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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1362-1369
IMMUNOBIOLOGY
From the Institute of Medical Microbiology and Immunology,
University of Copenhagen, Denmark.
Using mice deficient of E-selectin and E/P-selectin, we have studied
the requirement for endothelial selectins in extravasation of
leukocytes at sites of viral infection, with major emphasis on the
recruitment of virus-specific TC1 cells. Lymphocytic
choriomeningitis virus (LCMV)-induced meningitis was used as
our primary experimental model. Additionally, localized subdermal
inflammation and virus clearance in internal organs were analyzed
during LCMV infection. The generation of CD8+ effector T
cells in infected mutants was unimpaired. Quantitative and qualitative
analysis of the inflammatory exudate cells in intracerebrally infected
mice gave identical results in all strains of mice. Expression of
endothelial selectin was also found to be redundant regarding the
ability of effector cells to eliminate virus in nonlymphoid organs.
Concerning LCMV-induced footpad swelling, absent or marginal reduction
was found in E/P-sel
Leukocyte rolling is considered a pivotal element in
the multistep cascade leading to cell extravasation at sites of
inflammation.1,2 Rolling is mediated primarily by adhesion
molecules belonging to the selectin family that comprises 3 members2: P- and E-selectin expressed on vascular
endothelium and L-selectin expressed on leukocytes. All 3 members are
cell surface molecules with a common structure containing an N-terminal
lectin domain with a high affinity for certain glycosylated ligands.
P-selectin is constitutively found in secretory granules of platelets
and endothelial cells and on activation is rapidly mobilized to the
plasma membrane.3,4 Moreover, transcription is upregulated
in cytokine-activated endothelial cells in vivo.5 In
contrast, E-selectin is only transcriptionally regulated and appears on
the cell surface a few hours after exposure to
cytokines.6,7 The third member, L-selectin, is found on most leucocytes8 and is involved in leukocyte rolling in
addition to serving as the primary adhesion receptor for lymphocyte
entry into peripheral lymph nodes.9-11 Several studies have
suggested that P- and E-selectins are at least partially redundant and
can replace each other at inflammatory sites in
vivo.2,12,13
The use of neutralizing antibodies and genetic engineered mice with
null mutations in the genes encoding E-, P-, or E/P-selectin have
clearly evidenced the importance of these molecules in leukocyte extravasation and inflammatory reactions.2,13 From a
functional point of view, it has been found that E/P-selectin deficient
(E/P-sel Few in vivo studies have been performed specifically addressing the
role of endothelial selectins in recruitment of T cells to sites of
inflammation. Migration of CD4+ T cells into inflamed skin
is found to be dependent on expression of E- and
P-selectin18,19 and, in addition, evidence has been presented indicating that P- and E-selectin may be critically involved
in preferential recruitment of TH1 versus TH2
cells.20 Similarly, oxazolone-induced contact
hypersensitivity, which is believed to be initiated by recruitment of
TH1 cells, has been shown to be reduced in P-selectin
deficient mice and almost absent in E- and P-selectin double mutant
mice.21,22 However, to our knowledge similar specific
information is not available for CD8+ effector T cells.
Concerning the recruitment of mononuclear cells to the central nervous
system (CNS), varied results have been obtained. Thus, CD4+
lymphocytes appear to cross the blood-brain barrier independently of E-
and P-selectin expression in mice with experimental autoimmune encephalitis.23 However, the influx of leukocytes in
cytokine-induced meningitis has been shown to be severely impaired in
E- and P-selectin double mutant mice.24
In the current study, the role of endothelial selectins in recruitment
of leukocytes to infected sites during viral infection was analyzed,
with a major emphasis on the recruitment of virus-specific TC1 cells (CD8+ T cells secreting the same
cytokines as TH1 cells25). TC1
cells are a major arm of the antiviral host response, and play a
significant role in the acute clearance of many viruses acting as
killer cells and/or as local producers of antiviral cytokines, eg,
interferon- Using primarily E-selectin deficient mice and E/P-selectin double
deficient mice,14 we have studied the LCMV-induced
inflammatory response assessed as susceptibility to ic infection and as
footpad swelling after local challenge. Because clearance of LCMV is a direct result of effector T-cell homing to infected
organs,39,40 virus elimination was used as an additional
parameter for the efficiency and functional impact of the inflammatory
response. We found the expression of endothelial selectins to be
redundant concerning the formation, composition, and magnitude of the
inflammatory exudate. Also with regard to the clinically relevant
parameters such as susceptibilty to ic infection and virus clearance,
endothelial selectins appeared superfluous. Consequently, our findings
strongly indicate that the migration of TC1 effector cells
to many sites of viral infection can proceed without local expression
of selectins, and that TH1 and TC1 may differ
in their requirements for extravasation.
Mice
Virus
Virus titration Virus titrations were carried out by ic inoculation of 10-fold dilutions of 10% organ suspension into young adult Swiss mice. Titration endpoints were calculated by the Kärber method and expressed as mean lethal doses (LD50).Survival study Mortality was used to evaluate the clinical severity of acute LCMV-induced meningitis. Mice were checked twice daily for a period of 14 days or until 100% mortality was reached.Assay of LCMV-specific delayed-type hypersensitivity (DTH) Three different approaches were used to assess LCMV-specific DTH. (1) Mice were infected locally in the right hind footpad (fp) with 103 LD50 of LCMV, and the local swelling reaction was followed between day 6 and 17 pi. (2) Mice were infected iv with the same dose of virus and challenged in the right hind footpad with 30 µL of an immunodominant class I restricted peptide (LCMV GP33-41, 50 µg/mL) on day 8 pi; footpad swelling was measured 16, 24, 48, and 72 hours later. (3) Mice were inoculated in their right hind fP with 30 µL of virus containing 103 LD50 of LCMV. Four hours later they were injected iv with 5 × 107 splenic lymphocytes from wild-type donors, infected 8 days previously with the same dose of virus iv. Donor cells were routinely treated with mitomycin C (25 µg/mL, to prevent secondary expansion in the recipients) and depleted of plastic adherent cells by incubation for 1 hour at 37°C in tissue culture flasks. Footpad thickness was measured 16, 24, 48, and 72 hours after cell transfer, and to compensate for interexperimental variation wild-type recipients given the same donor cells were always included as a positive standard. Footpad thickness was measured with a dial caliper (Mitutoyo 7309, Mitutoyo Co, Tokyo, Japan), and virus-specific swelling was determined as the difference in thickness of the infected/challenged right and the uninfected/unchallenged left foot.42,43Inhibition of adoptive DTH response with soluble VCAM-1-Ig chimeric protein (sVCAM-1) LCMV-primed donor splenocytes treated as described previously were incubated with sVCAM-144(kindly provided by L. Burkly, Biogen Inc, Cambridge, MA) or human IgG (Jackson ImmunoResearch) for control (0.5 mg/108 cells/mL) for 30 minutes before injection into preinfected recipients (see above).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 erythrocytes were lysed by 0.83% NH4Cl treatment (Gey's solution). CSF exudate 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.29,43Cytotoxic assays Virus-specific cytotoxic T lymphocyte (TC) activity was assayed in a standard 51Cr-release assay using histocompatible MC57G cells infected with LCMV for 48 hours as specific targets; uninfected MC57G cells served as control targets. Assay time was 5 hours, and percent specific release was calculated as described previously.41,42Monoclonal antibodies The following mAb were all purchased from PharMingen (San Diego, CA) as rat antimouse antibodies: FITC conjugated anti-CD49d (common -chain of LPAM-1 and VLA-4, R1-2), phycoerythrin (PE) conjugated
anti-CD8a,53-67 biotin conjugated anti-CD62L (L-selectin,
MEL-14), PE conjugated anti-CD162 (P-selectin glycoprotein-1, PSGL-1,
2PH1), FITC conjugated anti-Mac-1 (M1/70), and PE conjugated
anti-IFN- (XMG1.2).
Flow cytometric analysis One × 106 cells were stained with labeled mAbs in staining buffer (1% rat serum, 1% bovine-serum albumin [BSA], 0,1% NaN3 in phosphate-buffered saline [PBS]) for 20 minutes in the dark at 4°C and subsequently washed. Cells incubated with biotin-conjugated Ab were further incubated with steptavidin-Tri-color (Caltag Laboratories, San Francisco, CA) and washed. After washing twice, cells were fixed with 1% paraformaldehyd. For visualization of LCMV-specific CD8+ T cells, splenocytes (107 cells/mL) were incubated with an immunodominant MHC class I-resticted epitope (LCMV GP 33-41, 0.1 µg/mL), monensin (3 µmol) and IL-2 (100 IU/mL) for 5 hours, after which cells were surface labeled and fixed. Then the cells were permeabilized using PBS/saponin (0.05%), and anti-IFN- was added.
After incubation for 20 minutes in the dark, cells were washed twice in
PBS/saponin.31 Samples were analyzed using a FACSCalibur
(Becton Dickinson, San Jose, CA), and 1 to 2 × 104
viable mononuclear cells were gated using a combination of forward angle and side scatter to exclude dead cells and debris. Data analysis
was carried out using the Cell Quest program, and results are presented as contour plots.45
Cell surface phenotype of LCMV-activated T cells We have previously shown that LCMV infection induces the generation of a large subset of CD8+ T cells with an activated phenotype (CD44high LFA-1high VLA-4high L-sellow) and capacity to exert effector functions (cytolysis and IFN- release) (reviewed in Thomsen
et al34). Most, if not all, of the expanded T-cell
population represents antigen-specific cells as recently disclosed
through staining with specific peptide/MHC class I
tetramers.46 To evaluate these cells with regard to their
ability to participate in selectin-dependent binding, splenocytes from
day 8-infected mice were analyzed for expression of L-selectin and
PSGL-1, the best described receptor for P-selectin.47 In addition, the surface phenotype of LCMV-specific T cells was visualized through brief stimulation with an immunodominant LCMV-derived peptide
(LCMV GP 33-41), followed by staining for IFN- intracellularly. Our
results (Figure 1) revealed, as expected,
that all LCMV-specific CD8+ T cells are of the
VLA-4high phenotype. In addition, we confirm that these
cells express low levels of L-selectin. In contrast, the level of
PSGL-1 was found to be increased on a large proportion of activated
CD8+ T cells. As CD8+ T cells found at sites of
inflammation are recruited exclusively from this activated subset (data
not shown), we considered it pertinent to study the role of endothelial
selectins in targeting of effector T cells to sites of infection.
LCMV-induced CD8+ T cell activation in E/P-sel
 / and E/P-sel
/ mice in the analysis of CD8+
T-cell-mediated inflammatory reactions, initial experiments were carried out to ascertain that there was no impairment in the ability of
these mice to generate effector T cells belonging to this subset. Functional analysis of the effector cell capacity in mutant mice compared with wild-type mice revealed an unimpaired virus-specific cytotoxic T-cell response, as there was no significant difference in
the ability of splenic T cells to lyse virus-infected MC57G target
cells 8 days after iv infection with LCMV in either E/P-sel / or E-sel / compared with wild-type mice
(Figure 2). Direct visualization of
antigen-specific T cells through detection of IFN-+
cells gave similar results (data not shown). Furthermore, because the
inflammatory response in LCMV-infected mice has previously been found
to directly correlate with the number of activated CD8+ T
cells generated in the spleen,35,45 the frequency of
splenic CD8+ T cell with this phenotype
(VLA-4high) was analyzed in ic-infected mice on day 7 pi.
The number of activated CD8+ T cells tended to be higher in
E-sel / mice and slightly lower in E/P-sel
/ mice compared with wild-type mice (21% [15%-21%], 30% [27%-33%], and 26% [14%-30%] for E/P-sel /,
E-sel / and wild type mice, respectively, medians (and
ranges) of 4 mice), but none of these differences were statistically
significant. Thus, the generation of CD8+ effector T cells
seems to be unimpaired in infected mice lacking expression of
endothelial selectins, allowing direct comparison of leukocyte
migration to infected sites between these animals and wild-type mice.
Role of endothelial selectins in the outcome of IC infection with LCMV To study the role of E- and P-selectin in the recruitment of lymphocytes to the LCMV-infected meninges, E/P-sel/,
E-sel /, and wild-type mice were infected ic with
103 LD50 of LCMV and clinical susceptibility to
meningitis, measured as mortality, was determined. Surprisingly, both
groups of mutant mice developed LCMV-induced meningitis and succumbed
to the infection to the same degree as did wild-type mice (Figure
3); if anything, E/P-sel /
mice tended to die earlier than wild-type mice. Quantitative and
qualitative analyses of the cellular exudate were performed in
parallel. No significant differences in the number of mononuclear cells
contained in the CSF were revealed either on day 6 or 7 pi, and the
composition of the inflammatory exudate with regard to CD8+
T cells and Mac-1+ monocytes/macrophages was found to be
similar in all 3 strains of mice (Table 1).
Altogether, the above findings indicate that recruitment of
virus-activated CD8+ T cells to the LCMV-infected meninges
do not require local expression of endothelial selectins.
Virus-induced DTH in the absence of endothelial selectins Another classical model of LCMV-induced CD8+ T-cell-mediated inflammation is the primary footpad swelling reaction that is the response to subdermal viral challenge.43,48,49 To study the role of endothelial selectins in this DTH-like reaction, E/P-sel/ mice and wild-type B6 mice were infected in the
right hind footpad with 103 LD50 of LCMV, and
footpad swelling was measured between day 6 and 17 pi. No significant
difference in the response pattern of mutants and wild-type mice was
observed (Figure 4), indicating that, also,
this subdermal inflammatory response could proceed in the absence of
endothelial selectins. However, a relatively high degree of
interindividual variation is intrinsic to this type of assay and this
may mask minor differences in the kinetics. Some of the interindividual
variation is likely to result from small variations in local virus
replication and the time point of subsequent generalized virus spread.
Therefore, we additionally measured the response of iv-infected mice to
local challenge (on day 8 pi) with an immunodominant viral MHC
class I-restricted peptide (LCMV GP33-41); previous results have
clearly established that this is a valid way of assessing
CD8+ T-cell dependent responses.33,50 Under
these conditions, a slightly reduced response was observed in E/P-sel
/ mice, but not in E-sel / mice (Figure
5). However, in all mice, a very substantial inflammatory reaction was induced, and similar results were
obtained in mice primed 2 months earlier (data not shown), demonstrating that the redundancy of endothelial selectins did not
simply result from the high number of recently activated effector cells
present in mice undergoing acute infection.
Virus clearance in nonlymphoid organs is independent of E- and
P-selectin expression
Selectins are generally assumed to play an essential role in the
recruitment of leukocytes to inflamed tissue by mediating the initial
tethering and rolling required before firm adhesion can be
established.1 Several studies that use monoclonal antibody against selectins, as well as studies from knockout mice, have evidenced the general importance of these molecules in inflammatory reactions (recently reviewed in 2). Moreover, recent
evidence indicates that endothelial selectins (E- and P-selectin) are
needed for CD4+ T cells to migrate into inflamed
skin.18,19 However, no studies have previously
systematically addressed the role of these selectins in the migration
of CD8+ effector T cells, which are central to clearance of
many viral infections. Consequently, the current study was undertaken
to investigate the requirement for local expression of selectins in
extravasation of TC1 cells at sites of viral infection.
We wish to thank Grethe Thørner Andersen and Lone Malte for expert
technical assistance. Daniel Bullard is gratefully acknowlged for
providing us with breeder pairs of E- and E/P-selectin knockout mice
and Linda Burkly for providing soluble VCAM-1-Ig chimeric protein.
Submitted June 8, 1999; accepted October 7, 1999.
Supported by the Danish Medical Research Council, The Biotechnology
Center for Cellular Communication, the Foundation for Advancement of
Medical Science, and the Novo Nordisk Foundation.
Reprints: Allan Randrup Thomsen, Institute of Medical
Microbiology and Immunology, Panum Institute, 3C Blegdamsvej, DK-2200
N, Copenhagen, Denmark.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
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Abstract
Introduction
