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*
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and
Department of Pathology, University of Tennessee, Memphis, TN 38163
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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.
Assessment of Vß4+CD8+ T cell stimulatory
activity using murine gammaherpesvirus-68-specific T cell hybridomas
generated from latently infected mice supports the idea that
CD4+ T cells control levels of the stimulatory ligand that
drives the Vß4+CD8+ T cells. As
Vß4+CD8+ T cell expansion also correlates
with levels of activated B cells, these data raise the possibility that
CD4+ T cell-mediated B cell activation is required for
optimal expression of the stimulatory ligand. In addition, in cases of
low ligand expression, there may also be a direct role for
CD4+ T cell-mediated help for
Vß4+CD8+ T cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1/106 spleen cells, and remain stable
at this level (6). Late in the infection, after the
clearance of lytic virus from the lung, a syndrome similar to the
infectious mononucleosis associated with the human gammaherpesvirus
EBV, develops. Hallmarks of this syndrome include splenomegaly, due to
increased numbers of cycling CD4+ T cells,
CD8+ T cells, and B cells, and lymphocytosis of
the peripheral blood, due to increased numbers of activated
CD8+ T cells, dominated by those bearing
Vß4+TCR (7, 8). The
Vß4+CD8+ T cell response
does not appear to result from an outgrowth of cells responding to
viral epitopes expressed during acute infection (9, 10).
Rather, the response has several unusual features in that the
Vß4+ T cell expansion is not classically MHC
restricted (8, 11) (C. L. Hardy, R. D. Cardin, E.
Flaño, P. Nguyen, D. L. Woodland, R. W. Williams, and M. A.
Blackman, manuscript in preparation), and appears to be independent of
presentation by classical MHC class I or MHC class II molecules
(11). Identification of the stimulatory ligand remains
elusive, but its expression correlates with peak levels of splenic
latency 2 wk after infection (11). The requirement for CD4+ T cells in antiviral CD8+ T cell responses is not absolute, and may be controlled by variables such as the virulence or dose of the virus, and the activation state of the APC, including whether the APC are virally infected. It has been suggested that CD4+ T cells may be particularly important for the maintenance of cytolytic T cells and preventing reemergence of infectious virus in chronic infections (reviewed in Refs. 12, 13). Indeed, in the MHV-68 virus model, a progressive reactivation of lytic virus in the lung was seen in CD4-deficient, MHC class II-/- mice (6). Further analysis of CD8+ effector function for MHV-68 lytic epitopes in this model showed it to be intact, and it was concluded that the CD4+ T cells were either required for the Ab response, suggesting a critical role for Ab in controlling latent viral infection, or for the generation of CTL for epitopes other than those that dominated the acute response (14). The importance of Ab in controlling lytic virus after reactivation was directly shown in studies in MHV-68-infected, B cell-deficient µMT mice (4).
A role for CD4+ T cells in several aspects of the complex pathogenesis associated with MHV-68 infection has been previously reported. A requirement for CD4+ T cells in the splenomegaly induced by MHV-68 infection has been demonstrated (7, 15). In addition, CD4+ T cells were required for the nonspecific B cell activation and polyclonal Ab secretion associated with MHV-68 infection (16), as well as, not surprisingly, for the generation of the specific humoral response (17). Our previous experiments established that there was no Vß4 expansion in MHC class II-deficient mice (8). These mice lack both MHC class II molecules and CD4+ T cells. Our early experiments with CD4 depletion suggested that the lack of Vß4 expansion was due to the absence of MHC class II molecules, as CD4 depletion just before the time of Vß4 expansion did not ablate the expansion (8). However, our subsequent analysis suggesting that MHC class II molecules are not necessary for stimulation of Vß4+ hybridomas with latently MHV-68-infected spleen cells, reopened the possibility that CD4+ T cells were required early in the response (11). Thus, the experiments described in the present study analyze the requirement for CD4+ T cells in the Vß4+CD8+ T cell expansion associated with early stages of latent MHV-68 infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J (B6), C57BL/6-Ifngtm1Ts
(IFN--/-) (18), and
C57BL/6-Cd4tm1Mak
(CD4-/-) (19) mice were purchased
from The Jackson Laboratory (Bar Harbor, ME). H-2
IAb-deficient C2D mice (MHC class
II-/-) (20) (licensed from
GenPharm International, Mountain View, CA) were bred at St. Jude
Children’s Research Hospital (Memphis, TN). Mice were housed under
specific pathogen-free conditions before MHV-68 infection at 8–16 wk
of age, and in BL 3 containment after infection.
Virus stocks and infection and sampling of mice
The stock of MHV-68 (clone G2.4) was obtained from Prof. A. A. Nash (Edinburgh, U.K.), propagated in OMK cells (ATCC 1566CRL), and titered on NIH-3T3 (ATCC CRL1568) monolayers, as previously described (6). Mice were anesthetized with Avertin (2,2,2-tribromoethanol) and infected intranasally with 600 PFU MHV-68 in a total volume of 40 µl of PBS. Splenocytes and/or peripheral blood were analyzed at various times after infection.
CD4+ T cell depletion
To deplete the CD4+ T cell subset, mice were i.p. injected with 500 µl of a CD4-specific mAb (GK1.5), in the form of either a 1/5 dilution of ascites or neat concentrated culture supernatant. Depletions were started at the time of infection or 1 wk later, and continued at 2-day intervals until the mice were sacrificed for analysis.
LacZ hybridoma assay
The characterization of Vß4+CD8+ lacZ-inducible T cell hybridomas that specifically respond to MHV-68-infected spleen cells 14 days postinfection has been previously described (11). Spleen cells were T cell depleted using anti-Thy-1 mAb AT83 (21) and a mixture of rabbit and guinea pig complement (Cedarlane Laboratories, Hornby, Ontario, Canada), before being used as stimulator cells. A total of 106 stimulator cells were plated in 96-well flat-bottom plates, and titrated in 2-fold dilutions. LacZ-inducible T cell hybridomas 4BH-98 and 5BH-11 were added as 105 cells/well, and incubated overnight. ß-galactosidase activity was assessed in individual cells, as previously described (10, 11), using 5-bromo-4-chloro-3-indolyl ß-D-galactopyranoside (X-Gal) as the substrate, and blue cells were counted under the microscope. The background stimulation was determined by using naive APCs as stimulators.
Flow cytometry
After erythrocyte lysis in hemolytic Gey’s solution, spleen and
blood cells were stained for FACS analysis using combinations of the
following Abs and lectins: CD44 (clone IM7; PharMingen, San Diego, CA),
CD62L (clone Mel-14; PharMingen), TCR Vß4 (KT-4; PharMingen), CD8
(clone CT-CD8; Caltag, Burlingame, CA), and peanut agglutinin (PNA;
Sigma, St. Louis, MO). A total of 20,000 live cells were gated and
acquired on a FACScan flow cytometer, and the data were analyzed using
CellQuest software (Becton Dickinson Immunocytometry Systems, San
Jose, CA).
Infective center assay
The frequency of latently infected cells was estimated by an infective center assay, dependent upon the ability of latently infected cells to reactivate upon in vitro culture with susceptible cells, as previously described (6). Serial dilutions (in triplicate) of T cell-depleted splenocytes were plated onto monolayers of NIH-3T3 cells, and the next day overlaid with carboxymethyl cellulose. After 6 days of culture, plaques were quantitated after methanol fixation and Giemsa staining. As this assay will also measure lytic virus, samples were simultaneously assayed after one cycle of freeze/thaw to assess the possible contribution of lytic virus to the titers. Control experiments, conducted to confirm that this procedure does not reduce the titer of cell-associated lytic virus, showed <20% reduction in lytic viral titers.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The requirement for CD4+ T cells in the
activation of CD8+ T cells following the
establishment of MHV-68 latency was analyzed in three experimental
models of CD4-deficient mice: 1) B6 mice that had been depleted of
CD4+ T cells by in vivo injection of anti-CD4
Abs, 2) CD4-/- (knockout) mice, and 3)
CD4-deficient, MHC class II-/- (knockout) mice.
Peripheral blood was analyzed on days 14 and 21 after infection, time
points we have previously shown to precede and correlate, respectively,
with increased levels of activated CD8+ T cells
and expansion of the Vß4+ subset
(8). Analysis of all three models of
CD4+ T cell deficiency showed that there was no
increase of Vß4+CD8+ T
cells in the peripheral blood (Fig. 1
A) or spleen (data not
shown). In contrast, there were variable and less marked effects on the
increased percentage of CD8+ T cells in the
peripheral blood (Fig. 1B). It should be noted that, as
expected in the absence of CD4+ T cells, there
were higher levels of CD8+ T cells in the
CD4-/- and MHC class
II-/- mice before infection. Despite the
variable increase in the proportion of CD8+ T
cells in the peripheral blood in the absence of
CD4+ T cells, the CD8+ T
cells were still highly activated, as assessed by
PNAhigh, CD62Llow, and
CD44high expression (Fig. 2).
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We have previously generated a panel of
Vß4+ T cell hybridomas from latently infected
mice that can be used to monitor in vivo expression of the
uncharacterized ligand that drives
Vß4+CD8+ T cell
activation. Previous studies have shown that the hybridomas are
specifically reactive to spleen cells isolated from MHV-68-infected
mice, but not to spleen cells or cell lines that were lytically
infected in vitro. In addition, the Vß4+ T cell
stimulatory activity is not detected in spleen cells during the early,
lytic stages of the infection, despite the fact that low levels of
latent virus are detectable as early as day 6. Rather, the
Vß4+ T cell stimulatory activity correlates
precisely with the establishment of peak levels of splenic latency at
14 days after infection (11). Thus, to determine
whether CD4+ T cells are required for generation
of the stimulatory ligand, spleen cells were isolated from the three
models of CD4-deficient mice 14 days after MHV-68 infection, and were
used to stimulate Vß4+ T cell hybridomas. The
data in Fig. 4 show that day 14 spleen
cells from CD4-/- mice and CD4 Ab-depleted mice
were unable to stimulate a representative hybridoma, and, consistent
with our previous report (11), there was a dramatically
reduced stimulation of the hybridoma by spleen cells from infected MHC
class II-/- mice. Similar results were obtained
with a second hybridoma (data not shown). The analysis also showed that
Ab depletion initiated 7 days after infection was as efficient as
depletion from the time of infection in preventing hybridoma
stimulation (Fig. 4A), consistent with the comparable effect
on in vivo expansion of
Vß4+CD8+ T cells (Fig. 3
). As in vitro hybridoma stimulation is dependent on TCR ligation, but
is independent of other factors such as costimulation and
CD4+ T cell help, these data indicate that the
ligand that drives
Vß4+CD8+ T cells is
absent, or reduced below the threshold required for in vivo activation,
in CD4-deficient mice, and suggest that the lack of
Vß4+CD8+ T cell expansion
in the CD4-deficient mice is because CD4+ T cells
are required for optimal expression of the stimulatory ligand.
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10-fold
lower levels of latently infected spleen cells at day 14, the peak of
latency (Fig. 5). Analysis of the
CD4-/- and Ab-depleted mice showed that there
was an even greater (>100-fold) reduction in latency levels at day 14.
As expected, latency levels were declining in the control B6 spleen
cells by day 21 (6). However, the levels of latency in the
MHC class II-/- and Ab-depleted animals
remained unchanged, and latency levels increased 10-fold in the
CD4-/- animals between days 14 and 21.
Consistent with a previous report (16), the absence of
CD4+ T cells resulted in reduced percentages of
activated splenic B cells in all three models of CD4 depletion (Fig. 6).
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), differences in these
models became apparent with extended kinetic analysis. Unexpectedly,
there was a late emergence of
Vß4+CD8+ T cells in the
CD4-/-, but not MHC class
II-/- animals (Fig. 7), that correlated with the late
appearance of activated B cells in the CD4-/-
mice (Fig. 8). These results suggest that
there may be additional factors controlling the effect of
CD4+ T cells on Vß4+ T cell
expansion that differ between the two experimental models, and/or that
CD4-/- animals develop compensatory mechanisms
that are not found in the MHC class II-/-
animals.
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IFN- is produced at high levels in the spleen and lymph nodes
during MHV-68 infection (22). Numbers of IFN--secreting
CD4+ T cells, including virus-specific as well as
bystander-activated CD4+ T cells, increase
gradually in the spleen, attaining peak levels at 14 days after
infection (23). It has been shown that these cells mediate
virus-specific effector function through IFN- (24),
raising the possibility that the requirement for
CD4+ T cells for
Vß4+CD8+ T cell
activation is also mediated through IFN-. To test this possibility,
levels of Vß4+CD8+ T
cells were assessed in MHV-68-infected
IFN--/- mice. The data show normal levels of
Vß4+CD8+ T cells (Fig. 9) and CD8+ T cell
activation (data not shown) in IFN--/- mice.
The ability of infected spleen cells from
IFN--/- mice to stimulate a representative
MHV-68-specific Vß4 hybridoma was also assessed (Fig. 10). Interestingly, there was an
8-fold increase in hybridoma stimulation by day 14 spleen cells from
MHV-68-infected IFN--/- mice relative to B6
controls, which correlates with an increase in latency levels at day 14
(data not shown). Both the hybridoma reactivity and latency had
returned to normal levels by day 17 (data not shown). These data
reinforce the correlation between latency and expression of the ligand
for Vß4+CD8+ T cell
stimulation (11). The increased hybridoma stimulation and
the high levels of
Vß4+CD8+ T cells in
MHV-68-infected IFN--/- mice rule out the
possibility that the requirement for CD4+ T cells
is mediated through IFN-.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A requirement for CD4+ T cells for generation of
the ligand is consistent with the idea that B cell activation is
associated with the activation of
Vß4+CD8+ T cells. The
demonstration that late expansion of
Vß4+CD8+ T cells observed
in CD4-/-, but not MHC class
II-/- mice, is accompanied by the late
emergence of activated (PNAhigh) B cells supports
this possibility. Previous analysis of CD4-/-
mice described the development of a population of
CD4-CD8-
(double-negative) TCRß+ T cells that
compensate functionally for CD4+ T cell help for
B cells and facilitate isotype switching (25). This
population of cells has not been described for MHC class
II-/- mice, and these mice are incapable of
undergoing isotype switching (20, 26). An association
between Vß4+CD8+ T cell
expansion and B cell activation is also consistent with the finding
that there is no Vß4+CD8+
T cell expansion in B cell-deficient µMT mice or
CD40L-/- mice 27 .
It is possible that the stimulatory ligand is expressed exclusively by latently infected, activated B cells. Alternatively, Vß4 stimulation may be dependent on a threshold level of expression of the ligand, controlled by the level of latent infection, which in turn may be dependent on CD4+ T:B interactions. The latter possibility is consistent with the recent report that B cells may control levels of latency despite the fact that they are not required for the establishment of MHV-68 latency (28). In support of a threshold effect is the finding that spleen cells from MHV-68-infected MHC class II-/- mice are capable of weak hybridoma stimulation, although these mice do not show Vß4 expansion after MHV-68 infection. Of relevance to this point is our finding that there were activated B cells in the MHC class II-/- mice 14 days after infection, although reduced compared with the B6 mice, but there was no evidence for B cell activation at this time point in the CD4-/- or CD4 Ab-depleted mice.
The finding that spleen cells from infected MHC class II-/- mice can stimulate T cell hybridomas in vitro, but not drive expansion of naive Vß4+CD8+ T cells in vivo, raises the possibility that CD4+ T cells are also required as helper cells for Vß4+CD8+ T cell expansion, in addition to their role in generation of the ligand. CD4+ T cell help might only be required in vivo in situations of reduced levels of latency, and correspondingly low levels of stimulatory ligand.
It should be emphasized that, in contrast to the essential role for B cell activation in the establishment of EBV latency (29), B cells do not appear to be required for MHV-68 latency. Latency can be established in B cell-deficient mice, and cells other than B cells can be latently infected (4, 5, 30). In addition, there is no conservation of latency-associated genes between the two viruses (31). The current studies do not address requirements for the establishment of latency, but do suggest that activated B cells may be a requirement for Vß4+CD8+ T cell expansion. As Vß4+CD8+ T cell expansion has also been linked to early stages in the establishment of latency, further characterization of latent gene expression in activated B cells is clearly important.
Expansion of Vß4+CD8+ T cells is prevented whether CD4+ T cells are depleted at the time of infection or 7 days after infection. Taking the current results together with our previously published report showing that CD4+ T cell depletion at day 11 did not affect Vß4 expansion (8), the data suggest that Vß4 expansion becomes independent of CD4+ T cells sometime between 7 and 11 days of infection, just before the major increase in levels of latency that peaks at 14 days. Again, this is consistent with the hypothesis that Vß4+CD8+ T cells are responding to a ligand expressed during latent infection, and that CD4+ T cells are required for ligand expression.
It should be noted that, despite the lack of Vß4+CD8+ T cell expansion, there was still substantial CD8+ T cell activation in the CD4-deficient animals. This is consistent with data showing that Vß4+ T cells are only one component of the CD8+ T cell lymphocytosis in the peripheral blood. Although there is not a relative increase in the percentage of T cells bearing TCR Vß elements other than Vß4, there is generalized CD8+ T cell activation indicated by the characteristic CD44high, CD62Llow, PNAhigh phenotype. This may represent both nonspecific activation driven by the cytokine-rich milieu of the spleen during the infection (22), and specific activation, driven by latent Ags (32) (E. Usherwood and D. L. Woodland, manuscript in preparation) or late lytic Ags (9, 10). The presence of CD8+ T cells in the peripheral blood reactive to latent or lytic viral epitopes would be consistent with recent studies in EBV (33, 34).
MHV-68 infection elicits high levels of IFN--secreting
CD4+ T cells (22, 23, 24). However, the
present studies showed no reduction of
Vß4+CD8+ T cell expansion
in IFN--/- mice, indicating that IFN- is
not functioning in the CD4 requirement for
Vß4+CD8+ T cell
expansion. Although high levels of IFN- are induced during MHV-68
infection, analysis of MHV-68-infected
IFN--/- mice showed that IFN- was not
essential for recovery from acute intranasal infection, and there
appeared to be little effect on splenomegaly and the establishment of
viral latency (35). In contrast, disruption of the
characteristic splenomegaly was observed in IFN-R-deficient mice,
characterized by infiltration of the spleen with granulocytes, reduced
numbers of CD4+ and CD8+ T
cells and B cells, and a 10–100-fold increase in levels of latent
virus (36). The reasons for differences in the two models
are unclear, but it was suggested previously that the IFN-R might
act as the receptor for another cellular or viral cytokine
(36).
Previous studies have shown that expression of the Vß4+CD8+ T cell stimulatory ligand correlates with the peak of splenic latency as measured by the infective center assay, consistent with the hypothesis that a viral or cellular gene product expressed during latency is driving the unusual T cell activation (11). In the current study, we have shown that the striking expansion of Vß4+CD8+ T cells in the peripheral blood of MHV-68-infected mice is dependent on CD4+ T cells. It is our hypothesis that CD4+ T cells are required for optimal expression of the stimulatory ligand, perhaps due to a requirement for CD4+ T cell help for B cell activation leading to establishment of a particular pattern of latency. In addition, CD4+ T cells may also be important for conventional T cell help for Vß4+CD8+ T cells, particularly in cases in which there is suboptimal expression of the ligand. Whether Vß4+CD8+ T cells are stimulated by a ligand expressed exclusively on B cells, whether quantitative and/or qualitative differences in latency control their stimulation, and the identification of the stimulatory ligand are currently under investigation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marcia A. Blackman, Department of Immunology, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105. E-mail address:
3 Abbreviations used in this paper: MHV-68, murine gammaherpesvirus-68; PNA, peanut agglutinin.
Received for publication April 30, 1999. Accepted for publication July 7, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-herpesvirus reactivation in CD4-deficient mice. Proc. Natl. Acad. Sci. USA 95:15565. genes. Science 259:1739.-herpesvirus in B cell-deficient mice is mediated by IFN-. Proc. Natl. Acad. Sci. USA 96:5135. Interferon is not essential for recovery from acute infection with murine gammaherpesvirus 68. J. Virol. 71:3916.[Abstract]
interferon receptor-deficient mice infected with murine gammaherpesvirus: a role for CD8 T cells. J. Virol. 71:4278.[Abstract]
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 B. Ebrahimi, B. M. Dutia, D. G. Brownstein, and A. A. Nash Murine Gammaherpesvirus-68 Infection Causes Multi-Organ Fibrosis and Alters Leukocyte Trafficking in Interferon-{{gamma}} Receptor Knockout Mice Am. J. Pathol., June 1, 2001; 158(6): 2117 - 2125. [Abstract] [Full Text] [PDF]
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G. T. Belz and P. C. Doherty Virus-Specific and Bystander CD8+ T-Cell Proliferation in the Acute and Persistent Phases of a Gammaherpesvirus Infection J. Virol., May 1, 2001; 75(9): 4435 - 4438. [Abstract] [Full Text]
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 C. L. Hardy, S. L. Silins, David. L. Woodland, and M. A. Blackman Murine {gamma}-herpesvirus infection causes V{beta}4-specific CDR3-restricted clonal expansions within CD8+ peripheral blood T lymphocytes Int. Immunol., August 1, 2000; 12(8): 1193 - 1204. [Abstract] [Full Text] [PDF]
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E. Flano, S. M. Husain, J. T. Sample, D. L. Woodland, and M. A. Blackman Latent Murine {gamma}-Herpesvirus Infection Is Established in Activated B Cells, Dendritic Cells, and Macrophages J. Immunol., July 15, 2000; 165(2): 1074 - 1081. [Abstract] [Full Text] [PDF]
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