68) was made in a similar manner and
has been described previously (17).
Virus challenge
Mice were anesthetized with avertin (2,2,2-tribromoethanol)
before intranasal (i.n.) challenge with 105 PFU
of WSN-OVAI or WSN-PEPII in 30 µl of PBS. Both
influenza viruses were grown and titered in the Manin Darby canine
kidney, MDCK, fibroblast cell line, obtained from the American Type
Culture Collection (Manassas, VA). The WSN-p56 virus was grown and
titered (by determining the 50% infectious dose endpoint for eggs,
EID50) in embryonated hen’s eggs and mice were
infected i.p. with 5.0 x 105
EID50. Mice were also primed i.p. with
106 or 3 x 107 PFU,
respectively, of recombinant vaccinia viruses expressing OVA (Vacc-OVA)
(18) or the p56 epitope of HV-68 (Vacc-p56)
(17). The Vacc-OVA was supplied by Dr. J. Bennink
(National Institute of Allergy and Infecctious Diseases, National
Institutes of Health, Bethesda, MD). Mice that were primed and boosted
with Vacc-p56 and WSN-p56 (17) were later challenged i.n.
with 106 EID50 of the
B/Hong Kong/73 (B/HK) influenza B virus, which does not generate a
CD8+ T cell response cross-reactive with that
caused by the WSN influenza A virus.
Adoptive transfer experiments
Spleen cells from unprimed Thy1.2+ TCR-transgenic donor females were transferred i.v. to female, unirradiated, B6.PL Thy1.1+ recipients. The number of cells transferred is indicated in each figure. Recipient animals were challenged with virus(es) as indicated within 24–72 h of transfer.
Flow cytometric analysis
Spleen, lymph node, and BAL lymphocyte populations were stained
as aliquots of 2 x 105 cells with
various combinations of mAbs to CD8
(53-6.72 or CT8a), Thy1.1
(OX-7), Thy1.2 (30-H12), TCR-V2
(B20.1), TCR-V
5 (MR9-4), CD44 (IM7), and
anti-CD62L (MEL-14) conjugated to FITC, PE, biotin,
allophycocyanin, or PE-cyanine 5. The conjugated mAbs were
purchased from BD PharMingen (San Diego, CA) or Caltag Laboratories
(Burlingame, CA) and are referenced in their current catalogs.
Biotinylated mAbs were developed with streptavidin-Red670 (Life
Technologies, Bethesda, MD). Tetrameric complexes of
H-2Kb/OVA257–264
(KbOVA257),
H-2Db/influenza NP366–374
(DbNP366), and
H-2Db/p56 epitope of HV-68
(Dbp56) were prepared and used as described
previously (8, 19). All cells were analyzed with CellQuest
software (BD Biosciences, San Diego, CA), using either a BD Biosciences
FACScan in three-color mode or a BD Biosciences FACSCalibur in
four-color mode.
Single cell IFN- assay
Spleen, mediastinal lymph node (MLN), and macrophage-depleted
BAL populations were cultured for 6 h in 96-well round-bottom
plates at 5 x 105 to 8 x
105 cells per well in complete medium containing
10 µg/ml brefeldin A (Epicenter Technologies, Madison, WI), with or
without 10 µM of the OVA (SIINFEKL) or influenza NP (ASNENMETM)
peptides. After culture, the cells were placed on ice, washed in
PBS/brefeldin A (10 µg/ml), stained with a mixture of
anti-Thy1.2-FITC and anti-CD8-tricolor, washed again, fixed
with 1% formaldehyde, permeabilized in 0.5% saponin (Sigma-Aldrich,
St. Louis, MO), and stained with anti-IFN--PE (BD PharMingen)
for 30 min on ice. The lymphocytes were then washed and analyzed on the
FACScan in three-color mode with CellQuest software. The data were
viewed as two-parameter plots of Thy1 vs IFN- staining using a
combination lymphocyte and CD8+ gate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Traditionally, it has been difficult to study the role of Ag in
the recruitment of naive T cells. The limitation of conventional
systems is that the prevalence of naive virus-specific
CD8+ T cells is too low for an accurate
experimental analysis. To solve the problem of the low frequency of
naive virus-specific T cells, we used TCR-transgenic T cells with a
defined specificity. Adoptive transfer of OVA peptide
(OVA257–264)-specific,
V2+V5+
(Fig. 1
A), naive (Fig. 1B), OT-I
Thy1.2+CD8+ T cells (Fig. 1, C and D) into congenic
Thy1.1+ hosts resulted in a detectable population
in the lymph nodes and spleen of even unimmunized mice (Fig. 1, C and D, and Fig. 2, A and B).
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A)
and MLN (Fig. 2B), compared with uninfected mice. Also,
WSN-OVAI infection resulted in a strong
recruitment of the OT-I T cells to the lung (Fig. 2C) where
up to 25% of the infiltrating CD8+ T cells were
Thy1.2+ (Fig. 3A). In contrast, infection of
the mice with the WSN-PEPII virus caused little change in the
prevalence of the transgenic cells in the MLN and spleen (Fig. 2, A and B) and little or no evidence of the cells
in the lung (Figs. 2C and 3B). Similar numbers
were returned by KbOVA257
tetramer staining (Fig. 3, D and E), confirming
the specificity of the Thy1.2 staining. Little of the OVA-specific
response was generated by the host Thy1.1+ T
cells in the WSN-OVAI-infected mice. This was
supported by OVA257–264-specific intracellular
IFN- secretion, with a distribution of OVA-responsive cells similar
to the Thy1.2+ and
tetramer+ fractions (data not shown). Although
these data suggest that T cell activation via Ag is a necessary
prerequisite for trafficking of CD8+ T cells to
the infected lung, it was still not clear whether Ag is required in the
tissue itself.
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To address the issue of whether Ag was required at the site of
inflammation (in this case the lung) to draw the T cells in, or just to
activate the T cells in the periphery, the following experiments were
conducted. OT-I spleen cells were adoptively transferred into
Thy1.1+ congenic hosts as above, followed 24
h later by simultaneous challenge with the irrelevant WSN-PEPII
influenza i.n. and Vacc-OVA i.p. Some animals received
WSN-OVAI or WSN-PEPII alone i.n. The i.p.
injection of vaccinia has previously been shown to produce infection in
the peritoneum and in the ovaries of female mice (20). The
animals coinfected with Vacc-OVA and the WSN-PEPII (Fig. 3, B and E) had a significant (3%) infiltration of
Thy1.2+Kb/OVA+
OT-I T cells in the BAL compared with animals infected with WSN-PEPII
alone (Fig. 3, C, F, and I). These
cells in the BAL had a profile characteristic of activated T cells
(CD44highCD62Llow) (Fig. 3, G and H). Thus the distal activation of
CD8+ T cells by Ag rapidly conveys the ability to
enter the inflamed lung and does not require Ag at the site for the
cells to get in. This suggests that the nonspecific recruitment of T
cells into the pneumonic lung in the absence of Ag is a consequence of
T cell activation.
Passive localization of CD8+ memory T cells to the pneumonic lung
The question remained as to whether the nonspecific localization
of T cells in the lung was a phenotype restricted to recently activated
T cells, or if resting memory cells could also be found in the inflamed
lung during an unrelated infection. A pool of naive
Thy1.2+ spleen cells from the transgenic mice
were adoptively transferred (5 x 106 per
mouse) into unirradiated congenic Thy1.1+ B6
recipients. To establish a resting memory T cell population, the
recipient mice were inoculated i.p. with 106 PFU
of Vacc-OVA within 72 h of transfer. The animals were then rested
for 6 wk to allow recovery from the vaccinia infection and to establish
a pool of quiescent memory T cells. At the end of the 6-wk rest period,
the animals were challenged with 103 PFU of
either the WSN-PEPII or the WSN-OVAI i.n. As
controls, some animals did not receive any influenza virus. The animals
were subsequently sampled at 5 and 11 days after the flu inoculation
for the presence and activation status of T cells with the transgenic
phenotype (Fig. 4). Animals infected with
the WSN-PEPII virus exhibited little change in the proportion (Fig. 4)
or number (Fig. 5) of
Thy1.2+ OT-I T cells in the MLN or spleen,
suggesting that little clonal expansion had occurred. In contrast,
there were substantial increases in the number of OT-I T cells in mice
receiving WSN-OVAI (Fig. 5). Despite the fact
that the proportion of transgenic T cells did not appear to change with
the WSN-PEPII infection, there was evidence of nonspecific recruitment
of the OVA-specific cells to the lung at 5 days after infection, which
subsequently subsided by day 11 (Figs. 4, 5A, and 6). The
transient nature of this nonspecific recruitment was evident in the
Kb/siinfekl tetramer staining as well as the
intracellular IFN- response to the siinfekl peptide (Fig. 6), further indicating that these cells
were OVA specific and responsive. For example, the IFN-
response to the OVA257–264 peptide in the
WSN-PEPII-infected mice was higher at day 5 (4.5%) than at day 11
(<1%). Conversely, the OVA-specific IFN- response increased from
14 to 28% between days 5 and 11 in the
WSN-OVAI-infected mice (Fig. 6). As a positive
control, the specific recruitment of the transgenic T cells by the
WSN-OVAI virus infection was substantial and
exhibited the early kinetics that are a hallmark of the recall
response. Thus, without the Ag in the tissue, memory
CD8+ T cells are present in the lung early in the
infection, as are recently activated cells. However, these early T cell
immigrants are not maintained in the lung unless they encounter their
specific ligand.
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To be sure that the results with the OT-I T cells were not an
artifact of the transgenic nature of the cells, the experiment was
repeated in a nontransgenic system. Memory T cells specific for the
Dbp56 epitope of the HV-68 virus were
generated by priming B6 mice i.p. with Vacc-p56. A second pool of
traceable memory CD8 T cells specific for the
DbNP366 epitope of the
influenza A virus were generated by nonrespiratory i.p. challenge 1 mo
later with recombinant influenza A/WSN-p56, also further stimulating
the p56-specific T cells. These mice were subsequently infected i.n.
with the unrelated B/HK influenza B virus after a further 7-wk
interval, and the spleen, MLN, and BAL populations were analyzed. Data
were gathered for the total CD8+ T cell counts
(Fig. 7, A–C) as
well as the prevalence of HV-68-p56-specific and influenza A virus
NP-specific CD8+ T cells using the
Dbp56 and
DbNP366 tetramers,
respectively (Fig. 7, D–F).
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1–2% of the
CD8+ T cells in the spleen were specific for
either Dbp56 or
DbNP366 (day 0; Fig. 7, A and D). The MLN were small (day 0; Fig. 7, B and E), a characteristic feature of B6 mice
that have not been challenged with a respiratory virus
(1). Of the small number of CD8+
lymphocytes recovered by BAL from what were essentially normal lungs,
few were virus specific (day 0; Fig. 7, D and F).
Within 5 days of the B/HK challenge, the number of memory
CD8+ T cells in the spleen specific for either
unrelated virus had fallen (Fig. 7D) and the size of the MLN
had shown some increase (Fig. 7, B and E). Peak
cell numbers were recorded in the MLN on day 7 (Fig. 7, B
and E) and in the lung on day 12 (Fig. 7, C and
F). At this stage, 5% of the CD8+
T cells recovered from these B/HK-infected mouse lungs were specific
for either Dbp56 or
DbNP366 (Fig. 7F). The kinetics of the nonspecific recruitment of the
nontransgenic memory CD8 T cells differed from those of the OT-I
transgenic cells. This may be due to differences in the nature of the
inflammatory process between influenza A and influenza B infections.
Alternatively, the diversity of the nontransgenic NP- and p56-specific
T cells compared with the transgenic OT-I T cells may result in a
higher degree of Ag cross-reactivity. In such a case, the observed
recruitment could then be specific. In either case, primed memory
T cells reactive to an apparently unrelated virus are consistently
recruited to sites of virus-induced inflammatory pathology, as
demonstrated by the earlier LDA experiments (11, 12). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using the OT-I CD8+ TCR-transgenic T cells and a combination of influenza and vaccinia viruses with and without the relevant OVA257–264 epitope, we have shown that naive CD8+ T cells are not recruited to the lung during a virus infection. Only when the T cells had been acutely activated by Ag, either distally via a nonrespiratory infection or when they were present as resting memory T cells, was there any evidence of T cells in the infected lung in the absence of Ag. Thus the features that allow T cells to enter inflamed tissue are unrelated to Ag and are acquired by the T cells upon activation, presumably in the secondary lymphoid organs. Furthermore, these features are preserved on resting memory T cells, allowing the memory T cells to enter a site of possible infection quickly, where they can surveil for Ag-positive targets.
The trafficking of T cells from blood to tissue is regulated at several levels. It is well established that, upon activation by Ag, CD8+ T cells down-modulate the expression of the lymph node homing receptor L-selectin (CD62L) (24, 25, 26, 27, 28) and up-regulate the integrins very late Ag (VLA)-4 and LFA-1 (27, 29, 30, 31). Consistent with this view is that influenza and parainfluenza virus-specific CD4 and CD8 T cells have been shown to express VLA-4 and have low levels of CD62L (24, 26, 28, 32, 33, 34, 35). Both acutely activated and memory virus-specific T cells also express the tissue ligand CD44 and ICAM-1 (26, 36, 37, 38, 39). Following activation by Ag in the secondary lymphoid organs, the T cells enter the circulation and roll along the vascular endothelium until they encounter the correct ligands (27, 30, 31, 40). Some tissue-specific ligands have been identified, such as L-selectin, E-selectin, and P-selectin for lymph node, skin, and gut homing T cells, respectively (24, 25, 27, 41, 42, 43). These tissue-specific ligands, or "addressins," tether the lymphocyte to the vasculature (27, 44, 45). Firm adhesion occurs next through interactions of LFA-1, ICAM-1, or VCAM (44, 46, 47). Engagement of VLA-4 (CD49d) partially activates the T cells, followed by diapedesis (31, 48, 49). For the lung, no lung tissue-specific ligands have yet been identified. Ag/MHC has been postulated to have a role in the activation of T cells at the vasculature (11, 12, 50, 51, 52, 53) and in the process of extravasation, although this now seems not to be the case. Once in the tissue, if Ag is present, the T cells may further proliferate or become activated to effector status (7, 12). T cells that do not encounter Ag presumably pass through the tissue and back into the lymph nodes or circulation, though some memory T cells may become nonspecifically activated by the inflamed microenvironment. This nonspecific activation of memory T cells in the infected lung can also cause them to proliferate and/or become susceptible to apoptosis (54, 55), leading to a reduction in immune memory for unrelated Ags (55). So acute or previous encounter with viral Ags endows T cells with the essential constellation of adhesion molecules that allow entry into tissue.
Certainly, adhesion is only one level of regulation for tissue trafficking. The recent explosion of information concerning the roles of chemokines in directing lymphocytes to the correct tissue, or even within a given tissue, is only beginning to clarify this aspect of T cell migration. To date, although it has been attempted (4, 56), no lung-specific chemokines have been identified that can explain how T cells get to the lung in viral infections. Macrophage chemotactic protein-1 is only one factor known to be important for recruiting T cells to the lung (5, 57), although this is in a model of allergic sensitization. The specific chemokines induced during respiratory infection with influenza have not been identified. Ag activation of T cells could serve to increase the chemokine responsiveness of the cells through up-regulation of chemokine receptors. The evidence presented in this paper suggests that, assuming chemokines are critical for the recruitment of T cells to the infected lung, responsiveness to these factors may be a feature only of activated or memory T cells and not of naive T cells.
Interestingly, although not the focus of these studies, there was
evidence that the host response to the OVA peptide was inhibited in the
presence the OVA-specific OT-I T cells (Fig. 6). Yet the host response
to the natural influenza epitope of the NP was not affected, either in
the primary or secondary responses. In a previous report
(58) similar OT-I T cells were shown to effectively
suppress the host response to both the
OVA257–264 epitope and an unrelated epitope via
competition for APCs. The differences between these studies are that
firstly, the APC presenting influenza Ags may not be limiting,
explaining why the NP response is intact even when the OT-I T cells had
been primed (Fig. 6). Secondly, the numerical advantage of the
transferred OT-I T cells in the primary challenge could explain the
inhibition of the host (Thy1.1) response to OVA. This advantage may be
partially overcome when the host T cells are primed with Vacc-OVA,
because there is some evidence of a weak host response to OVA during a
secondary response (Fig. 6). Interestingly, despite the fact that the
OT-I donors for these studies were not Rag deficient (59, 60), there was little evidence of a donor
(Thy1.2+) T cell response to the influenza NP
epitope, even though it is formally possible that some dual TCR OT-I
cells would be NP specific.
Nonlymphoid tissues are home to a surprisingly large number of memory T
cells (CD4 or CD8) (61, 62). Furthermore, these
tissue-residing T cells have activation and effector phenotypes
distinct from their counterparts in the lymph nodes and spleen
(61, 62). The hypothesis is that some memory T cells enter
tissue to provide secondary immunity regardless of where they have been
primed or what Ag specificity they possess (61, 62). The possibility emerges that, in our experiments where the
OT-I T cells were primed with Vacc-OVA i.p., the few OT-I T cells we
observed early in the secondary influenza infection were T cells
already present in the lung. However, mice that are maintained under
specific pathogen-free conditions, without a known respiratory virus
infection, have characteristically small MLNs and very few, if any, T
cells recoverable in the BAL (63). In fact, almost no
-HV68 p56- or flu NP-specific CD8 T cells were present in the BAL of
mice given a nonrespiratory priming (Fig. 7, C and
F). In contrast, virus-specific CD8 T cells are easily
recovered from the BAL of mice long after they have been infected with,
and cleared, a respiratory virus, even up to a year or more after the
initial infection (64, 65). This suggests that respiratory
infection is required to allow a significant number of T cells to enter
the airways and that the infection may permanently alter the
permeability of the lung to lymphocytes. This is supported by the
observation that the MLN is also permanently altered after respiratory
infections (63). The difference between these observations
and those of Masopust et al. (66) may be in the way
lymphocytes were isolated from the tissues. We sampled the lung by
lavage, whereas the other study was performed by homogenization of
perfused tissue. Thus, we cannot exclude the possibility that, after
priming with vaccinia, some memory T cells were present in the lung
tissue. Furthermore, in the present situation, the transient nature of
the memory CD8 T cells during the secondary influenza challenge (Figs. 4 and 6) suggests that there may be significant turnover of
lung-resident memory T cells during subsequent infections. The
long-term effects of this turnover for memory T cells in different
tissues and for immune protection are not known, but significant loss
of memory has been described following sequential virus infections
(67, 68). In any case, it is clear that naive T cells do
not have the capacity to enter the lung tissue or airways, even during
a respiratory infection, while activated and memory T cells
do.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David J. Topham, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 609, Rochester, NY 14642. E-mail address: david_topham{at}urmc.rochester.edu
3 Abbreviations used in this paper: BAL, bronchoalveolar lavage; i.n., intranasal(ly); LDA, limiting dilution analysis; NA, neuraminidase; NP, nucleoprotein; B/HK, B/Hong Kong/73; MLN, mediastinal lymph node; EID50, the 50% infectious dose endpoint for eggs; HV-68, -herpesvirus-68; Vacc-OVA, recombinant vaccinia virus expressing OVA; Vacc-p56, vaccinia recombinant expressing p56 epitope of HV-68; VLA, very late Ag; WSN, influenza A/WSN/33.
Received for publication July 24, 2001. Accepted for publication October 15, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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M. Coccoris, E. Swart, M. A. de Witte, J. W. J. van Heijst, J. B. A. G. Haanen, K. Schepers, and T. N. M. Schumacher Long-Term Functionality of TCR-Transduced T Cells In Vivo J. Immunol., May 15, 2008; 180(10): 6536 - 6543. [Abstract] [Full Text] [PDF]
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M. A. de Witte, A. Jorritsma, E. Swart, K. C. Straathof, K. de Punder, J. B. A. G. Haanen, C. M. Rooney, and T. N. M. Schumacher An Inducible Caspase 9 Safety Switch Can Halt Cell Therapy-Induced Autoimmune Disease J. Immunol., May 1, 2008; 180(9): 6365 - 6373. [Abstract] [Full Text] [PDF]
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G. Plesa, A. E. Snook, S. A. Waldman, and L. C. Eisenlohr Derivation and Fluidity of Acutely Induced Dysfunctional CD8+ T Cells J. Immunol., April 15, 2008; 180(8): 5300 - 5308. [Abstract] [Full Text] [PDF]
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P. Castiglioni, D. S. Hall, E. L. Jacovetty, E. Ingulli, and M. Zanetti Protection against Influenza A Virus by Memory CD8 T Cells Requires Reactivation by Bone Marrow-Derived Dendritic Cells J. Immunol., April 1, 2008; 180(7): 4956 - 4964. [Abstract] [Full Text] [PDF]
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 M. A. Schaller, L. E. Kallal, and N. W. Lukacs A Key Role for CC Chemokine Receptor 1 in T-Cell-Mediated Respiratory Inflammation Am. J. Pathol., February 1, 2008; 172(2): 386 - 394. [Abstract] [Full Text] [PDF]
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C.-H. Shen, Q. Ge, O. Talay, H. N. Eisen, A. Garcia-Sastre, and J. Chen Loss of IL-7R and IL-15R Expression Is Associated with Disappearance of Memory T Cells in Respiratory Tract following Influenza Infection J. Immunol., January 1, 2008; 180(1): 171 - 178. [Abstract] [Full Text] [PDF]
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M. V. Richter and D. J. Topham The {alpha}1beta1 Integrin and TNF Receptor II Protect Airway CD8+ Effector T Cells from Apoptosis during Influenza Infection J. Immunol., October 15, 2007; 179(8): 5054 - 5063. [Abstract] [Full Text] [PDF]
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N. K. Polakos, I. Klein, M. V. Richter, D. M. Zaiss, M. Giannandrea, I. N. Crispe, and D. J. Topham Early Intrahepatic Accumulation of CD8+ T Cells Provides a Source of Effectors for Nonhepatic Immune Responses J. Immunol., July 1, 2007; 179(1): 201 - 210. [Abstract] [Full Text] [PDF]
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H. Yoon, K. L. Legge, S.-s. J. Sung, and T. J. Braciale Sequential Activation of CD8+ T Cells in the Draining Lymph Nodes in Response to Pulmonary Virus Infection J. Immunol., July 1, 2007; 179(1): 391 - 399. [Abstract] [Full Text] [PDF]
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 M. M. Anis, S. A. Fulton, S. M. Reba, C. V. Harding, and W. H. Boom Modulation of Naive CD4+ T-Cell Responses to an Airway Antigen during Pulmonary Mycobacterial Infection Infect. Immun., May 1, 2007; 75(5): 2260 - 2268. [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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M. Richter, S. J. Ray, T. J. Chapman, S. J. Austin, J. Rebhahn, T. R. Mosmann, H. Gardner, V. Kotelianski, A. R. deFougerolles, and D. J. Topham Collagen Distribution and Expression of Collagen-Binding {alpha}1beta1 (VLA-1) and {alpha}2beta1 (VLA-2) Integrins on CD4 and CD8 T Cells during Influenza Infection J. Immunol., April 1, 2007; 178(7): 4506 - 4516. [Abstract] [Full Text] [PDF]
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 J. N. Agrewala, D. M. Brown, N. M. Lepak, D. Duso, G. Huston, and S. L. Swain Unique Ability of Activated CD4+ T Cells but Not Rested Effectors to Migrate to Non-lymphoid Sites in the Absence of Inflammation J. Biol. Chem., March 2, 2007; 282(9): 6106 - 6115. [Abstract] [Full Text] [PDF]
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D. O. Co, L. H. Hogan, J. Karman, E. Heninger, S. Vang, K. Wells, Y. Kawaoka, and M. Sandor Interactions between T Cells Responding to Concurrent Mycobacterial and Influenza Infections J. Immunol., December 15, 2006; 177(12): 8456 - 8465. [Abstract] [Full Text] [PDF]
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L. Sabbagh, C. C. Srokowski, G. Pulle, L. M. Snell, B. J. Sedgmen, Y. Liu, E. N. Tsitsikov, and T. H. Watts A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival PNAS, December 5, 2006; 103(49): 18703 - 18708. [Abstract] [Full Text] [PDF]
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M. R. Jenkins, R. Webby, P. C. Doherty, and S. J. Turner Addition of a Prominent Epitope Affects Influenza A Virus-Specific CD8+ T Cell Immunodominance Hierarchies When Antigen Is Limiting. J. Immunol., September 1, 2006; 177(5): 2917 - 2925. [Abstract] [Full Text] [PDF]
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 M. A. de Witte, M. Coccoris, M. C. Wolkers, M. D. van den Boom, E. M. Mesman, J.-Y. Song, M. van der Valk, J. B. A. G. Haanen, and T. N. M. Schumacher Targeting self-antigens through allogeneic TCR gene transfer Blood, August 1, 2006; 108(3): 870 - 877. [Abstract] [Full Text] [PDF]
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H. W. H. G. Kessels, K. Schepers, M. D. van den Boom, D. J. Topham, and T. N. M. Schumacher Generation of T Cell Help through a MHC Class I-Restricted TCR J. Immunol., July 15, 2006; 177(2): 976 - 982. [Abstract] [Full Text] [PDF]
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B. D. Medoff, B. Seed, R. Jackobek, J. Zora, Y. Yang, A. D. Luster, and R. Xavier CARMA1 Is Critical for the Development of Allergic Airway Inflammation in a Murine Model of Asthma. J. Immunol., June 15, 2006; 176(12): 7272 - 7277. [Abstract] [Full Text] [PDF]
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N. K. Polakos, J. C. Cornejo, D. A. Murray, K. O. Wright, J. J. Treanor, I. N. Crispe, D. J. Topham, and R. H. Pierce Kupffer Cell-Dependent Hepatitis Occurs during Influenza Infection Am. J. Pathol., April 1, 2006; 168(4): 1169 - 1178. [Abstract] [Full Text] [PDF]
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B. Koehn, S. Gangappa, J. D. Miller, R. Ahmed, and C. P. Larsen Patients, pathogens, and protective immunity: the relevance of virus-induced alloreactivity in transplantation. J. Immunol., March 1, 2006; 176(5): 2691 - 2696. [Abstract] [Full Text] [PDF]
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 A. L. van Lint, L. Kleinert, S. R. M. Clarke, A. Stock, W. R. Heath, and F. R. Carbone Latent Infection with Herpes Simplex Virus Is Associated with Ongoing CD8+ T-Cell Stimulation by Parenchymal Cells within Sensory Ganglia J. Virol., December 1, 2005; 79(23): 14843 - 14851. [Abstract] [Full Text] [PDF]
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C. W. Lawrence, R. M. Ream, and T. J. Braciale Frequency, Specificity, and Sites of Expansion of CD8+ T Cells during Primary Pulmonary Influenza Virus Infection J. Immunol., May 1, 2005; 174(9): 5332 - 5340. [Abstract] [Full Text] [PDF]
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M. Gough, M. Crittenden, U. Thanarajasingam, L. Sanchez-Perez, J. Thompson, D. Jevremovic, and R. Vile Gene Therapy to Manipulate Effector T Cell Trafficking to Tumors for Immunotherapy J. Immunol., May 1, 2005; 174(9): 5766 - 5773. [Abstract] [Full Text] [PDF]
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 M. Wojtasiak, C. M. Jones, L. C. Sullivan, A. C. Winterhalter, F. R. Carbone, and A. G. Brooks Persistent expression of CD94/NKG2 receptors by virus-specific CD8 T cells is initiated by TCR-mediated signals Int. Immunol., September 1, 2004; 16(9): 1333 - 1341. [Abstract] [Full Text] [PDF]
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A. Boissonnas, C. Combadiere, E. Lavergne, M. Maho, C. Blanc, P. Debre, and B. Combadiere Antigen Distribution Drives Programmed Antitumor CD8 Cell Migration and Determines Its Efficiency J. Immunol., July 1, 2004; 173(1): 222 - 229. [Abstract] [Full Text] [PDF]
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B. Garulli, Y. Kawaoka, and M. R. Castrucci Mucosal and Systemic Immune Responses to a Human Immunodeficiency Virus Type 1 Epitope Induced upon Vaginal Infection with a Recombinant Influenza A Virus J. Virol., January 15, 2004; 78(2): 1020 - 1025. [Abstract] [Full Text] [PDF]
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N. P. Goonetilleke, H. McShane, C. M. Hannan, R. J. Anderson, R. H. Brookes, and A. V. S. Hill Enhanced Immunogenicity and Protective Efficacy Against Mycobacterium tuberculosis of Bacille Calmette-Guerin Vaccine Using Mucosal Administration and Boosting with a Recombinant Modified Vaccinia Virus Ankara J. Immunol., August 1, 2003; 171(3): 1602 - 1609. [Abstract] [Full Text] [PDF]
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 M. Crittenden, M. Gough, J. Chester, T. Kottke, J. Thompson, A. Ruchatz, T. Clackson, F. L. Cosset, H. Chong, R. M. Diaz, et al. Pharmacologically Regulated Production of Targeted Retrovirus from T Cells for Systemic Antitumor Gene Therapy Cancer Res., June 15, 2003; 63(12): 3173 - 3180. [Abstract] [Full Text] [PDF]
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R. L. Reinhardt, D. C. Bullard, C. T. Weaver, and M. K. Jenkins Preferential Accumulation of Antigen-specific Effector CD4 T Cells at an Antigen Injection Site Involves CD62E-dependent Migration but Not Local Proliferation J. Exp. Med., March 17, 2003; 197(6): 751 - 762. [Abstract] [Full Text] [PDF]
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G. M. Winslow, A. D. Roberts, M. A. Blackman, and D. L. Woodland Persistence and Turnover of Antigen-Specific CD4 T Cells During Chronic Tuberculosis Infection in the Mouse J. Immunol., February 15, 2003; 170(4): 2046 - 2052. [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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N. Mojtabavi, G. Dekan, G. Stingl, and M. M. Epstein Long-Lived Th2 Memory in Experimental Allergic Asthma J. Immunol., November 1, 2002; 169(9): 4788 - 4796. [Abstract] [Full Text] [PDF]
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S. E. Hamilton and J. T. Harty Quantitation of CD8+ T Cell Expansion, Memory, and Protective Immunity After Immunization with Peptide-Coated Dendritic Cells J. Immunol., November 1, 2002; 169(9): 4936 - 4944. [Abstract] [Full Text] [PDF]
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