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*
Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington, New Zealand; and
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production by bronchoalveolar
lavage fluid CD8+ T lymphocytes in vitro. It also resulted
in decreased numbers of virus-specific CD8+ T lymphocytes
in the bronchoalveolar lavage fluid, lung, and spleen and lowered
virus-specific Ab titers. Mice treated with CTLA4-Ig were able to
control and clear the virus infection, but this was delayed compared
with controls. Treatment with Y100F-Ig, a mutant form of CTLA4-Ig which
selectively binds to CD80 and blocks the CD28-CD80 interaction leaving
CD28-CD86 binding intact, did not affect Ab production, spleen
cytotoxic precursors, or clearance of virus. However, Y100F-Ig
treatment had a clear effect on lung effector cell function. Secretion
of IFN- by bronchoalveolar lavage fluid CD8+ T
lymphocytes in vitro was decreased, and the number of virus-specific
CD8+ T lymphocytes in the bronchoalveolar lavage fluid and
lungs of infected mice was reduced. These results indicate that
CD28-dependent costimulation is important in the antiviral immune
response to an influenza virus infection. The individual CD28 ligand,
CD80, is important for some lung immune responses and cannot always be
compensated for by CD86. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CTLA4-Ig is a soluble chimeric protein consisting of the extracellular domain of CTLA-4 fused to the Fc portion of human IgG1. This molecule has been shown in a number of models to be powerfully immunosuppressive, through its ability to block CD28 interaction with CD80 and CD86. CTLA4-Ig has been shown to prevent organ transplant rejection (2, 3), lupus-like autoimmune disease (4), experimental autoimmune encephalomyelitis (5, 6), autoimmune oophoritis (7), and asthmatic lung inflammation (8) in experimental models. In addition, CTLA4-Ig has been proposed as a therapeutic agent for a number of immune-based disorders, and phase I clinical trials in patients with psoriasis vulgaris have recently been completed (9). If CTLA4-Ig is to be used in a clinical situation, its effect on clearance of infectious agents must be established. We have examined the antiviral immune response in a murine model of influenza infection during concurrent treatment with CTLA4-Ig.
Y100F-Ig is a mutant form of CTLA4-Ig that selectively binds CD80 and blocks CD28-CD80 interactions but leaves CD28-CD86 binding intact (10). We have previously shown in a model of Ag-induced airway eosinophilia that Y100F-Ig prevents the accumulation of eosinophils and lymphocytes in the lungs of immunized mice, but does not block Ag-induced systemic blood eosinophilia or IgE Ab production (10). These results suggested that CD80-dependent costimulation may be especially important for the development of immune responses in the lung. Further in vitro evidence also suggests that CD80 may be critical for the activation of T lymphocytes in the lung. The T cell stimulatory capacity of murine lung dendritic cells in vitro is reported to be almost exclusively dependent on expression of CD80 while CD86, although expressed, has a secondary role (11). To determine whether blockade of CD80-dependent costimulation can also inhibit other lung immune responses, we investigated the effect of Y100F-Ig treatment during an influenza virus infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J mice were bred and maintained at the Biomedical Research Unit of the Wellington School of Medicine. All animal experimental procedures used in this study were approved by the Wellington School of Medicine Animal Ethics Committee and conducted in accordance with the guidelines of the University of Otago (Dunedin, New Zealand).
Reagents
Chimeric proteins derived from the fusion of the extracellular portion of human or murine CTLA-4 to human IgG1 were used in these studies (12). Y100F-Ig is a mutant CTLA4-Ig in which the tyrosine at position 100 is substituted with phenylalanine (10). CTLA4-Ig and Y100F-Ig bind CD80 with indistinguishable kinetics, whereas binding of Y100F-Ig to CD86 is undetectable (10). The mAb L6-Ig, which has a human Fc region, was used as a control (12). Mice were injected i.p. with 200 µg of murine CTLA4-Ig, Y100F-Ig, or L6-Ig or 400 µg of human CTLA4-Ig, Y100F-Ig, or L6-Ig, beginning the day before infection, and continuing every 48 h throughout the experiment.
The H-2Db-binding influenza A peptide NP366-374 (ASNENMETM; see Ref. 13) was synthesized by Chiron Technologies (Victoria, Australia).
Virus
The A/HKx31 (H3N2) influenza A virus is a laboratory-generated recombinant with the external surface components of A/Aichi/2/68 (H3N2) and the internal components of A/PR8/8/34 (H1N1) (14). Virus stocks were grown in the allantoic cavities of 10-day-old embryonated chicken eggs and stored as infectious allantoic fluid at -80°C. Virus stock was shown to be endotoxin free by the Limulus amebocyte lysate assay (Sigma, St. Louis, MO). Virus titer was determined by agglutination of human erythrocytes and is expressed as hemagglutinating units (HAU).3 Mice were anesthetized by an i.p. injection of a mixture of ketamine and xylazine (Phoenix, Auckland, New Zealand), and 12 HAU of virus in a 30-µl volume of PBS was administered by intranasal inoculation.
Tissue sampling
Mice were anesthetized and exsanguinated from the vena cava. The trachea was cannulated and a bronchoalveolar lavage (BAL) performed with three consecutive washings with 0.8 ml of PBS, each of which was infused and withdrawn five times. BAL cells from individual mice were pooled, erythrocytes were lysed in 0.14 M NH4Cl and 17 mM Tris-HCl, and nucleated cells were adhered on plastic for 2 h at 37°C to remove macrophages. Lungs were perfused via the heart right ventricle with 10 ml of PBS, and minced lung tissue was digested with 2.4 mg/ml collagenase (Life Technologies, Auckland, New Zealand) and 0.1% DNase I (Sigma) for 1 h at 37°C. Lung-infiltrating lymphocytes were purified over a 65% Percoll gradient and the interphase cells were collected. Single-cell suspensions were prepared from spleen by teasing though nylon gauze, and erythrocytes were lysed.
Virus titers in lung tissue
Lungs were removed at various intervals after infection and stored at -80°C until further assay. Individual lung samples were homogenized in 1 ml of IMDM (Life Technologies). Homogenates were diluted serially 10-fold in IMDM supplemented with 2 µg/ml trypsin and plated in triplicate onto Madin-Darby canine kidney cells (15). The cultures were incubated for 7 days at 35°C. The culture supernatants were tested for the presence of viral hemagglutinin activity by mixing 50 µl of supernatant with 50 µl of a 0.4% suspension of human erythrocytes. Virus titers were determined by interpolation of the last dilutions that showed hemagglutination.
Cytotoxicity assay
The cytotoxic activity of BAL and spleen cells was determined using the just another method (JAM) test (16) on 5000 labeled EL4 cells that had been incubated in the presence or absence of 10 µg/ml NP366-374 peptide for 1 h at 37°C before the assay as described (17). The percentage of cytotoxicity was calculated from the mean of triplicate wells. BAL cells were tested directly ex vivo for cytotoxic activity. Spleen cells were first stimulated in vitro with 0.1 µM NP366-374 peptide for 5 days. All cultures were in IMDM containing 2 mM glutamine, 1% penicillin-streptomycin, 5 x 10-5 M 2-ME (Sigma), and 5% FCS (Life Technologies).
FACS Analysis
Anti-FcRII (2.4G2), anti-CD8 (2.43), and anti-CD4
(GK1.5) Ab were affinity purified from tissue culture supernatants
using protein G-Sepharose (Pharmacia Biotech, Uppsala, Sweden) and
conjugated with biotin. Anti-Vß8.3-FITC was obtained from PharMingen
(San Diego, CA). Cells were stained in PBS containing 2% FCS and
0.01% sodium azide as described (10) and analyzed on a
FACSort (Becton Dickinson, Mountain View, CA).
Enzyme-Linked Immunospot
Polyvinyl chloride 96-well plates (Nunc, Roskilde, Denmark) were
coated overnight at 4°C with 20 µg/ml AN18 (anti-IFN-) and
blocked with 10% BSA in PBS for 60 min at room temperature. After
washing, freshly explanted cells were added in serial dilutions. Cells
were incubated with or without 10 µg/ml of the peptide
NP366-374 for 6 h at 37°C in a 5%
CO2 incubator. After removal of cells, an
appropriate dilution of the secondary Ab XMG-D6-biotin was added and
incubated at 4°C overnight. Alkaline phosphatase-avidin conjugate was
added and incubated for 1 h at 37°C; spots representing single
IFN--producing cells were revealed using the substrate
5-bromo-4-chloro-3-indolyl phosphate (Sigma) and counted under an
inverted microscope.
Ab ELISA
Polyvinyl chloride 96-well plates (Nunc) were coated overnight at 4°C with 10 µg/ml purified Influenza x31 Ag (SPAFAS, Storrs, CT), and ELISA reactions were conducted as described previously (8). Ab titers are expressed in U/ml (reciprocal of 50% Ab titer).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the importance of CD28-dependent costimulation during
an influenza virus infection, mice were treated with i.p. injections of
CTLA4-Ig, or the isotype control L6-Ig, every 48 h beginning the
day before infection. To assess the role of the individual CD28 ligand
CD80, mice were treated with a mutant form of CTLA4-Ig, Y100F-Ig, which
does not bind to CD86 (10). Neither Y100F-Ig nor CTLA4-Ig
affected the total number of CD8+ T lymphocytes
detected in the BAL of mice infected with influenza virus at day 9
after infection. In contrast, treatment with CTLA4-Ig, but not
Y100F-Ig, considerably reduced the number of CD4+
T lymphocytes in the BAL as compared with the L6-Ig treated group (data
not shown). A JAM test using EL4 cells coated with the immunodominant
peptide NP366-374 was used to detect virus-specific CTL.
BAL cells from mice treated with CTLA4-Ig exhibited no cytotoxic
activity (Fig. 1
). No cytotoxic activity
was detected from BAL cells taken at day 12 after infection (data not
shown), indicating that lack of cytotoxicity was not due to a delay in
the kinetics of the appearance of CTLs in mice treated with CTLA4-Ig.
The effect of Y100F-Ig on the cytotoxic activity of BAL lymphocytes was
variable. In some experiments, the cytotoxic activity, although
slightly diminished, was comparable to that of controls (Fig. 1),
whereas in other experiments, it was partially reduced (data not
shown).
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). In
contrast, very little killing activity was detected from spleen
cell cultures from mice treated with CTLA4-Ig (Fig. 2). This suggests
that CTLA4-Ig causes a severe defect in the priming and/or expansion of
virus specific CD8+ T cells during influenza
virus infection.
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-secreting cells. BAL lymphocytes were
collected at day 9 after infection, restimulated in culture in the
presence or absence of NP366-374 peptide for 6 h, and
the number of IFN--secreting cells counted. High numbers of
IFN--producing cells could be demonstrated in the BAL of control
L6-Ig-treated mice, but only in the presence of NP366-374
peptide, indicating that cytokine production was Ag specific (Fig. 3). Very few lymphocytes were found
in the BAL of noninfected mice, and no IFN--secreting cells were
detected in lung-infiltrating lymphocytes isolated from noninfected
mice (data not shown). The number of cytokine-secreting cells was
severely reduced in mice treated with CTLA4-Ig although some effector
function was detected (Fig. 3). This is in contrast to the cytotoxic
assay where no CTL activity was apparent after CTLA4-Ig treatment. In
two separate experiments, Y100F-Ig reduced the number of
IFN--secreting cells in the BAL compared with controls (Fig. 3),
indicating that CD80-dependent costimulation was required for the
optimal development of IFN--secreting cells. The numbers of
IFN--secreting CD8+ T cells specific for
NP366-374 in lymph node and spleen were too low to allow a
meaningful comparison.
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Because only a small percentage of lymphocytes in the BAL are Ag
specific (18), it is possible that CTLA4-Ig and Y100F-Ig
are inhibiting either the infiltration of Ag-specific cells into the
lung or the further activation of cells to effector function once they
are in the lung. Therefore, we sought to determine the proportion of
Ag-specific cells in the BAL. Cells taken directly from the BAL of
infected mice exhibit a preferential accumulation of
Vß8.3+CD8+ T cells
(19), as the Vß8.3 TCR is selectively overrepresented in
the CD8+, NP366-374-specific
population. As an estimate of the proportion of Ag-specific cells, we
measured the expression of Vß8.3 on BAL lymphocytes by FACS analysis.
As expected, the usage of the Vß8.3 TCR on CD4+
cells was equivalent in all treatment groups and did not change over
the time course of the infection (Fig. 4). In contrast, the proportion of
Vß8.3-expressing cells in the CD8+ population
was significantly increased in the L6-Ig-treated group compared with
noninfected mice. The proportion of Vß8.3 cells was increased at day
9 and further expanded at day 13 (Fig. 4), presumably as a result of
more rapid clearance of non-virus-specific cells from the lung.
Infected mice treated with CTLA4-Ig had marginal or no increase in the
proportion of Vß8.3+CD8+
cells in both the lung and BAL. This suggests that very few
NP366-374-specific CD8+ T cells are
present in the lung and BAL fluid of CTLA4-Ig-treated mice. Finally, an
increase in the proportion of
Vß8.3+CD8+ cells was
detected in both the lung and BAL fluid of Y100F-Ig-treated mice (Fig. 4). This increase was usually, but not always, less profound than the
increase observed in control L6-Ig-treated mice (data not shown),
suggesting that lower numbers of Ag-specific cells were present in the
lung and BAL fluid of Y100F-Ig-treated mice.
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To determine the requirement of CD28-dependent costimulation for
Ab production, virus-specific IgG1 and IgG2a titers were measured in
CTLA4-Ig, Y100F-Ig, and L6-Ig-treated mice using an ELISA. Results
showed that both IgG1 and IgG2a were lowered by CTLA4-Ig treatment
(Fig. 5). The mean titer of IgG1 was
30-fold lower than in the L6-Ig controls, and the mean titer of IgG2a
was 7-fold lower. Levels of IgG1 and IgG2a were similar in Y100F-Ig-
and L6-Ig-treated mice (Fig. 5). Serum from noninfected mice had
undetectable levels of both IgG1 and IgG2a (data not shown). Mice
depleted of CD4+ T cells (20) and
mice deficient in expression of MHC class II molecules (J. M.
Lumsden and F. Ronchese, unpublished data) are still able to produce
influenza-specific Abs, especially IgG2a, albeit at a reduced level.
This suggests that a component of the Ab response to influenza virus
infection is CD4+ T cell independent, which may
explain why reasonable titers of Ab were detected even when
CD28-dependent costimulation was blocked.
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Influenza virus clearance is mediated by
CD8+ cytotoxic T cells, but other mechanisms such
as Ab can clear the infection when CD8+ cells are
absent (21, 22). To determine whether the defects in T
cell activity observed in mice treated with CTLA4-Ig or Y100F-Ig
influenced virus clearance, infectious virus titers were measured at
days 6 and 9 after infection. As shown in Fig. 6, Y100F-Ig did not alter the rate of
clearance of virus from infected lungs. In contrast, mice treated with
CTLA4-Ig showed delayed virus clearance. In other experiments, we found
that all mice treated with CTLA4-Ig had cleared the virus by day 12,
indicating that virus clearance is ultimately achieved in
CTLA4-Ig-treated mice (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CTLA4-Ig-treated mice had decreased Ab production, no detectable ex
vivo cytotoxic activity, and reduced Ag-specific secretion of IFN-
by BAL lymphocytes. The defect in CD8+ T cell
function was likely to be due to lack of priming and/or expansion of
virus specific CD8+ T cells, since the proportion
of CD8+ T cells expressing a Vß8.3 TCR, which
is preferentially expressed on NP366-374-specific
CD8+ T cells, was not increased. In addition, no
cytotoxic activity was detected even after lymphocyte culture in vitro
in the presence of specific peptide, to allow the activation of CTLp to
effector cells. We think these effects are due to a direct effect of
CTLA4-Ig on CD8+ T cell activation, rather than
to an indirect effect through inhibition of CD4+
T cell help. Mice that are deficient in CD4+ T
cells have an equivalent level of CTL activity in the BAL compared with
wild-type mice and are able to eliminate influenza virus from the lung
with near to normal kinetics (Refs. 23 and 24 and J. M. Lumsden and F.
Ronchese, unpublished results).
Immune responses to viral infectious agents are variously affected by
the blockade of the CD28 costimulatory pathway.
CD28-/- mice (25) and mice
transgenic for a soluble form of CTLA4-Ig (26)
infected with lymphocytic choriomeningitis virus generated a normal
CTL response. In contrast, infection with vesicular stomatitis virus
did not induce any measurable CTL activity. It was suggested that the
requirement for CD28 costimulation correlates inversely with viral
replication and that high Ag expression driven by these infectious
agents may decrease the dependency on the CD28 costimulatory signal,
essentially by increasing the strength of the Ag-specific "signal
one." Influenza virus causes a transient infection of epithelial
cells in the respiratory tract, but causes no productive infection of
cells in other tissues. This localized infection would be likely to
produce a lower level of Ag than viruses such as lymphocytic
choriomeningitis virus and may explain why CTLA4-Ig can inhibit the
immune response during an influenza infection. However, some T cell
activation must have occurred in mice treated with CTLA4-Ig. Mice
lacking T cells cannot control an influenza virus infection (27, 28), whereas mice treated with CTLA4-Ig were able to control and
clear the virus, although with delayed kinetics. The observed low level
of IFN- production by BAL cells also supports a limited degree of T
cell activation in CTLA4-Ig-treated mice.
In previous studies, we have reported that CD80 is essential to the
development of allergic lung inflammation in a murine model
(10). Treatment with Y100F-Ig drastically inhibited the
development of Ag-dependent airway eosinophilia, but had no effect on
blood eosinophilia or Ab production, indicating a preferential effect
on lung immune responses. A similar role for CD80 is also suggested by
the observations reported in this study. The cytotoxic activity of BAL
CD8+ lymphocytes was reduced, sometimes only
marginally (Fig. 1
), sometimes more significantly (data not shown). The
number of IFN--secreting cells in the BAL was also reduced, although
not as severely as in CTLA4-Ig-treated mice. Finally, the proportion of
Vß8.3+CD8+ cells in the
lung and BAL of infected mice treated with Y100F-Ig was generally, but
not always, reduced compared with that of controls. In contrast to this
partial but still clear effect on lung immune responses, Y100F-Ig had
no effect on systemic antiviral immune responses, as measured by spleen
cytotoxic activity and Ab titers. These data suggest that the function
of CD80 in lung immune responses is not as easily compensated for by
CD86, as it is in the case of systemic immune responses. The mechanism
for this effect of Y100F-Ig is still unclear, but one mechanism may be
to inhibit the proliferation of Ag-specific cells in the draining lymph
nodes. More accurate estimation of the numbers of Ag-specific cells
using tetrameric MHC class I reagents may elucidate this. It is also
possible that the reduced cytotoxicity and IFN- production by BAL
CD8+ cells was caused by a defect in the
acquisition of effector function once in the lung. The primary APC
presenting viral Ags in the lung is likely to be the dendritic cell.
Masten et al. (11) reported that the T cell stimulatory
capacity of murine lung dendritic cells in vitro is almost exclusively
dependent on expression of CD80, whereas CD86, although expressed, has
a secondary role. This may provide another hypothesis as to the
mechanism by which Y100F-Ig affects lung effector function. It would
also be interesting to see whether increased expression of CD86 on lung
APCs would overcome the requirement for CD80 for complete lung effector
cell activity.
Treatment with CTLA4-Ig and Y100F-Ig appeared to affect differentially
CD8+ T cell functions such as cytotoxicity and
IFN- production. CTL activity was completely inhibited by CTLA4-Ig
treatment. In contrast, IFN- production was still demonstrable
although at a much reduced level. The lack of cytotoxic activity by
CD8+ cells may reflect a lower sensitivity of
this assay or may indicate a higher dependence of cytotoxic function on
costimulatory signals. Other cases of differential costimulatory
requirements for different T cell functions have been reported in the
literature. The absence of costimulation during the in vitro activation
of a CD8+ T cell clone had differential effects
on certain TCR-dependent effector functions (29). In that
study, cytotoxic activity was not affected while IFN- production was
reduced. Recently, transgenic CD8+ T cells
rendered anergic in vivo were shown to produce IFN- in vivo but were
unable to proliferate or to kill target cells in vitro (30, 31). The difference in the activation status of the T cells
examined in the above studies (T cell clones vs naive T cells) may
explain the discrepancies in the observed effects. It is interesting
that, in our study, Y100F-Ig had an inverse effect on
CD8+ T cell function as compared with CTLA4-Ig.
CTLA4-Ig completely blocked cytotoxic activity but left some IFN-
production. Y100F-Ig had a consistent effect on IFN- production, but
affected cytotoxicity less extensively and less reproducibly. Again,
this suggests that although CD86 may provide sufficient costimulation
for some T cell functions, CD80 serves a specific function and is
required for some T cell activities. Since CD80 is reported to be
up-regulated slowly by APC (32, 33), its predominant role
may be in late T cell effector functions. Indeed, a recent paper
(34) described how acquisition of CTL activity by
CD8+ cells requires only one cell division, while
IFN- production is a late event (35).
In conclusion, we show that CD28-dependent costimulation is critical to the development of an effective anti-influenza virus immune response. We also present evidence in favor of an important role of CD80 in lung immune responses, confirming the hypothesis that CD80 and CD86 molecules have differential roles in the development of immune responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Franca Ronchese, Malaghan Institute of Medical Research, P.O. Box 7060, Wellington South, New Zealand. E-mail address:
3 Abbreviations used in this paper: HAU, hemagglutinating units; BAL, bronchoalveolar lavage; JAM, just another method.
Received for publication August 30, 1999. Accepted for publication October 13, 1999.
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References |
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1 inhibits antigen-induced lung eosinophilia but not Th2 cell development or recruitment in the lung. Eur. J. Immunol. 27:155.[Medline]
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N. L. Harris, M. Prout, R. J. Peach, B. Fazekas de St. Groth, and F. Ronchese CD80 Costimulation Is Required for Th2 Cell Cytokine Production But Not for Antigen-Specific Accumulation and Migration into the Lung J. Immunol., April 15, 2001; 166(8): 4908 - 4914. [Abstract] [Full Text] [PDF]
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S. Santra, D. H. Barouch, S. S. Jackson, M. J. Kuroda, J. E. Schmitz, M. A. Lifton, A. H. Sharpe, and N. L. Letvin Functional Equivalency of B7-1 and B7-2 for Costimulating Plasmid DNA Vaccine-Elicited CTL Responses J. Immunol., December 15, 2000; 165(12): 6791 - 6795. [Abstract] [Full Text] [PDF]
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 A. O. Tzianabos, A. Chandraker, W. Kalka-Moll, F. Stingele, V. M. Dong, R. W. Finberg, R. Peach, and M. H. Sayegh Bacterial Pathogens Induce Abscess Formation by CD4+ T-Cell Activation via the CD28-B7-2 Costimulatory Pathway Infect. Immun., December 1, 2000; 68(12): 6650 - 6655. [Abstract] [Full Text] [PDF]
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D. Conze, T. Krahl, N. Kennedy, L. Weiss, J. Lumsden, P. Hess, R. A. Flavell, G. Le Gros, R. J. Davis, and M. Rincon c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Have Distinct Roles in CD8+ T Cell Activation J. Exp. Med., March 25, 2002; 195(7): 811 - 823. [Abstract] [Full Text] [PDF]
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