Download Reconstitution of CD8 T cells is essential for the prevention of

Journal
of General Virology (1998), 79, 2099–2104. Printed in Great Britain
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SHORT COMMUNICATION
Reconstitution of CD8 T cells is essential for the prevention of
multiple-organ cytomegalovirus histopathology after bone
marrow transplantation
Ju$ rgen Podlech, Rafaela Holtappels, Nikolaus Wirtz, Hans-Peter Steffens and Matthias J. Reddehase
Institute for Virology, Johannes Gutenberg University, Hochhaus am Augustusplatz, 55101 Mainz, Germany
Cytomegalovirus (CMV) infection in the period of
temporary immunodeficiency after haematoablative treatment and bone marrow transplantation (BMT) is associated with a risk of graft failure
and multiple-organ CMV disease. The efficacy of
immune system reconstitution is decisive for the
prevention of CMV pathogenesis after BMT. Previous data in murine model systems have documented a redundancy in the immune effector
mechanisms controlling CMV. CD8 T cells proved to
be relevant but not irreplaceable as antiviral effectors. Specifically, in a state of long-term in vivo
depletion of the CD8 T-cell subset, CD4 T cells were
educed to become deputy effectors controlling CMV
by a mechanism involving antiviral cytokines. It is of
medical importance to know whether one can trust
in this ‘ flexible defence ’ in all clinical settings. It is
demonstrated here that reconstitution of CD8 T
cells is crucial for the prevention of fatal multipleorgan CMV disease under the specific conditions of
BMT.
Patients undergoing bone marrow transplantation (BMT)
associated with temporary immunodeficiency are at risk of fatal
cytomegalovirus (CMV) disease with multiple organ involvement (for reviews see Winston et al., 1990 ; Einsele et al., 1998).
Whether or not primary or recurrent CMV infections develop
into disease appears to be related to the efficacy of haematopoietic and immune system reconstitution. Specifically, early
reappearance of CD8 T cells is of positive prognostic value for
recovery (Reusser et al., 1991). Accordingly, restoration of
immunity to CMV by adoptive cytoimmunotherapy with
antiviral CD8 T-cell lines is in clinical trials (Riddell et al., 1992 ;
Walter et al., 1995). In BMT performed across minor or class I
major histocompatibility disparities, graft vs. host disease
(GvHD) is a further risk factor (Einsele et al., 1998). In a major
Author for correspondence : Matthias Reddehase.
Fax ­49 6131 395604. e-mail Matthias.Reddehase!uni-mainz.de
histocompatibility complex (MHC) class II-identical but MHC
class I-disparate setting, selective depletion of class I-restricted
CD8 T cells might be discussed as a regime for GvHD
prophylaxis. However, if CD8 T cells were the only effectors
Fig. 1. (A) Lethality of CMV infection after selective T-cell subset
depletion. Syngeneic BMT was performed on day 0 with BALB/c mice as
BM cell donors and recipients. Recipients were infected with 1¬105 p.f.u.
of purified murine CMV ca. 2 h after BMT. In vivo depletion of T-cell
subsets was performed twice, namely on days 7 and 14, by intravenous
administration of 1 mg of the respective antibody. Kaplan–Meyer plots
show the survival rates for 20 recipients per experimental group as a
function of time. (B) Efficacy and specificity of the T-cell subset depletions.
Pulmonary infiltrate leukocytes were isolated on day 21 and analysed by
three-colour cytofluorometry for the expression of TCR α/β (phycoerythrin
fluorescence, FL-2), CD4 (RED613 fluorescence, FL-3) and CD8 (FITC
fluorescence, FL-1). Gates were set on lymphocytes and on positive FL-2
in order to restrict the analysis to α/β T cells. Dot plots show the log FL-3
(ordinate) versus log FL-1 (abscissa) intensities for 20 000 α/β T cells.
The percentages of CD4 and CD8 T cells are given in the respective
quadrants.
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J. Podlech and others
Fig. 2. Enhancement of CMV replication in tissues by selective depletion of CD8 T cells. Virus replication on day 21 after BMT
(see Fig. 1) was monitored by in situ DNA hybridization specific for the murine CMV genome. The label is provided by new
fuchsin, yielding a brilliant red colour. The counterstaining was done with haematoxylin. Bars represent 25 µm throughout. The
overview photographs document a selected tissue area of ca. 0±3 mm2. For tissues with even distribution of the infected cells,
numbers in the lower left corners of the photographs indicate the number of infected cells counted for a representative area of
10 mm2 compiled from five BMT recipients per experimental group. Arrows in panels A3–C3 point to sites of interest resolved
to greater detail in corresponding panels A3*–C3**. (Panels A) Sections of liver parenchyma, demonstrating inflammatory foci
sequestering infected hepatocytes. Note the pronounced intranuclear inclusion bodies containing the viral DNA in the late stage
of the virus replicative cycle. (Panels B) Sections of repopulated spleen tissue. The infection is localized in the stroma rather
than within follicles. (Panels C) Brain tissue including the third ventricle in coronal section. Note the infection of choroid plexus
epithelial cells (C3*) and of ependymal cells (C3**).
CBAA
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Fatal multiple-organ cytomegalovirus disease
Fig. 3. Multiple-organ CMV infection and histopathology. Pairs of photographs compare virus replication in tissues after specific
depletion of the CD4 T-cell subset (left) and the CD8 T-cell subset (right). The viral genome was detected as in Fig. 2 by in
situ DNA hybridization. Bars represent 25 µm throughout. The photographs document a selected tissue area of 0±04 mm2.
Numbers in the lower left corners give the number of infected cells counted in representative areas of 10 mm2 (panels A–D, G
and H) or of 2 mm2 (E and F), compiled from five BMT recipients per experimental group. (A1, A2) Lung tissue with infected
cells in proximity to bronchioles (b). (B1, B2) Gastrointestinal infection, represented by infection of the lamina propria in the
villi of small intestine, shown in transverse section. Note that infected cells are also found in the colon and the gastric mucosa
(not depicted). (C1, C2) Infected cells in the mucous acini of the submandibular gland. The inset shows infected acinar
epithelial cells resolved to greater detail. Cytoplasmic spots of staining (arrows) represent the virion DNA of numerous
monocapsid virions that are packaged in huge vacuoles for secretion. (D1, D2) Myocardial infection. Cardiac muscle cells and
endothelial cells are the main target cells in the heart muscle. (E1, E2) Infection of the adrenal cortex. Shown are foci of
infection localized in the zona glomerulosa (zg) underneath the capsule as well as in the zona fasciculata (zf). (F1, F2)
Infection of the adrenal medulla. Panel F1 includes the junction between adrenal medulla (m) and the X zone (xz) of the
adrenal cortex. (G1, G2) Selective infection of the glomeruli in the kidney cortex and absence of infection in the convoluted
cortical tubules. (H1, H2) Absence of infection in the tubular system of the kidney medulla. Opposed arrows mark tubules in
longitudinal section.
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J. Podlech and others
controlling CMV, such a treatment would entail a risk of
promoting the progression of subclinical CMV infection to
severe organ disease.
Murine models have been instrumental in studying specific
aspects of CMV pathogenesis. Depending on the genetic
background, the immune control of murine CMV infection in
the immunocompetent host is dominated by MHC-unrestricted natural killer (NK) cells or by MHC-restricted CD8 T
cells (Lathbury et al., 1996). Murine CMV infection of the
genetically susceptible BALB}c mouse inbred strain (MHC
haplotype H-2d) so far represents the model closest to human
CMV pathogenesis. Specifically, in this model, CD8 T cells
appeared to be the principal antiviral effectors (Reddehase et
al., 1985 ; for a review see Koszinowski et al., 1993). Upon
adoptive transfer for pre-emptive cytoimmunotherapy of
murine CMV disease in the immunocompromised host,
antiviral CD8 T cells prevented lethality as well as histopathology by controlling virus replication (Reddehase et al.,
1987 a, b, 1988 ; Dobonici et al., 1998). Furthermore, they
limited the establishment of latent infection (Steffens et al.,
1998 a). In these immunotherapy protocols, CD4 T cells
derived from infected donors did not confer antiviral protection, and the protective CD8 T cells did not depend on a
helper function of CD4 T cells. Thus, CD8 T cells proved to be
dominant and autarkic in the control of murine CMV. This
straight view was challenged by the finding that BALB}c mice
which were long-term depleted of the CD8 subset controlled
murine CMV infection perfectly well (Jonjic! et al., 1990). Along
the same line of evidence, β-2m!/! mutants on C57BL}6 (H-2b)
genetic background cleared the productive infection, even
though they were lacking functional MHC class I molecules
and, associated with this defect, were also lacking CD8 T cells
(Polic! et al., 1996). Thus, irrespective of the genetic background,
the knockout of CD8 T cells was compensated. Notably, in
both models, this compensation was not performed by NK
cells but required CD4 T cells and was mediated by the
induction of cytokines, specifically of interferon-γ and tumour
necrosis factor-α (Pavic! et al., 1993 ; Luc) in et al., 1994).
Apparently, in the absence of the CD8 T-cell subset, the
immune system gets reorganized and can then cope with CMV
infection by an alternative mechanism of defence.
Is this now a licence to deplete CD8 T cells for GvHD
prophylaxis in CMV-infected recipients of MHC class Idisparate BMT ? Can we generally count on the flexibility of
the immune system ? The answer to these questions is of
medical importance and of theoretical interest. It will tell us
whether in the specific situation of immunological reconstitution after BMT the newly generated CD4 T cells can
functionally replace the CD8 T-cell subset.
We approached the problem by experimental syngeneic
BMT performed with BALB}c mice as bone marrow (BM) cell
donors and haematoablated BALB}c mice as transplantation
recipients. A concurrent infection, initiated on the day of BMT
by intraplantar application of 10& p.f.u. of murine CMV strain
CBAC
Smith does not lead to CMV disease provided that the number
of transplanted BM cells suffices for an effective repopulation
of the recipient BM (Steffens et al., 1998 a, b). Insufficient
reconstitution, however, is associated with fatal CMV disease
(Mutter et al., 1988), including a pathogenesis within the BM
that is characterized by the infection of BM stroma cells and a
deficiency in the expression of stroma cell-derived haematopoietins (Mayer et al., 1997 ; Dobonici et al., 1998 ; Steffens et
al., 1998 b). On the basis of this previous experience, BMT was
herein performed with 1¬10( BM cells and haematoablative
treatment of the recipients with 6 Gy of total-body "$(Cs γirradiation in order to achieve a high rate of survival (Fig. 1 A,
+). Elimination in vivo of reconstituting CD4 T cells by
intravenous infusions of anti-CD4 monoclonal antibody YTS
191.1 (Cobbold et al., 1984) on days 7 and 14 was not
associated with significant lethality (Fig. 1 A, E). This finding
is not trivial, as it implies that CD4 T cells are dispensable for
survival not only with respect to a direct effector function but
also as helper cells for other immune effectors. Further,
depletion of CD4 T cells is known to preclude the generation
of antiviral antibody (Jonjic! et al., 1989). Thus, antibodies are
apparently not essential for prevention of fatal murine CMV
disease after BMT. This conclusion is in accordance with the
previous finding of effective resolution of primary murine
CMV infection in B-cell-deficient µ-chain!/! mice (Jonjic! et al.,
1994). By contrast, in vivo elimination of reconstituting CD8 T
cells with anti-CD8 monoclonal antibody YTS 169.4 (Cobbold
et al., 1984) on days 7 and 14 resulted in absolute lethality (Fig.
1 A, D). It should be noted that CD8 depletion was not fatal
after BMT in the absence of infection (not shown). The efficacy
of the depletions was monitored by three-colour cytofluorometric analysis of T cells that were infiltrating the lungs, a
major organ site of CMV pathogenesis and latency (Reddehase
et al., 1985 ; Balthesen et al., 1993). Pulmonary interstitial
leukocytes were isolated (Holt et al., 1985) and were labelled
with fluorochromated antibodies specific for T-cell receptor
(TCR) α}β, CD4 and CD8. Pulmonary T cells were analytically
selected by gating on positive TCR α}β expression, and the
subset composition is documented by dot plots of CD4 vs
CD8 expression (Fig. 1 B). The in vivo depletions proved to be
effective and specific, eradicating CD4 and CD8 T cells,
respectively. Most importantly, the treatment not only
depleted lymphoid tissues but indeed prevented any recruitment of the respective T-cell subsets to an important
organ site of CMV pathogenesis. In conclusion, survival was
strictly linked to the presence of CD8 T cells.
So far, the data have suggested that the reconstituted CD8
T cells did perform their protective function by controlling
virus replication. Hard evidence was provided by a detailed in
situ analysis of CMV replication and histopathology after
BMT (Figs 2 and 3). Productive murine CMV infection was
monitored by in situ hybridization detecting the viral DNA
that is found in infected cells accumulated in an intranuclear
inclusion body during the late phase of the virus replicative
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Fatal multiple-organ cytomegalovirus disease
cycle. The staining was performed essentially as described in a
recent report (Mayer et al., 1997), except that the sensitivity of
detection was enhanced by replacing the previously used
1±5 kbp gB gene DNA probe with a mixture of digoxigenized
plasmids containing HindIII fragments A, I and K, representing
51±2 kbp of the murine CMV strain Smith genome (Ebeling et
al., 1983 ; Rawlinson et al., 1996).
Fig. 2 shows the effect of T-cell subset depletions on virus
replication at 3 weeks after BMT in liver (Fig. 2, top row),
spleen (centre row) and brain (bottom row). In these organs,
murine CMV replication was almost completely prevented by
immune reconstitution after BMT if no T-cell depletion was
performed (Fig. 2, first column). Depletion of the CD4 T-cell
subset resulted in only a slight enhancement of virus replication
in liver and spleen with only single cells positive in the
documented tissue area (Fig. 2, second column). By contrast,
depletion of the CD8 T-cell subset was associated with a
dramatic increase in the number of infected cells, and, under
these conditions, murine CMV disseminated also to the brain
(Fig. 2, third column for overview and fourth column for
details). It should be noted that simultaneous depletion of CD4
and CD8 T cells gave results indistinguishable from those seen
with selective CD8 T-cell depletion (not shown). In the liver,
the hepatocyte is the predominant target cell of murine CMV
infection (Fig. 2, A3 and A3*). Infiltrating mononuclear cells
sequester infected hepatocytes, resulting in inflammatory foci
(panel A3*) that are reminiscent of NK cell foci described
recently in another model system of murine CMV hepatitis
(Salazar-Mather et al., 1998), with the notable difference that
the inflammation observed here in CD8 T-cell-depleted mice
was apparently not protective. Infected cells in the spleen are
likely to represent stromal cells (panel B3*). Virus replication in
the brain is confined to the ventricles (panel C3). Infected cell
types are the cerebrospinal fluid-producing choroid plexus
epithelial cells (panel C3*) as well as the ependymal cells lining
the ventricle cavity (panel C3**). Interestingly, the restricted
distribution of this β-herpesvirus in the brain resembles that of
a neuroattenuated variant of herpes simplex virus type 1 which
also infects ependymocytes and destroys the ependymal lining
(Kesari et al., 1998).
Fig. 3 compiles the results obtained after CD4 as well as
after CD8 T-cell depletion for further sites relevant to CMV
disease. The histological findings were alike in undepleted and
in CD4 T-cell-depleted recipients, and therefore the results for
the undepleted group are not separately presented.
The lungs and the gastrointestinal system (Fig. 3 A, B)
belong to a group of organs, including those already shown in
Fig. 2, in which significant virus replication occurred only in
the absence of CD8 T cells. Infected cell types in the lungs are
interstitial fibroblasts, pneumocytes and cells of the capillary
endothelium (Reddehase et al., 1985). Notably, only single
infected cells were found scattered in the lungs of CD4 T-celldepleted mice (Fig. 3, A1), whereas expansion to extended foci
of infection occurred after depletion of CD8 T cells (panel A2).
In the stomach, small intestine (panel B) and large intestine,
infection is localized in the lamina propria.
By contrast, salivary glands (panel C), heart (panel D),
adrenal gland cortex as well as medulla (panels E and F) and
kidney cortex (panel G) are sites at which murine CMV
replicates also in undepleted (not shown) and in CD4 T-celldepleted mice. This result was not unexpected for salivary
glands and kidney, which represent known sites of asymptomatic virus shedding also in the immunocompetent host.
Notably, in the acinar epithelial cells of salivary glands, viral
DNA is detectable also in cytoplasmic inclusions, which
correspond to vacuoles filled with numerous monocapsid
virions shown previously by electron microscopy (Jonjic! et al.,
1989). In the kidney cortex, infection is confined to the
glomeruli (panel G). Notably, tubules in the kidney medulla
were not infected (panel H).
In summary, in the salivary glands and, unexpectedly, also
in the adrenal medulla, virus replication was not significantly
controlled by either T-cell subset early after BMT. By contrast,
depletion of CD8 T cells led to enhanced virus replication in
most relevant organs resulting in fatal multiple-organ disease,
including hepatitis, splenitis, ventriculitis, pneumonitis, gastroenterocolitis, a moderate carditis, cortical adrenalitis and
glomerulitis.
In conclusion, in this setting of experimental BMT and
murine CMV infection, CD4 T cells or other effectors
apparently did not compensate for CD8 T cells in the control
of virus replication and disease. The precise conditions for the
development of alternative antiviral mechanisms in long-term
CD8 T-cell deficient mice have never been defined. Our data
are therefore not in conflict with previous work, but they
clearly tell us that the alternative antiviral defence mechanisms
are not educed when CD8 T cells get depleted during
haematopoietic reconstitution. We hence predict that CD8 Tcell depletion for GvHD prophylaxis will be a great risk in
BMT patients who are positive for human CMV.
This work was supported by grants to M. J. R. by the Deutsche
Forschungsgemeinschaft, project DFG RE 712}3-2 and Sonderforschungsbereich 311, project A18.
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Received 6 April 1998 ; Accepted 29 May 1998
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