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Type II Receptor-Transduced Bone Marrow Leads to Myeloid Expansion and Inflammatory Disease1
* Department of Urology, Northwestern University Medical School, Chicago, IL 60611;
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892; and
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
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Abstract |
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regulation of immune homeostasis has been investigated in
the context of cytokine knockout (TGF- null) mice, in which
particular TGF- isoforms are disrupted throughout the entire
organism, as well as in B and T cell-specific transgenic models, but to
date the immunoregulatory effects of TGF- have not been addressed in
the context of an in vivo mouse model in which multi-isoform TGF-
signaling is abrogated in multiple leukocyte lineages while leaving
nonhemopoietic tissue unaffected. Here we report the development of a
murine model of TGF- insensitivity limited to the hemopoietic tissue
of adult wild-type C57BL/6 mice based on retroviral-mediated gene
transfer of a dominant negative TGF- type II receptor targeting
murine bone marrow. Unlike the lymphoproliferative syndrome observed in
TGF-1-deficient mice, the disruption of TGF- signaling in bone
marrow-derived cells leads to dramatic expansion of myeloid cells,
primarily monocytes/macrophages, and is associated with cachexia and
mortality in lethally irradiated mice reconstituted with dominant
negative receptor-transduced bone marrow. Surprisingly, there was a
notable absence of T cell expansion in affected animals despite the
observed differentiation of most cells in the T cell compartment to a
memory phenotype. These results indicate not only that TGF- acts as
a negative regulator of immune function, but that lack of functional
TGF- signaling in the myeloid compartment of adult mice may trigger
suppression of lymphocytes, which would otherwise proliferate when
rendered insensitive to TGF-. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a highly pleiotropic 25-kDa cytokine secreted by
most cell types of the immune system and is known to play a variety of
immunoregulatory roles, including the maintenance of lymphocyte
homeostasis in vivo (1, 2, 3). Knockout mice deficient in
TGF-1 production show both embryonic and neonatal lethality as the
result of a multifocal inflammatory response (4, 5), while
TGF-2- and TGF-3-deficient mice suffer from a broad range of
developmental defects (6, 7, 8). Transgenic mice with
targeted disruptions of TGF- signaling in T cells (9, 10) or B cells (11) display lymphocyte-mediated
autoimmune pathology, and while these latter transgenic approaches have
helped to elucidate the role of TGF- signaling in individual
leukocyte lineages, they leave open the question of immune pathology
arising in adult mice as the result of TGF- signaling perturbation
in multiple leukocyte subtypes in adult animals. To study the effect of
TGF- on the cells of the immune system as a whole without
compromising TGF- signaling in peripheral tissues, it is necessary
to isolate the effect of an experimental model to the hemopoietic
compartment. Such an approach allows for the study of TGF- immune
regulation in the context of a host animal bearing normal TGF-
cytokine and receptor expression patterns elsewhere, insuring that
TGF- regulation of nonimmune processes, e.g., cell growth and
differentiation, will be maintained.
TGF- signaling is mediated through a pair of heterodimeric surface
receptors, TGF- type I and type II (12). The type II
receptor provides a suitable target for disruption of the signaling
pathway via a dominant negative receptor approach
(13, 14, 15), as it is responsible for binding to activated
soluble extracellular ligand, wherein it recruits the type I receptor
into the signaling complex and initiates downstream signaling mediated
by the Smad family of proteins (16, 17, 18). While
TGF- type II receptor knockout mice are nonviable due to defective
yolk sac vasculogenesis in the embryo (19), targeted
disruption of the TGF- signaling pathway has been effectively
achieved in a number of murine models by restricting the expression of
a dominant negative type II TGF- receptor
(TBRIIDN)3 in the tissue of
interest, including the lymphocyte transgenic models discussed above as
well as in nonlymphoid tissue such as the mammary gland
(20) and pancreas (21). Therefore, we opted
to disrupt TGF- signaling by overexpressing a type II receptor
construct with a truncated cytoplasmic domain in cells of the
hemopoietic compartment through the use of retrovirally mediated gene
transfer into murine bone marrow. Successfully infected murine bone
marrow was then used to repopulate lethally irradiated adult C57BL/6
recipients, allowing for reconstitution of the host with
TGF--insensitive leukocytes of all hemopoietic-derived subtypes
(e.g., T cells, B cells, monocyte/macrophages, granulocytes, NK cells,
and bone marrow-derived dendritic cells). Given the neonatal lethal
phenotype of the TGF- knockout mouse, we expected that a systemic
inflammatory phenotype would develop in the reconstituted adult mice,
deriving primarily from lymphocyte-mediated autoimmunity. Unexpectedly,
our results demonstrate that adult mice reconstituted with
TGF--insensitive bone marrow develop dramatic expansion of myeloid,
rather than lymphoid, cells in addition to a spontaneous
differentiation of T cells from a naive to a memory phenotype, with
mice developing marked cachexia within 3–4 mo posttransplant.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The TBRIIDN was excised from PCDNA3-TBRIIDN by BamHI/EcoRI digestion and inserted into the pMig-internal ribosomal entry sequence (IRES)-green fluorescence protein (herein designated MSCV-GFP) vector by first linearizing pMig with EcoRI and ligating in an EcoRI/BamHI adapter (5'-AATTGGATCCGCGGCCGCG-3', 3'-CCTAGGCGCCGGCGCTTAA-5'). These clones were designated MSCV-TBRIIDN and were screened by sequencing for correct orientation and insert number.
Production of retroviral supernatant
GP293 pantropic packaging cells (Clontech, Palo Alto, CA) were seeded at a density of 2.5 x 106 cells in T-25 collagen I-coated flasks (BIOCOAT; BD Biosciences, Mountain View, CA) 24 h before transfection in antibiotic-free DMEM/10% FBS. Cells were transfected using Lipofectamine Plus (Life Technologies, Gaithersburg, MD) with 2 µg pMig-TBRIIDN or pMig-GFP plus 2 µg vesicular stomatitis virus G plasmid for 12 h in serum-free medium and an additional 12 h after the addition of an equal volume of 20% FBS/DMEM. After 24 total h of transfection, the cells were washed gently in PBS, and fresh complete DMEM was added to the flasks, which were incubated for an additional 24 h before collection of supernatant.
Bone marrow isolation
Six- to 10-wk-old C57BL/6 (Ly5.2; Harlan Sprague-Dawley, Indianapolis, IN) or B6.SJL (Ly5.1; The Jackson Laboratory, Bar Harbor, ME) donor mice were anesthetized and injected i.p. with 5 mg 5-fluorouracil in 0.5 cc PBS. Five days later mice were sacrificed by cervical dislocation, and hind femora and tibiae were isolated and cleaned of muscle and soft tissue. Isolated bones were cut at the ends, and marrow was aseptically flushed in complete DMEM using 26-gauge needles (BD Biosciences) into 50-ml tubes, passed through a 40-µm pore size cell strainer (Falcon; BD Biosciences), and centrifuged at 500 x g. Pelleted cells were resuspended in 1x Pharmlyse (BD PharMingen, San Diego, CA) hypotonic ammonium chloride lysing solution to remove RBC from suspension and pelleted as described above before resuspension of cells at 1–2 x 106/ml in 24-well plates. Recombinant cytokines (R&D Systems, Minneapolis, MN) were added at concentrations of 20 ng/ml IL-3, 50 ng/ml IL-6, and 100 ng/ml stem cell factor and were replaced every 2 days of culture.
Infection of bone marrow culture and reconstitution of mice
After 48 h of culture, bone marrow cells were spun at 1000 x g, and supernatant was aspirated and replaced with infection mixture consisting of 1 ml viral supernatant, 10 µg/ml Polybrene (Sigma-Aldrich, St. Louis, MO), and HEPES buffer. Plates were centrifuged at 1000 x g for 90 min at room temperature, followed by addition of fresh cytokine-containing medium. This process was repeated at 72 h postisolation, followed by an additional 2 days of activation before transplant. Recipient C57BL/6 mice were irradiated in split doses of 800 and 400 rad, 3 h apart, in a Gammacell-40 irradiator (Atomic Energy of Canada, Mississauga, Ontario, Canada), and 1–2 x 106 cells were injected in PBS via warmed tail veins using 27-gauge needles. Transplant recipients were housed in pathogen-free facilities at the Center for Comparative Medicine, Northwestern University Medical School, and were maintained on trimethoprim/sulfamethoxazole for 4 wk after bone marrow transplant. All animal procedures were conducted under guidelines set by the animal care and use committee at Northwestern University Medical School.
Western blotting for Smad-2 phosphorylation
NIH-3T3 cells infected with pMig-TBRIIDN were trypsinized and collected in cold lysis buffer containing 1 mM Na2VO3 and centrifuged to remove cellular debris. Protein lysate was run on a Novex/10% acrylamide gel and blotted onto a polyvinylidene difluoride membrane. Blots were probed using anti-Smad2 (Upstate Biotechnology, Lake Placid, NY), anti-phospho-Smad2 (Upstate Biotechnology), or anti-GAPDH (Chemicon, Temecula, CA) mAb and visualized using ECL (Amersham Pharmacia Biotech, Piscataway, NJ) chemiluminescence kit.
Flow cytometric analysis of GFP expression in transplant recipients
Single-cell suspensions of bone marrow, spleen, or lymph nodes were obtained, and RBC were lysed as described above. The cells were resuspended in cold flow buffer (3% FBS and 0.1% sodium azide in PBS). All Abs and strepavidin-coupled fluorochromes were obtained from BD PharMingen, except as noted, and stained cell populations were analyzed for fluorescence on a FACSCalibur (BD Biosciences) in the Northwestern University Medical School Department of Microbiology/Immunology.
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Results |
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To develop a model of TGF- signal down-regulation that affects
all subclasses of leukocytes, but is strictly confined to cells of the
hemopoietic compartment, we employed a retrovirally mediated gene
transfer protocol targeting 5-fluorouracil-treated cultured
murine bone marrow. As shown in Fig. 1
A, we ligated a truncated
sequence of the human TGF- type II receptor into an MSCV-based
bicistronic retroviral vector coexpressing GFP under the control of the
5' long terminal repeat viral promoter (22, 23). The
truncated receptor sequence contained both the extracellular ligand
binding domain as well as the transmembrane domain, but lacks the
cytoplasmic kinase domain responsible for mediating intracellular
TGF- signaling. Vesicular stomatitis virus G pseudotyped virus was
generated in GP293 packaging cells, and the supernatant was used to
infect ex vivo target cells cultured in IL-3, IL-6, and stem cell
factor. Transfer efficiency into primary bone marrow cells using this
approach was consistently 90% as assayed by GFP expression (data not
shown), thus making it possible for us to forgo further FACS to obtain
a high expressing population of donor cells. Functional analysis of the
dominant negative receptor expressed in mouse bone marrow cells
indicated that Smad-2 phosphorylation was absent in TBRIIDN-transduced
cells treated with 10 ng/ml TGF- in culture, but not in
mock-infected cells or cells infected with vector controls expressing
GFP alone (Fig. 1B), indicating specific abrogation of the
TGF-/Smad signal pathway in transgene-positive cells.
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To express the dominant negative receptor on all
lineages of the hemopoietic compartment without affecting
nonhemopoietic tissue, we isolated bone marrow from C57BL/6
(Ptprcb, Ly5.2[CD45.2]) mice and
transduced these cells ex vivo with the MSCV-TBRIIDN virus before
reinfusion into lethally irradiated (1200 rad) C57BL/6 or congenic
B6.SJL (Ptprca, Ly5.1[CD45.1])
recipients. Survival of GFP control bone marrow transfer recipients was
>90% (21 of 22) at 6 mo post-transfer, confirming that the ex vivo
culture protocol did not deplete the marrow of hemopoietic stem cells
(HSC) (24, 25) or compromise the ability of the HSC to
mediate long term radioprotection, and complete blood counts indicated
comparable hematologic recovery of RBC, platelet, and WBC populations
in both TBRIIDN mice and GFP controls (data not shown). Long term
transgene expression in the bone marrow of transplant recipients was
confirmed by flow cytometric analysis at 6 mo posttransplant, which
indicated no significant reduction of GFP expression in either TBRIIDN
or GFP-transduced mice (Fig. 1
C). Expression of the viral
progenome in hemopoietic lineages was assessed by flow cytometric
analysis for GFP expression 2–3 mo after bone marrow transplant. As
shown in Fig. 2, this regimen was
effective in reconstituting both myeloid (Mac-1, Gr-1, CD11c) and
lymphoid (CD3, B220, NK1.1) lineages with a high proportion of donor
(GFP+) cells. Transcriptional silencing in
differentiating cell types, often a major concern in retroviral models
of gene expression, was assayed by comparing
CD45.2+ (donor) and CD45.1+
(recipient) expression on GFP- bone marrow cells
and splenocytes. While both bone marrow and isolated splenocytes were
repopulated almost entirely by GFP+ cells (Figs. 1C and 2), the GFP- fraction of the
spleen in both TBRIIDN and control mice was found to contain
predominantly donor cells (data not shown), indicating a moderate loss
of gene expression in maturing leukocytes, largely confined to the NK
cell and T cell compartment.
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TBRIIDN-bone marrow transfer recipients showed no gross
abnormalities for 
1–2 mo after bone marrow transplant, at which
time both T and B cell development in the thymus and bone marrow,
respectively, appeared phenotypically normal (data not shown); however,
mice began to exhibit a progressive cachexic phenotype at time points
between 2–3 mo (Fig. 3A),
including ruffled fur, hunched posture, and dramatic weight loss of
nearly 50% (26.4 ± 0.6 vs 14.4 ± 1.2 g) compared with
littermate GFP controls (p < 0.05;
n = 10/group). The mortality of mice receiving
TBRIIDN-transduced bone marrow transplants was significantly increased
compared with that of mice transplanted with marrow transduced with GFP
vector controls (Fig. 3B). Because transgenic mice
expressing a dominant negative TGF- receptor specifically in T cells
(10) displayed an autoimmune phenotype at 6 mo of age,
we suspected that the TBRIIDN bone marrow recipients could develop
autoreactive immunity at an accelerated pace, given that all leukocyte
subclasses were expressing the dominant negative receptor. To determine
whether the observed cachexic phenotype was associated with
lymphoproliferative disease, we analyzed splenocytes from affected mice
for the expression of various lineage determinants and compared the
total cell numbers and proportions of leukocyte subtypes to those for
GFP controls. Flow cytometric analysis of splenocytes from TBRIIDN mice
displaying cachexia revealed a dramatic expansion of a subpopulation of
splenocytes displaying an altered forward/side scatter profile (Fig. 4). Analysis of these cells revealed that
they were negative for lymphocyte cell surface markers
(CD3/B220/NK1.1), suggesting that the expanded population was of
myeloid origin. Indeed, staining of these cells for CD11b (Mac-1)
indicated that monocytes/macrophages are probably the primary
constituent of the expanded subpopulation (Fig. 4, inset),
and total splenic Mac-1high counts in TBRIIDN
mice were 34.7 x 106 vs 7.8 x
106 for GFP controls
(p < 0.05; n = 3/group).
Histological analysis of TBRIIDN mice (Fig. 5) indicated a significant mononuclear
infiltration into the extravascular tissue of the lungs, with an acute
inflammatory infiltrate present in the bronchioles consisting primarily
of polymorphonuclear cells, possibly due to leakage into the airspaces
as the result of tissue damage around the alveolar spaces. The
possibility of acute infection in the bronchiole appears unlikely given
that all transplant recipients were maintained in pathogen-free barrier
facilities for the duration of the experiment.
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Transgenic mouse models of TGF- insensitivity in T cells have
indicated a spontaneous differentiation to a memory-like
CD44high phenotype in vivo. To investigate
whether T cells derived from engrafted HSC expressing the viral TBRIIDN
transgene spontaneously differentiated to an activated or memory
phenotype, we examined the expression of activation markers CD44,
CD62L, and CD25 (IL-2R). While levels of CD25 expression remained
essentially unchanged between both groups throughout the experimental
time course (data not shown), CD8+ T cells
recovered from spleens displayed a CD44high
phenotype (Fig. 6) as early as 6 wk
post-transplant, consistent with the transgenic models discussed above.
While CD44 up-regulation was an early event, usually taking place
before the onset of obvious morbidity, CD62L down-regulation appeared
to be a temporally independent event and was typically not observed in
either CD4 or CD8 T cells before 3–4 mo of age (data not shown),
usually well after the onset of the cachexic phenotype. In older
TBRIIDN mice, CD62L was down-regulated significantly (Fig. 6) on both
CD4/CD8 cells, but total T cell counts recovered from the spleens of
highly moribund mice were not elevated over those of control mice (data
not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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insensitivity limited to
hemopoietic tissue, but not limited to expression on a single leukocyte
subtype, and characterized the gross pathology of the resulting immune
syndrome in mice. Lethally irradiated C57BL/6 mice reconstituted with
bone marrow expressing TBRIIDN exhibited immune-mediated pathology
manifested by inflammation of peripheral tissue and a gradual cachexic
phenotype, leading to significantly increased mortality.
The retroviral gene transfer approach allowed us to examine the role of
TGF- signaling in immune homeostasis only so far as it involves the
immune compartment and eliminated the possible contribution of other
tissues to the observed phenotype, as is the concern with
non-tissue-specific cytokine knockouts. For example, TGF-1 knockout
mice show aberrant expression of MHC II on nonimmune tissue
(26), possibly contributing to the autoimmune inflammatory
phenotype. The cytokine knockout approach also leaves open the
possibility of TGF- signaling through redundant activity mediated by
TGF-2 or TGF-3, which may account for the phenotypic difference
seen between the autoimmune phenotype of the TGF-1 knockout mouse
and the nonviability of the TGF- type II receptor knockout.
The major technical concern in generating a model of TGF-
insensitivity using retroviral targeting of HSC is that mature
leukocytes derived from primitive transduced precursors will exhibit
transcriptional silencing of the transgene due either to multiple
stages of differentiation involving chromosome remodeling or perhaps as
a function of time (27). In the model described here there
was little if any silencing of the viral progenome as assayed by flow
cytometry for GFP expression in the unfractionated bone marrow of
reconstituted host mice, with the GFP+ fraction
typically 95%. Although there was evidence of limited transgene
silencing in the mature leukocytes of TBRIIDN-reconstituted mice, it
appears that the change in the activation profile of T cells to a
memory (CD44highCD62low)
phenotype was not absolutely dependent on maintaining transgene
expression for the life span of the individual cell; rather, it appears
that early phenotypic changes occurred before down-regulation of the
TBRIIDN or, alternatively, that differentiation to a memory phenotype
resulted from activation pathways mediated by other leukocytes rendered
insensitive to TGF-. It is notable that there was an absence of
dramatic CTL proliferation even among those mice exhibiting the most
acute symptoms, suggesting that lymphoproliferation in the above
mentioned T cell transgenic mice may involve a complex regulatory
pathway that is, in fact, inhibited in the context of overall immune
TGF- insensitivity, a surprising finding given the TGF- knockout
phenotype. The differentiation to a CD44high
phenotype in TBRIIDN T cells of both CD4 and CD8 lineage was dramatic
and essentially total. Decreased surface expression of CD62L
(L-selectin), typical of memory T cells, was not observed in our
retroviral model until 3–4 mo after bone marrow transfer. The total
number of splenic T cells was not observed to increase dramatically at
any point in the time course of the experiment, including after the
development of gross abnormalities in the mice.
TGF- is noted to exert often contradictory regulatory effects on
numerous leukocyte lineages, and it has been observed that the effect
of TGF- on a given cell type is often dependent on the overall
cytokine milieu in which the signaling takes place. This also appears
to be the case for TGF- signaling in monocyte/macrophages, where the
balance between inflammatory cytokines such as IFN-
and TGF- may
direct M-CSF-dependent bone marrow precursors toward either an
osteoclastic or a cytocidal response to TNF-
, respectively
(28). This model suggests that in the absence of TGF-
signaling, as is the case with TBRIIDN-bearing precursor cells,
M-CSF-dependent precursors may be biased toward an IFN--responsive
cytocidal pathway, which could help explain the dramatic expansion of
Mac-1high mononuclear cells in lymphoid tissue
and peripheral blood reported here. Further studies in our laboratory
are currently being conducted on mouse models deficient in various
proinflammatory cytokines to determine whether mediation of the
observed wasting phenotype is critically dependent on
macrophage-secreted products such as TNF-. Another line of
investigation underway seeks to determine whether inducible NO synthase
production of NO by activated macrophages may mediate an
anti-proliferative effect on the T cell compartment in our model,
which is suggested by up-regulation of inducible NO synthase in
TGF-1 knockout mice (29, 30) as well as by established
mechanisms of NO-mediated T cell suppression in infectious disease
(31) and cancer (32). Furthermore, the
flexibility of the retroviral approach will allow us to examine
phenotypes generated by reconstitution with TBRIIDN-transduced bone
marrow in transgenic mice deficient in T cell-mediated immunity, which
may help to define the role of Ag-specific immune responses in the
pathology described here.
The issue of TGF- regulation of stem cell differentiation is open to
further study by the use of this retroviral model, and it must be
considered a possibility that the absence of functional TGF-
signaling in bone marrow precursors could introduce a developmental
bias in the normal differentiation program from primitive, uncommitted
precursor cells to myeloid or lymphoid lineage-committed progenitors.
It is clear from our data that expression of TBRIIDN does not preclude
HSC engraftment or multilineage reconstitution of the hemopoietic
compartment, but this does not address the issue of development per se,
other than to indicate that there is no obvious block of development in
any one particular leukocyte lineage. TGF- has been hypothesized to
act as a critical regulator of HSC growth and cell cycle regulation
(33, 34, 35, 36) via its effects on cyclin-dependent kinase
inhibitors (37, 38, 39) and may play a pivotal role in the
maintenance of a quiescent stem cell pool in vivo. TBRIIDN-repopulated
C57BL/6 mice lose their ability to repopulate lethally irradiated mice
in a serial transplant assay (A. H. Shah, W. B. Tabayoyong, and
C. Lee, unpublished observations), while defects in hemopoiesis and
vasculogenesis have been reported in both cytokine (40)
and type II receptor (19) transgenic mice.
We believe that the model described here offers a useful approach to
define the in vivo role of TGF- in immune regulation and
hemopoiesis. The facts that the model is based on wild-type mice and
can be easily modified to generate similar models on a variety of
available genetic backgrounds give this approach a practical advantage
over using transgenics, which are typically available in a limited
number of strains.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Chung Lee, Department of Urology, Tarry 11-715, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: c-lee7{at}northwestern.edu
3 Abbreviations used in this paper: TBRIIDN, dominant negative TGF- type II receptor; CD62L, CD62 ligand; GFP, green fluorescent protein; HSC, hemopoietic stem cells; IRES, internal ribosomal entry sequence; MSCV, murine stem cell virus.
Received for publication March 14, 2002. Accepted for publication July 18, 2002.
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A. H. Shah, W. B. Tabayoyong, S. D. Kundu, S.-J. Kim, L. Van Parijs, V. C. Liu, E. Kwon, N. M. Greenberg, and C. Lee Suppression of Tumor Metastasis by Blockade of Transforming Growth Factor {beta} Signaling in Bone Marrow Cells through a Retroviral-mediated Gene Therapy in Mice Cancer Res., December 15, 2002; 62(24): 7135 - 7138. [Abstract] [Full Text] [PDF]
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