| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
6 mo after virus
inoculation. Since the impairment of immune function seems to be
more pronounced in CD40L-deficient mice than in mice lacking either
CD4+ cells or B cells, these results indicate that CD40L is
pivotal to sustain efficient antiviral immune surveillance, including
CD8+ T cells, and suggest that CD40L is critically involved
in cellular interactions in addition to T-B
cooperation. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CD40L-/- mice (B6,129-Cd40ltm1Imx) were bred from homozygous breeding pairs obtained from The Jackson Laboratory (Bar Harbor, ME). Wild-type (wt) 129/Sv and C57BL/6 mice were purchased from Bomholtgaard (Ry, Denmark). Mice from outside sources were always allowed to acclimatize for at least 1 wk before use; at that time the animals were 7 to 10 wk old. B cell-deficient (µMT/µMT) mice were the progeny of breeding pairs obtained from National Institutes of Health (Bethesda, MD). These mice were bred using heterozygous female and homozygous males, and the offspring was selected by testing sera in a sandwich ELISA for the presence of IgM; heterozygous littermates were used as wt controls. Animals were housed under controlled (specific pathogen-free) conditions that included the testing of sentinels for unwanted infections according to Federation of European Laboratory Animal Science Association standards; no such infections were revealed.
Virus
LCMV of the Armstrong strain (LCMV-ARM, clone 53b) was kindly provided by M. B. A. Oldstone (Scripps Clinic and research Foundation, La Jolla, CA) (20). LCMV of the Traub strain (LCMV-Traub) was produced and stored as described previously (21). Virus titrations were conducted by intracerebral (i.c.) inoculation of 10-fold dilutions into young adult Swiss mice. Titration endpoints were calculated by the Kärber method and expressed as mean LD50. For determination of organ titers, 10% organ homogenates were used as starting material.
Infection
Mice were infected i.v. in a volume of 0.3 ml. Unless otherwise specified, the virus dose was 103 LD50 of LCMV-Traub or 4800 plaque-forming units (PFU) of LCMV-ARM. In a few experiments, mice were infected i.c. with 200 PFU of LCMV-ARM. An i.v. injection of LCMV into immunocompetent mice normally results in transient, immunizing infection, whereas i.c. inoculation induces a fatal, T cell-mediated meningitis from which the animals succumb between days 6 and 8 postinfection (p.i.) (22).
LCMV-induced inflammation
i.c. infection was used to evaluate the ability to raise a CD8+ T cell-mediated inflammatory response. Eight mice per group were infected, and three mice per group were sacrificed on day 6 p.i. for analysis of cell infiltration into cerebrospinal fluid (CSF); the remaining mice were used to establish the mortality pattern.
Cell preparations
Spleens were removed from mice killed by ether anesthetization. Single-cell suspensions were obtained by pressing the organs through a fine steel mesh, and E were lysed by 0.83% NH4Cl treatment (Gey’s solution). CSF cells were obtained from the fourth ventricle of mice that had been ether-anesthetized and exsanguinated; background level in uninfected mice is <100 cells/µl (23).
Proliferation assay
Splenocytes from individual mice were plated at 0.5, 1, and 2 x 105 cells/well in 96-well flat-bottom microtiter plates, and IL-2 responsiveness was evaluated as proliferation for 24 h in the presence of 10 IU/ml of murine rIL-2 (Genzyme, Cambridge, MA) (9). Cultures were marked by adding 1 µCi of [3H]TdR per well (specific activity of 2 Ci/mmol) during the last 6 h of incubation.
Memory CTL restimulation
Splenocytes (50 x 106 cells) from mice primed with LCMV were transferred into histocompatible wt mice, irradiated (700 rad), and infected with 103 LD50 of LCMV on the day before cell transfer. At 4 days posttransplantation, the spleens of recipients were harvested, and LCMV-specific cytotoxicity of splenocytes was assayed (8, 9). This approach was chosen to mimic the conditions of natural stimulation as much as possible.
Cytotoxicity assay
Virus-specific CTL activity was assayed in a standard 51Cr release assay (24) using histocompatible MC57G cells infected with LCMV for 48 h as specific targets; uninfected MC57G cells served as control targets (9). The assay time was 5 h, and the percentage of specific release was calculated as described previously (21).
Serum IFN-
Blood was taken from mice infected i.v. 8 days earlier, and serum was isolated and frozen until analysis. Cytokine levels were quantitated using a sandwich ELISA (Endogen, Cambridge, MA); the limit of detection was 15 pg/ml.
mAbs
The following mAbs were purchased from PharMingen (San Diego,
CA) as rat anti-mouse Ab: FITC-conjugated anti-CD49d (common
4-chain of lymphocyte Peyer’s patch high endothelial
venule adhesion molecule-1 and very late Ag-4) (R1-2, IgG2b);
biotinylated anti-L-selectin (CD62L) (Mel-14, IgG2b); FITC-,
phycoerythrin (PE)-, and Cy-Chrome-conjugated anti-CD8a (53-6.7,
IgG2a); PE-conjugated anti-IFN- (XMG1.2, IgG1); and biotinylated
anti-CD25 (IL-2R) (7D4, IgM).
Flow cytometric analysis
Cells were stained with directly labeled mAb and washed. In the
case of the biotin-conjugated Ab, cells were additionally incubated
with streptavidin-Tri-color (Caltag Laboratories, San Francisco, CA).
Finally, cells were washed and fixed with 1% paraformaldehyde (25).
The presence of intracellular IFN- was revealed as recently
described (26). Briefly, splenocytes were stimulated in vitro for
6 h with anti-CD3
in the presence of monensin, labeled with
mAbs against appropriate cell surface markers, washed, fixed,
permeabilized, and stained with anti-cytokine Ab. Samples were
analyzed using a Becton Dickinson FACSCalibur (Mountain View,
CA), and 1 to 5 x 104 viable mononuclear cells
were gated using a combination of low angle and side scatter to exclude
dead cells and debris. Data analysis was conducted using the Lysis II
program (Becton Dickinson), and results are presented as dot
plots or histograms. Splenocytes from uninfected controls analyzed in
parallel were used to set cutoffs for levels of expression. For
analysis of DNA content, cells were stained with 7-aminoactinomycin D
(7-AAD) (Sigma, St. Louis, MO) as follows (27): after staining for cell
surface markers, cells were washed in FACS medium and then in PBS
containing 0.03% saponin. The 7-AAD (4 µg/ml in PBS-saponin) was
then added, and cells were incubated at room temperature and shielded
from light for 30 min. Thereafter, samples were analyzed.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In recent studies, CD40L-/- mice have been found to
mount a normal primary CTL response to LCMV (17, 19). To ascertain that
this was also the case under our experimental settings, we first
infected groups of CD40L-/- mice and wt B6 mice with a
moderate dose of an LCMV strain that spreads slowly in the host
(LCMV-ARM); no impairment of the primary LCMV-specific CTL response in
CD40L-/- mice was observed using this virus strain (Fig. 1
). Furthermore, the generated CTLs are
of biologic significance, as the generation of LCMV-specific CTLs was
followed by severe meningeal inflammation (day 6 p.i.: 11 x
103 and 9 x 103 cells/µl CSF in GKO and
wt mice, respectively) and mortality (100% mortality, median time to
death 7 days for both strains) in i.c.-infected mice and by a marked
reduction of virus levels in i.v.-infected animals (see Figs. 7 and 9).
We subsequently infected similar groups of mice i.v. with a moderate
dose of LCMV-Traub, which spreads much earlier and more rapidly than
LCMV-ARM. Using the Traub strain, a different outcome was observed
(Fig. 2): CD40L-/- mice
initially raised a CTL response essentially matching that in wt mice,
but low CTL activity was observed on day 10 p.i. in a substantial
proportion (three of eight) of infected GKOs. Notably, this breakdown
of CTL responsiveness correlated with markedly impaired virus control
in vivo.
|
|
|
|
To further evaluate the role of CD40L in the primary T cell
response to infection with LCMV-Traub, we analyzed in greater detail
the expansion and differentiation of the CD8+ cell subset
in infected GKOs. During acute LCMV infection, the number of
CD4+ T cells remains relatively constant, whereas the
CD8+ population greatly expands (27); many of the generated
cells differentiate into an activated phenotype with a high capacity
for the production of IFN- (25, 26, 28). Flow cytometric analysis
(Figs. 3 and
4) of the CD8+ T cell subset
on day 6 p.i. demonstrated that as many cells were actively
cycling in CD40L-/- mice as in wt animals (Fig. 4). All
of these cells had an activated phenotype (4
integrinhigh L-selectinlow) (Fig. 3), and most
expressed high levels of CD25 (IL-2R chain) (Fig. 4). To ascertain
that the expressed IL-2R represented functionally active receptors,
we additionally evaluated the responsiveness of splenocytes to IL-2 in
vitro. Corresponding to the phenotypic analysis, the in vitro
proliferative response to low amounts of IL-2 was essentially identical
in GKO and wt mice (Fig. 5); previous
results have demonstrated that the majority of proliferating cells are
CD8+ cells (9, 28). Higher proportions of activated
CD8+ T cells were found on day 8 p.i., at which time
20 to 40% of these cells stained positively for intracellular IFN-
regardless of the donor genotype (Figs. 3 and 4); levels of IFN- in
serum tended to be slightly lower in infected CD40L-/-
mice, but overlapping values were observed (611 [413 - 1200]
pg/ml vs 1110 [880 - 2924] pg/ml, median (range) of
three mice per group). On day 10 p.i., 40% of the splenocytes
from wt mice were CD8+ cells, most of which had an
activated phenotype (Fig. 3). However, only 25% of splenocytes in
GKOs were CD8+ cells, and fewer had an activated phenotype.
This correlated with a diminished spleen cell number that was less than
half of that in wt mice. Overall, the above results reveal that CD40L
is not essential for the initial activation, expansion, and
differentiation of the CD8+ subset in LCMV-infected mice.
However, activated CD8+ cells disappear from the spleen
prematurely, and CTL responsiveness is rapidly impaired in the absence
of CD40L.
|
|
|
To substantiate that a lack of CD40L results in permanent
impairment of CTL responsiveness and not just a transient decrease in
CTL activity, splenocytes from CD40L-/- mice and wt
animals that had been infected 80 days earlier with LCMV-Traub were
tested for their capacity to generate a secondary CTL response. As seen
in Figure 6, no recall response could be
detected in any of four GKOs tested, whereas high CTL activity could be
generated using splenocytes from all (five of five) wt mice. Since
restimulation of CTL activity only marginally depends upon
CD4+ cells (8), the complete failure to respond must
reflect either a marked deletion of CTLp with specificity for LCMV
or a substantially reduced capacity of these cells to undergo extensive
clonal expansion.
|
To evaluate the relevance of the above findings with regard
to the ability of CD40L-/- mice to exert long-term
control of virus replication in vivo, we followed blood virus titers in
GKO and wt animals infected with LCMV-Traub. As seen in Figure 7
, some CD40L-/- mice could
partially control the infection for a limited period, but invariably
virus control broke down; at 2 mo after virus inoculation, high
titers of virus were found in the circulation of all GKOs tested.
Evaluation of virus levels in organs (Fig. 8) revealed that viremia was associated
with high levels of virus in the internal organs of GKOs, whereas
little or no virus was detected in similarly infected wt mice. Reducing
the inoculum by two logs tended to delay the breakdown of virus control
but did not substantially change the final outcome of infection (Fig. 7). Notably, GKOs were clinically more severely affected by infection
with the lower virus dose, which is in keeping with the possibility
that exhaustion of CTL responsiveness was delayed, thus resulting
in a prolonged immunologic conflict in these permanently infected mice.
|
, GKOs initially control the LCMV-ARM infection well,
and no virus is detected in the circulation for >2 mo. However, virus
eventually does appear in the circulation, and this appearance is
associated with substantial virus replication in the internal organs
(Fig. 9). Thus, CD40L is required for
permanent control of virus replication even in mice infected with a
strain of LCMV that only spreads slowly in the host and has a limited
potential for causing persistent infection (4, 5). Long-term control of virus replication in B cell-deficient mice infected with LCMV-ARM
The fact that long-term control of virus replication is impaired
even in CD40L-/- mice infected with LCMV-ARM was
surprising, as previous analyses have indicated that LCMV-ARM, in
contrast to LCMV-Traub, is well controlled in B cell-deficient mice (8, 29). To investigate whether this difference between
CD40L-/- mice and B cell-deficient mice was real or
merely reflected that capacity to control virus replication previously
had not been evaluated sufficiently late in B cell-deficient mice, we
followed virus titers in B cell-deficient mice infected with the same
dose of LCMV-ARM used above to infect CD40L-/- mice.
Evaluation of virus titers in lungs and liver (Fig. 10) on days 70 to 90 p.i. revealed
little virus in B cell-deficient mice, confirming earlier findings.
However, significant amounts of virus were detected in the lungs after
150 days. Thus, even B cell-deficient mice have some reduced
capacity for long-term control of virus replication following infection
with a slowly spreading LCMV strain; however, antiviral immune
surveillance is clearly less compromised than in CD40L-/-
mice (cf Fig. 9).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
At present, we do not know precisely how CD40L is involved in maintaining efficient antiviral immune surveillance. It is evident from these and previous findings (17, 19) that CD40L is not required for virus-induced activation, expansion, or differentiation of CD8+ cells. Nor is this ligand needed for the targeting of effector T cells to infected areas and the formation of an inflammatory exudate (30), and we have preliminary data indicating that virus-induced macrophage activation is unimpaired in LCMV-infected CD40L-/- mice (31, 32). Furthermore, Oxenius et al. have recently presented data indicating that virus-induced Th cell activation and effector function is unimpaired except for T-B collaboration (18). Therefore, we originally initiated these studies based on the assumption that CD40L was required primarily for the appropriate interaction of CD4+ cells and B cells. However, contrary to our expectations, the results obtained seem to indicate that the antiviral immune response is even more compromised in CD40L-/- mice than in class II-deficient mice (lacking CD4+ cells) or B cell-deficient mice (8, 9). This finding could reflect a difference in the genetic background of the involved KO mice: both class II-deficient and B cell-deficient mice are on a C57BL background, whereas CD40L-/- mice are on a mixed C57BL,129 background, and earlier studies have clearly demonstrated that the non-MHC background may markedly influence T cell responsiveness and the outcome of infection with LCMV (24, 33, 34). However, we included both C57BL/6 and 129 wt controls in many of the experiments and never observed any difference between these strains in their responsiveness toward LCMV. Furthermore, low responsiveness to LCMV has always been found to be recessive (24, 33, 34). However, we cannot rule out the possibility that a minor difference in the capacity to cope with the infection, which is irrelevant in fully immunocompetent wt mice, may become exposed in mice with a defective Cd40L gene. Nevertheless, a more likely explanation is that the defect in CD40L-/- mice is of a more complex nature than merely impaired T-B cooperation. Obviously, lack of CD40L markedly impairs Ab formation (17, 18, 19), and an increased virus load is known to contribute to exhaustion of the CTLp population (4, 24). However, the breakdown of CTL activity in LCMV-Traub-infected mice has already started around day 10 p.i., at which timepoint Abs contribute only marginally to virus elimination (8). Therefore, an increased virus load due to lack of antiviral Abs cannot explain this finding. Furthermore, the high virus titers eventually observed in LCMV-ARM-infected CD40L-/- mice cannot be reproduced in B cell-deficient mice. Marginal impairment of the virus-specific CTL response around day 10 p.i. has been noted previously in CD4+ cell-deficient, class II KO mice (9), but not nearly to the extent observed in CD40L-/- mice; furthermore, class II KO mice control virus replication efficiently for at least 3 to 4 wk before a gradual reappearance of viremia is observed (8). Consequently, our findings raise the possibility that CD40L/CD40 interaction may provide a direct signal promoting the survival of primed CD8+ cells. A precondition would be that CD40L and/or CD40 is expressed on cells belonging to this subset. Supporting this possibility, low levels of CD40L may be found on some activated CD8+ T cells (35, 36, 37). Using flow cytometry, we have not, however, been able to demonstrate expression of CD40L on LCMV-activated CD8+ cells, but this does not exclude the possibility that this molecule is expressed on the minority of virus-specific cells that escape activation-induced apoptosis and become the long-term precursors for the continued CTL surveillance in LCMV-infected mice. Also CD40 has been found on CD8+ cells (38), and we are presently investigating this possibility in LCMV-infected mice. However, even if CD40L/CD40 should be involved in preventing apoptosis of activated CD8+ cells, this is probably not the sole mechanism underlying the complete collapse of immune surveillance in mice lacking CD40L. Clearly Ab production is impaired (17, 18, 19), and this molecule may also be required for the maintenance of CD4+ T cell memory (30). Additionally, CD40L has been found to exert a direct antiviral activity against certain viruses (39). Indeed, the severity of the impairment and the speed with which it proceeds even in mice infected with a low dose of virus suggest that this molecule serves several critical functions in the complex network of cellular interactions that provide the basis for solid immunity.
In conclusion, our results clearly demonstrate that CD40L is a crucial molecule for the maintenance of effective long-term immune surveillance in virus-infected mice. Given that the understanding of the mechanisms underlying optimal memory function is critical to the designing of effective vaccines and probably also to meaningful manipulations of the immune system in chronically infected individuals (e.g., HIV-infected patients), our studies clearly prompt further analysis of the cellular and molecular interactions that are critical in this respect.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Allan Randrup Thomsen, Institut of Medical Microbiology and Immunology, the Panum Institute, 3C Blegdamsvej, Copenhagen, DK-2200 N, Denmark. E-mail address:
3 Current address: Department of Immunology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105.
4 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; CTLp, CTL precursor; KO, knockout; CD40L, CD40 ligand; CD40L-/-, CD40L KO; wt, wild-type; ARM, Armstrong strain; i.c., intracerebral; PFU, plaque-forming units; p.i., postinfection; CSF, cerebrospinal fluid; PE, phycoerythrin; 7-AAD, 7-aminoactinomycin D; GKO, gene KO;
Received for publication April 10, 1998. Accepted for publication June 25, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4 integrin expression. Int. Immunol. 8:707.This article has been cited by other articles:
|
|
 |
|
  L. Rapetti, S. Meunier, C. Pontoux, and C. Tanchot CD4 Help Regulates Expression of Crucial Genes Involved in CD8 T Cell Memory and Sensitivity to Regulatory Elements J. Immunol., July 1, 2008; 181(1): 299 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. H. Hernandez, L. Shen, and K. L. Rock CD40 on APCs Is Needed for Optimal Programming, Maintenance, and Recall of CD8+ T Cell Memory Even in the Absence of CD4+ T Cell Help J. Immunol., April 1, 2008; 180(7): 4382 - 4390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fuse, S. Bellfy, H. Yagita, and E. J. Usherwood CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand J. Immunol., April 15, 2007; 178(8): 5227 - 5236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bartholdy, S. O. Kauffmann, J. P. Christensen, and A. R. Thomsen Agonistic Anti-CD40 Antibody Profoundly Suppresses the Immune Response to Infection with Lymphocytic Choriomeningitis Virus J. Immunol., February 1, 2007; 178(3): 1662 - 1670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W Yao, L Hertel, and L.M Wahl Dynamics of recurrent viral infection Proc R Soc B, September 7, 2006; 273(1598): 2193 - 2199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fang and L. J. Sigal Antibodies and CD8+ T Cells Are Complementary and Essential for Natural Resistance to a Highly Lethal Cytopathic Virus J. Immunol., November 15, 2005; 175(10): 6829 - 6836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Thimme, V. Appay, M. Koschella, E. Panther, E. Roth, A. D. Hislop, A. B. Rickinson, S. L. Rowland-Jones, H. E. Blum, and H. Pircher Increased Expression of the NK Cell Receptor KLRG1 by Virus-Specific CD8 T Cells during Persistent Antigen Stimulation J. Virol., September 15, 2005; 79(18): 12112 - 12116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Wodarz and A. R. Thomsen Effect of the CTL proliferation program on virus dynamics Int. Immunol., September 1, 2005; 17(9): 1269 - 1276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yu, C. Kovacs, F. Y. Yue, and M. A. Ostrowski The Role of the p38 Mitogen-Activated Protein Kinase, Extracellular Signal-Regulated Kinase, and Phosphoinositide-3-OH Kinase Signal Transduction Pathways in CD40 Ligand-Induced Dendritic Cell Activation and Expansion of Virus-Specific CD8+ T Cell Memory Responses J. Immunol., May 15, 2004; 172(10): 6047 - 6056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Sun and M. J. Bevan Cutting Edge: Long-Lived CD8 Memory and Protective Immunity in the Absence of CD40 Expression on CD8 T Cells J. Immunol., March 15, 2004; 172(6): 3385 - 3389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Christensen, S. O. Kauffmann, and A. R. Thomsen Deficient CD4+ T Cell Priming and Regression of CD8+ T Cell Functionality in Virus-Infected Mice Lacking a Normal B Cell Compartment J. Immunol., November 1, 2003; 171(9): 4733 - 4741. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Howard, K. L. Neville, L. M. Haynes, M. C. Dal Canto, and S. D. Miller CD154 Blockade Results in Transient Reduction in Theiler's Murine Encephalomyelitis Virus-Induced Demyelinating Disease J. Virol., February 1, 2003; 77(3): 2247 - 2250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tsunetsugu-Yokota, H. Tamura, M. Tachibana, K. Ogata, M. Honda, and T. Takemori Selective expansion of perforin-positive CD8+ T cells by immature dendritic cells infected with live Bacillus Calmette-Guerin mycobacteria J. Leukoc. Biol., July 1, 2002; 72(1): 115 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Christensen, J. P. Christensen, N. N. Kristensen, N. J. V. Hansen, A. Stryhn, and A. R. Thomsen Role of CD28 co-stimulation in generation and maintenance of virus-specific T cells Int. Immunol., July 1, 2002; 14(7): 701 - 711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. V. Serbina, V. Lazarevic, and J. L. Flynn CD4+ T Cells Are Required for the Development of Cytotoxic CD8+ T Cells During Mycobacterium tuberculosis Infection J. Immunol., December 15, 2001; 167(12): 6991 - 7000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bartholdy, J. P. Christensen, D. Wodarz, and A. R. Thomsen Persistent Virus Infection despite Chronic Cytotoxic T-Lymphocyte Activation in Gamma Interferon-Deficient Mice Infected with Lymphocytic Choriomeningitis Virus J. Virol., November 15, 2000; 74(22): 10304 - 10311. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Kopf, A. J. Coyle, N. Schmitz, M. Barner, A. Oxenius, A. Gallimore, J.-C. Gutierrez-Ramos, and M. F. Bachmann Inducible Costimulator Protein (Icos) Controls T Helper Cell Subset Polarization after Virus and Parasite Infection J. Exp. Med., July 3, 2000; 192(1): 53 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wodarz, R. M. May, and M. A. Nowak The role of antigen-independent persistence of memory cytotoxic T lymphocytes Int. Immunol., April 1, 2000; 12(4): 467 - 477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Afford and S Randhawa Demystified ...: Apoptosis Mol. Pathol., April 1, 2000; 53(2): 55 - 63. [Abstract] [Full Text]
|
|
|
|
|
|
S. Skov, M. Bonyhadi, N. Odum, and J. A. Ledbetter IL-2 and IL-15 Regulate CD154 Expression on Activated CD4 T Cells J. Immunol., April 1, 2000; 164(7): 3500 - 3505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. O. Andreasen, J. E. Christensen, O. Marker, and A. R. Thomsen Role of CD40 Ligand and CD28 in Induction and Maintenance of Antiviral CD8+ Effector T Cell Responses J. Immunol., April 1, 2000; 164(7): 3689 - 3697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Lifson, J. L. Rossio, R. Arnaout, L. Li, T. L. Parks, D. K. Schneider, R. F. Kiser, V. J. Coalter, G. Walsh, R. J. Imming, et al. Containment of Simian Immunodeficiency Virus Infection: Cellular Immune Responses and Protection from Rechallenge following Transient Postinoculation Antiretroviral Treatment J. Virol., March 15, 2000; 74(6): 2584 - 2593. [Abstract] [Full Text]
|
|
|
|
|
|
K. Mozdzanowska, K. Maiese, and W. Gerhard Th Cell-Deficient Mice Control Influenza Virus Infection More Effectively Than Th- and B Cell-Deficient Mice: Evidence for a Th-Independent Contribution by B Cells to Virus Clearance J. Immunol., March 1, 2000; 164(5): 2635 - 2643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-i. Hwang, M. H. Nahm, D. E. Briles, D. Thomas, and J. M. Purkerson Acquired, but Not Innate, Immune Responses to Streptococcus pneumoniae Are Compromised by Neutralization of CD40L Infect. Immun., February 1, 2000; 68(2): 511 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Wodarz and M. A. Nowak Specific therapy regimes could lead to long-term immunological control of HIV PNAS, December 7, 1999; 96(25): 14464 - 14469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nansen, T. Jensen, J. P. Christensen, S. O. Andreasen, C. Ropke, O. Marker, and A. R. Thomsen Compromised Virus Control and Augmented Perforin-Mediated Immunopathology in IFN-{gamma}-Deficient Mice Infected with Lymphocytic Choriomeningitis Virus J. Immunol., December 1, 1999; 163(11): 6114 - 6122. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
