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Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia; and
Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
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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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HSV-1 does not appear to replicate within the lymph nodes draining the site of cutaneous infection (10, 11). Early investigators found only low virus-specific precursor cell frequencies within these sites with little cytotoxic activity, suggesting that full effector arming required some form of migration of primed, but functionally immature, CTL (12, 13). This notion was reinforced by their finding that in vitro culture of lymph node cells in the absence of Ag resulted in the appearance of strong levels of specific cytotoxicity. However, armed virus-specific CD8+ T cells can be found in lymph nodes that drain the site of cutaneous HSV-1 infection (10). Given these apparently contradicting observations, we were interested in determining the point at which these T cells were activated and armed before their migration to other sites. Using a combination of tetrameric class I-peptide complexes, in vivo cytotoxicity assays and fluorescently labeled TCR-transgenic T cell proliferation to address these issues, we have found that HSV-1-specific T cells are rapidly activated and armed within draining lymph nodes shortly after localized infection. Although they also proliferate within this location, they are found to undergo the bulk of their expansion outside the lymph node compartment.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice and the glycoprotein B (gB) T-I-transgenic mice were obtained from the Department of Microbiology and Immunology, University of Melbourne Animal House and kept in specific pathogen-free conditions. The gBT-I mice express a transgenic TCR from a CTL clone that recognizes the HSV-1 gB498–505 determinant in complex with H-2Kb. The derivation of these animals will be described in more detail elsewhere (14). Six- to 8-wk-old mice were infected in the hind foot with 5 x 104 PFU of HSV-1 KOS strain, and the spleen and popliteal and axillary lymph node cells were examined at the times described.
mAbs and Kb-gB tetramer
The following mAbs were purchased from BD PharMingen (San Diego,
CA): anti-CD8
-APC (53-6.7), anti-CD25-FITC (7D4),
anti-CD44-FITC (IM7), and anti-CD62L-FITC (MEL-14). The
Kb-gB tetramers containing the immunodominant gB
peptide, gB498–505, were prepared essentially using the
protocol by Altman et al. (15) as described elsewhere
(10).
Flow cytometric analysis
Briefly, 1 x 106 cells were stained with an excess of Abs on ice for 20 min. Cells were then washed with PBS containing 1% BSA. Finally, the cells were stained with the Kb-gB tetramers for 20 min at 37°C and washed as previously described (10). Propidium iodide was added before analysis and used to exclude dead cells. Data were collected on 1 x 105 live cells on a FACScan flow cytometer using CellQuest software (BD Biosciences, San Jose, CA)
In vivo CTL assay
To prepare target cells to detect in vivo cytotoxic activity, erythrocytes were removed from naive C57BL/6 spleen and lymph node cell suspensions by osmotic lysis. The cells were then washed and split into two populations. One population was pulsed with 10-6 M gB peptide, incubated at 37°C for 45 min, and labeled with a high concentration of CFSE (2.5 µM) (CFSEhigh cells). The second control target population was left without peptide and was labeled with a low concentration of CFSE (0.25 µM) (CFSElow cells). For i.v. injection, an equal number of cells from each population was mixed together, such that each mouse received a total of 20 x 106 cells in 150 µl of PBS. Cells were injected into mice that had previously been infected with HSV-1 a number of days earlier as described and 4 h later sacrificed for their lymph nodes and spleens. Cell suspensions were analyzed by flow cytometry, and each population was detected by their differential CFSE fluorescence intensities. Up to 1 x 104 CFSE-positive cells were collected for analysis. To calculate specific lysis, the following formula was used: ratio = (percentage CFSElow/percentage CFSEhigh). Percentage specific lysis = [1 - (ratio unprimed/ratio primed) x 100].
In vivo proliferation assay
Naive gBT-I lymph nodes were removed and the resulting
single-cell suspension was incubated with CFSE (2.5 µM) at 37°C for
10 min. The cells were then washed and resuspended in HBSS so that each
mouse received 2 x 106 cells i.v. At
various times after the transfer of the CFSE-labeled gBT-I cells, mice
were injected in the hind foot with 5 x 104
PFU of HSV-1 as described previously. After a maximum of 96 h
since the first infection, all mice were sacrificed and their popliteal
lymph nodes and spleens were taken and single-cell suspensions were
made. Cells were stained with anti-CD8-APC Ab as described and
the resulting suspensions were run on a FACScan flow cytometer. Data
were collected on between 2 x 103 and
1 x 104 CFSE-positive CD8-positive cells
and analyzed using CellQuest software (BD Biosciences). As the cells
divide the CFSE intensity is halved, giving peaks of different
intensities that correlate with the number of cell divisions.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Footpad infection with HSV-1 results in a localized infection that does not spread to the draining popliteal lymph node (10). We wanted to compare the kinetics of CTL accumulation and activation within the draining lymph nodes with that observed in the remainder of the lymphoid compartment. The CD8+ T cell response to HSV-1 in C57BL/6 mice is largely directed to the immunodominant determinant from the gB, gB498–505 (16, 17). To identify the gB-specific CD8+ T cells responding to HSV-1, MHC class I tetrameric complexes were constructed, incorporating the gB epitope. C57BL/6 mice were immunized with HSV-1 in the hind feet, the popliteal lymph nodes and spleen were removed, and the cells were stained with anti-CD8 Ab and tetramer over a period of 9 days.
Given the localized nature of the infection, we were surprised that
tetramer-positive cells appeared almost simultaneously in both lymph
node and spleen at around day 5 after infection (Fig. 1
). The frequency of gB-specific T cells
rapidly increased from near background levels at day 4 after infection
to 
5% of both spleen and lymph node CD8+ T
cells by day 5 after infection. Although this time represented the peak
of gB-specific T cells found in the lymph node, the levels continued to
increase within the spleen for another 2 days, reaching 13% of all
CD8+ T cells in this site 7–8 days after
infection. Interestingly, the proportion of gB-specific T cells
declined rapidly within the draining lymph nodes, especially compared
with the spleen, dropping to levels of <0.7% of
CD8+ T cells in that site by day 9 after
infection (Fig. 1). Moreover, gB-specific T cells appeared to be
selectively excluded from non-draining lymph nodes throughout the
course of the response (Fig. 1). These data indicate that having left
the draining popliteal lymph nodes, HSV-1-specific T cells do not
readily re-enter peripheral lymph node tissues, at least within the
first 9 days after infection. Finally, while both splenic and lymph
node T cells have down-regulated CD62L expression and express stable
activation markers like CD44, there is differential expression of CD25
(Fig. 2). Only lymph node gB-specific T
cells express this molecule at appreciable levels. This is consistent
with a scenario where only T cells within the draining popliteal lymph
nodes are undergoing antigenic stimulation while those found within the
spleen represent a postmigratory population.
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Originally we expected a much clearer lag in the initial appearance of tetramer-positive cells within the splenic compartment given that the immune response was expected to start within the draining popliteal lymph nodes. It could be argued that some virus-specific T cells may have already left the priming site and expanded within the spleen by the time tetramer-detectable levels were reached, and this might explain the near simultaneous appearance of tetramer-staining CTL. In an attempt to detect the presence of gB-specific T cells within draining nodes before day 5 after infection and before significant effector migration, we directly determined whether HSV-1-specific cytotoxic effector cells were present using an in vivo cytotoxicity assay (18, 19). This method involves the in vivo selective lysis of fluorescently labeled gB peptide-pulsed splenocytes. We chose a fairly rapid 4-h assay period with the reasoning that it would minimize migration of dying target cells from other sites and more likely measure the presence of CTL effector cells in the organs under investigation.
Fig. 3A shows the extent of
lysis of peptide-pulsed splenocytes at the peak of the response in the
popliteal lymph nodes (day 5) 4 h after they had been transferred
into the infected host. There was near complete loss of the
peptide-pulsed peak, whereas the peak corresponding to targets labeled
only with CFSE is readily detected. This selective loss of
peptide-pulsed target cells translates to a specific lysis of >95%.
We evaluated the development of this response over the course of
infection (Fig. 3B). Low but reproducible levels of killing
were seen within the draining popliteal lymph nodes as early as day 2
after infection (15%). This killing is T cell mediated since no
detectable lysis could be observed in RAG knockout mice (data not
shown). Lysis of peptide-pulsed targets was first seen in the spleen at
day 4 after infection, with an average specific lysis of 12% (Fig. 3B). From these early points and also the half-maximal
values, there was an approximate 48-h lag in appearance of killing
between lymph node and spleen. Moreover, the in vivo cytotoxicity assay
revealed the presence of specific effector cells 2–3 days before they
were detectable using Kb-gB tetramer complexes (Fig. 1
).
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The flow cytometry data showed that although maximal gB-specific
cell numbers were found in the draining lymph nodes at day 5 after
infection, these T cells were first stimulated at least 3 days earlier
since low, but consistent, cytotoxicity was measurable 2 days after
infection. To confirm that gB-specific T cells were activated so soon
after infection, we made use of gB-specific T cells from the
TCR-transgenic mouse, gBT-I, which encodes a transgenic receptor for
this determinant. When labeled with the dye CFSE, these cells halve
their fluorescence intensity on every cell division
(20, 21, 22). Fig. 4 shows that
by 48 h after infection, gB-specific transgenic T cells found
within popliteal lymph nodes have already undergone between one and
four rounds of cell division. Interestingly, examination of the spleen
showed that gB-specific T cells remained largely undivided at this
time, highlighting that there was little Ag-specific stimulation in
this compartment, at least within the first few days after infection.
Proliferating T cells were first seen in the spleen no earlier than day
3 after infection when they appeared in small numbers as a broad peak
with low fluorescence intensity relative to undivided cells. Unlike the
lymph node where early cell division was clearly evident, the bulk of
splenic T cells had already undergone considerable cell division at
first detection. More dramatically, there was a massive influx of
gB-specific transgenic T cells that had undergone multiple rounds of
proliferation at 4 days after infection. Significantly, the division
profile in both spleen and lymph node appears identical at this time
point. This suggests that the splenic gB-specific T cells were
activated at approximately the same time as those found in the
popliteal lymph node, that they were most likely derived from the
latter population, and that they were released as a burst at around day
4 after infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Given the early appearance of specific lysis as well as cell
proliferation in draining lymph nodes, it was at first surprising that
we could only detect tetramer-staining T cells from day 5 after
infection and then with similar proportions in both lymph nodes and
spleen. However, from the CFSE proliferation data we calculate that
gB-specific cells divide every 5–6 h (data not shown). This means that
the 5% of tetramer-staining CD8+ T cells in the
lymph node (Fig. 1) at this time could have been expanded from levels
as low as 0.2% of the CD8+ population over the
prior 24-h period. The simultaneous appearance of tetramer-positive
cells in lymph node and spleen could also signify a sudden release of
specific CTL from the responding node rather than a steady trickle of
cells from the beginning of the response. It is known that specific
lymphocytes suddenly appear in efferent lymphatics draining responding
lymph nodes after a refractile period during which these cells are
thought to be undergoing Ag-specific stimulation (24, 25).
Therefore, CTL might not leave the lymph node until the increasing CTL
frequency exceeds some threshold such as the Ag presentation capacity
of this compartment. Consistent with this, proliferating gB-specific
transgenic T cells did not appear in the spleen in appreciable numbers
until a sudden burst around day 4 after infection. This burst coincided
with the first time that cytotoxicity was seen in this compartment and
before tetramer levels appeared in either site. There was little
difference in the proliferation profile of CFSE-labeled gBT-I cells in
lymph node or spleen, suggesting that both populations were subjected
to the same stimulation event, most likely within the former location
relatively shortly after infection, and that cell division per se did
not determine release from this site.
A progressive migration of activated T cells from the draining lymph nodes to the spleen is consistent with the finding that CD25 was expressed by the lymph node T cells but already down-regulated by the time those cells had reached the spleen. Interestingly, CD25 up-regulation has been associated with the acquisition of cytotoxic effector function (26, 27). We do not dispute this assertion, but the fact that gB-specific cytotoxicity was found in the spleen in the absence of CD25 on specific T cells suggests that its continued expression is not required for maintenance of effector function. Moreover, CD25+ lymphoid cells are also known to contain already stimulated HSV-1-specific CTL precursors that are capable of dividing in the absence of further encounter with Ag (26). Recent studies have shown that T cells only require a very brief exposure to Ag to fully progress along their maturation pathway in the total absence of further stimulation (28, 29). Thus, once the activation program has been set in motion in the draining lymph nodes, CD8+ T cells can continue to proliferate after they leave this site in the absence of any further stimulation. Consistent with this extra-lymph node expansion, if one takes into account the cellularity in each organ then the maximum value of 5% at the day 5 peak translates to around 5 x 104 gB-specific T cells per lymph node while levels of nearly 2.5 x 106 cells were found in the spleen at the peak time of day 7 after infection. An analogous splenic expansion of CTL has been seen in another example of a localized infection involving pulmonary influenza infection (30).
Finally, gB-specific CTL did not re-enter lymph nodes once they were activated and had migrated to the spleen, since they were not seen to accumulate in the nonresponding lymph nodes. This is consistent with the down-regulation of CD62L that is required for naive lymphocyte movement through the high endothelial venules (1, 2). It further reinforces the notion that those gB-specific T cells found early in the draining popliteal lymph nodes were there because they were either in the process of being stimulated or had only recently encountered Ag and had yet to leave this site. Once they emerged, they then appeared within the spleen most likely enroute to sites of localized infection. Overall, this study shows that the activation, arming, and expansion of HSV-1-specific CTL occurs very quickly after infection, followed by the rapid dissemination of the resultant migratory effector pool which is responsible for limiting the extent of local viral replication.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Francis R. Carbone, Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, 3010, Australia. E-mail address: fcarbone{at}unimelb.edu.au and Dr. William R. Heath, Immunology Division, Walter and Eliza Hall Institute of Medical Research Parkville, Victoria, 3050, Australia. E-mail address: heath{at}wehi.edu.au
3 Abbreviations used in this paper: HSV-1, herpes simplex virus 1; gB, glycoprotein B.
Received for publication August 13, 2001. Accepted for publication November 16, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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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J. Publicover, E. Ramsburg, and J. K. Rose A Single-Cycle Vaccine Vector Based on Vesicular Stomatitis Virus Can Induce Immune Responses Comparable to Those Generated by a Replication-Competent Vector J. Virol., November 1, 2005; 79(21): 13231 - 13238. [Abstract] [Full Text] [PDF]
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H. Nishimura, T. Yajima, H. Muta, E. R. Podack, K. Tani, and Y. Yoshikai A Novel Role of CD30/CD30 Ligand Signaling in the Generation of Long-Lived Memory CD8+ T Cells J. Immunol., October 1, 2005; 175(7): 4627 - 4634. [Abstract] [Full Text] [PDF]
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A. Ploss, A. Tran, E. Menet, I. Leiner, and E. G. Pamer Cross-Recognition of N-Formylmethionine Peptides Is a General Characteristic of H2-M3-Restricted CD8+ T Cells Infect. Immun., July 1, 2005; 73(7): 4423 - 4426. [Abstract] [Full Text] [PDF]
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P. Kleindienst, C. Wiethe, M. B. Lutz, and T. Brocker Simultaneous Induction of CD4 T Cell Tolerance and CD8 T Cell Immunity by Semimature Dendritic Cells J. Immunol., April 1, 2005; 174(7): 3941 - 3947. [Abstract] [Full Text] [PDF]
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S. M. M. Haeryfar, R. J. DiPaolo, D. C. Tscharke, J. R. Bennink, and J. W. Yewdell Regulatory T Cells Suppress CD8+ T Cell Responses Induced by Direct Priming and Cross-Priming and Moderate Immunodominance Disparities J. Immunol., March 15, 2005; 174(6): 3344 - 3351. [Abstract] [Full Text] [PDF]
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A. Lang and J. Nikolich-Zugich Development and Migration of Protective CD8+ T Cells into the Nervous System following Ocular Herpes Simplex Virus-1 Infection J. Immunol., March 1, 2005; 174(5): 2919 - 2925. [Abstract] [Full Text] [PDF]
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Y. Hoshino, S. K. Dalai, K. Wang, L. Pesnicak, T. Y. Lau, D. M. Knipe, J. I. Cohen, and S. E. Straus Comparative Efficacy and Immunogenicity of Replication-Defective, Recombinant Glycoprotein, and DNA Vaccines for Herpes Simplex Virus 2 Infections in Mice and Guinea Pigs J. Virol., January 1, 2005; 79(1): 410 - 418. [Abstract] [Full Text] [PDF]
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A. C. Kirby, M. Sundquist, and M. J. Wick In Vivo Compartmentalization of Functionally Distinct, Rapidly Responsive Antigen-Specific T-Cell Populations in DNA-Immunized or Salmonella enterica Serovar Typhimurium-Infected Mice Infect. Immun., November 1, 2004; 72(11): 6390 - 6400. [Abstract] [Full Text] [PDF]
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D. C. Jackson, Y. F. Lau, T. Le, A. Suhrbier, G. Deliyannis, C. Cheers, C. Smith, W. Zeng, and L. E. Brown A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses PNAS, October 26, 2004; 101(43): 15440 - 15445. [Abstract] [Full Text] [PDF]
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J. Publicover, E. Ramsburg, and J. K. Rose Characterization of Nonpathogenic, Live, Viral Vaccine Vectors Inducing Potent Cellular Immune Responses J. Virol., September 1, 2004; 78(17): 9317 - 9324. [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. T. Stock, S. N. Mueller, A. L. van Lint, W. R. Heath, and F. R. Carbone Cutting Edge: Prolonged Antigen Presentation after Herpes Simplex Virus-1 Skin Infection J. Immunol., August 15, 2004; 173(4): 2241 - 2244. [Abstract] [Full Text] [PDF]
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P. Wong, M. Lara-Tejero, A. Ploss, I. Leiner, and E. G. Pamer Rapid Development of T Cell Memory J. Immunol., June 15, 2004; 172(12): 7239 - 7245. [Abstract] [Full Text] [PDF]
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D. M. Brainard, W. G. Tharp, E. Granado, N. Miller, A. K. Trocha, X.-H. Ren, B. Conrad, E. F. Terwilliger, R. Wyatt, B. D. Walker, et al. Migration of Antigen-Specific T Cells Away from CXCR4-Binding Human Immunodeficiency Virus Type 1 gp120 J. Virol., May 15, 2004; 78(10): 5184 - 5193. [Abstract] [Full Text] [PDF]
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N. Garbi, B. Arnold, S. Gordon, G. J. Hammerling, and R. Ganss CpG Motifs as Proinflammatory Factors Render Autochthonous Tumors Permissive for Infiltration and Destruction J. Immunol., May 15, 2004; 172(10): 5861 - 5869. [Abstract] [Full Text] [PDF]
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H. Lauterbach, K. M. Kerksiek, D. H. Busch, E. Berto, A. Bozac, P. Mavromara, R. Manservigi, A. L. Epstein, P. Marconi, and T. Brocker Protection from Bacterial Infection by a Single Vaccination with Replication-Deficient Mutant Herpes Simplex Virus Type 1 J. Virol., April 15, 2004; 78(8): 4020 - 4028. [Abstract] [Full Text] [PDF]
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 M.-E. Blais, G. Gerard, M. M. Martinic, G. Roy-Proulx, R. M. Zinkernagel, and C. Perreault Do thymically and strictly extrathymically developing T cells generate similar immune responses? Blood, April 15, 2004; 103(8): 3102 - 3110. [Abstract] [Full Text] [PDF]
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M. J. Fuller, A. Khanolkar, A. E. Tebo, and A. J. Zajac Maintenance, Loss, and Resurgence of T Cell Responses During Acute, Protracted, and Chronic Viral Infections J. Immunol., April 1, 2004; 172(7): 4204 - 4214. [Abstract] [Full Text] [PDF]
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C. L. Ahonen, C. L. Doxsee, S. M. McGurran, T. R. Riter, W. F. Wade, R. J. Barth, J. P. Vasilakos, R. J. Noelle, and R. M. Kedl Combined TLR and CD40 Triggering Induces Potent CD8+ T Cell Expansion with Variable Dependence on Type I IFN J. Exp. Med., March 15, 2004; 199(6): 775 - 784. [Abstract] [Full Text] [PDF]
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A. Khanolkar, M. J. Fuller, and A. J. Zajac CD4 T Cell-Dependent CD8 T Cell Maturation J. Immunol., March 1, 2004; 172(5): 2834 - 2844. [Abstract] [Full Text] [PDF]
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C. Lane, J. Leitch, X. Tan, J. Hadjati, J. L. Bramson, and Y. Wan Vaccination-Induced Autoimmune Vitiligo Is a Consequence of Secondary Trauma to the Skin Cancer Res., February 15, 2004; 64(4): 1509 - 1514. [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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C. He, S. Schenk, Q. Zhang, A. Valujskikh, J. Bayer, R. L. Fairchild, and P. S. Heeger Effects of T Cell Frequency and Graft Size on Transplant Outcome in Mice J. Immunol., January 1, 2004; 172(1): 240 - 247. [Abstract] [Full Text] [PDF]
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A. van Lint, M. Ayers, A. G. Brooks, R. M. Coles, W. R. Heath, and F. R. Carbone Herpes Simplex Virus-Specific CD8+ T Cells Can Clear Established Lytic Infections from Skin and Nerves and Can Partially Limit the Early Spread of Virus after Cutaneous Inoculation J. Immunol., January 1, 2004; 172(1): 392 - 397. [Abstract] [Full Text] [PDF]
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T. C. Yang, K. Dayball, Y. H. Wan, and J. Bramson Detailed Analysis of the CD8+ T-Cell Response following Adenovirus Vaccination J. Virol., December 15, 2003; 77(24): 13407 - 13411. [Abstract] [Full Text] [PDF]
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K. Benlhassan-Chahour, C. Penit, V. Dioszeghy, F. Vasseur, G. Janvier, Y. Riviere, N. Dereuddre-Bosquet, D. Dormont, R. Le Grand, and B. Vaslin Kinetics of Lymphocyte Proliferation during Primary Immune Response in Macaques Infected with Pathogenic Simian Immunodeficiency Virus SIVmac251: Preliminary Report of the Effect of Early Antiviral Therapy J. Virol., December 1, 2003; 77(23): 12479 - 12493. [Abstract] [Full Text] [PDF]
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A. Ploss, G. Lauvau, B. Contos, K. M. Kerksiek, P. D. Guirnalda, I. Leiner, L. L. Lenz, M. J. Bevan, and E. G. Pamer Promiscuity of MHC Class Ib-Restricted T Cell Responses J. Immunol., December 1, 2003; 171(11): 5948 - 5955. [Abstract] [Full Text] [PDF]
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M. Pellegrini, G. Belz, P. Bouillet, and A. Strasser Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim PNAS, November 25, 2003; 100(24): 14175 - 14180. [Abstract] [Full Text] [PDF]
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J. M. Curtsinger, C. M. Johnson, and M. F. Mescher CD8 T Cell Clonal Expansion and Development of Effector Function Require Prolonged Exposure to Antigen, Costimulation, and Signal 3 Cytokine J. Immunol., November 15, 2003; 171(10): 5165 - 5171. [Abstract] [Full Text] [PDF]
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G. D. Luker, J. L. Prior, J. Song, C. M. Pica, and D. A. Leib Bioluminescence Imaging Reveals Systemic Dissemination of Herpes Simplex Virus Type 1 in the Absence of Interferon Receptors J. Virol., October 15, 2003; 77(20): 11082 - 11093. [Abstract] [Full Text] [PDF]
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K. A. N. Messingham, V. P. Badovinac, and J. T. Harty Deficient Anti-Listerial Immunity in the Absence of Perforin Can Be Restored by Increasing Memory CD8+ T Cell Numbers J. Immunol., October 15, 2003; 171(8): 4254 - 4262. [Abstract] [Full Text] [PDF]
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 R. S. Allan, C. M. Smith, G. T. Belz, A. L. van Lint, L. M. Wakim, W. R. Heath, and F. R. Carbone Epidermal Viral Immunity Induced by CD8{alpha}+ Dendritic Cells But Not by Langerhans Cells Science, September 26, 2003; 301(5641): 1925 - 1928. [Abstract] [Full Text] [PDF]
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S. Suvas, U. Kumaraguru, C. D. Pack, S. Lee, and B. T. Rouse CD4+CD25+ T Cells Regulate Virus-specific Primary and Memory CD8+ T Cell Responses J. Exp. Med., September 15, 2003; 198(6): 889 - 901. [Abstract] [Full Text] [PDF]
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C. M. Smith, G. T. Belz, N. S. Wilson, J. A. Villadangos, K. Shortman, F. R. Carbone, and W. R. Heath Cutting Edge: Conventional CD8{alpha}+ Dendritic Cells Are Preferentially Involved in CTL Priming After Footpad Infection with Herpes Simplex Virus-1 J. Immunol., May 1, 2003; 170(9): 4437 - 4440. [Abstract] [Full Text] [PDF]
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N. W. Marten, S. A. Stohlman, J. Zhou, and C. C. Bergmann Kinetics of Virus-Specific CD8+-T-Cell Expansion and Trafficking following Central Nervous System Infection J. Virol., February 15, 2003; 77(4): 2775 - 2778. [Abstract] [Full Text] [PDF]
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P. M. Gray, G. D. Parks, and M. A. Alexander-Miller High Avidity CD8+ T Cells Are the Initial Population Elicited Following Viral Infection of the Respiratory Tract J. Immunol., January 1, 2003; 170(1): 174 - 181. [Abstract] [Full Text] [PDF]
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S. N. Mueller, C. M. Jones, C. M. Smith, W. R. Heath, and F. R. Carbone Rapid Cytotoxic T Lymphocyte Activation Occurs in the Draining Lymph Nodes After Cutaneous Herpes Simplex Virus Infection as a Result of Early Antigen Presentation and Not the Presence of Virus J. Exp. Med., March 4, 2002; 195(5): 651 - 656. [Abstract] [Full Text] [PDF]
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