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Journal of Virology, May 1999, p. 4518-4523, Vol. 73, No. 5
Department of Internal Medicine, Division of
Infectious Diseases, School of Medicine, University of California
Davis, Davis, California
Received 24 November 1998/Accepted 1 February 1999
The objective of this study was to determine the effects of primary
simian immunodeficiency virus (SIV) infection on the prevalence and
phenotype of progenitor cells present in the gastrointestinal epithelia
of SIV-infected rhesus macaques, a primate model for human
immunodeficiency virus pathogenesis. The gastrointestinal epithelium
was residence to progenitor cells expressing CD34 antigen, a subset of
which also coexpressed Thy-1 and c-kit receptors, suggesting that the CD34+ population in the intestine
comprised a subpopulation of primitive precursors. Following
experimental SIVmac251 infection, an early increase in the proportions
of CD34+ Thy-1+ and CD34+
c-kit+ progenitor cells was observed in the
gastrointestinal epithelium. In contrast, the proportion of
CD34+ cells in the thymus declined during primary SIV
infection, which was characterized by a decrease in the frequency of
CD34+ Thy-1+ progenitor cells. A severe
depletion in the frequency of CD4-committed CD34+
progenitors was observed in the gastrointestinal epithelium 2 weeks
after SIV infection which persisted even 4 weeks after infection. A
coincident increase in the frequency of CD8- committed
CD34+ progenitor cells was observed during primary SIV
infection. These results indicate that in contrast to the primary
lymphoid organs such as the thymus, the gastrointestinal epithelium may
be an early extrathymic site for the increased prevalence of both
primitive and committed CD34+ progenitor cells. The
gastrointestinal epithelium may potentially play an important role in
maintaining T-cell homeostasis in the intestinal mucosa during primary
SIV infection.
Human immunodeficiency virus (HIV)
infection has been demonstrated to cause a progressive loss in the
frequency of hematopoietic progenitors in the bone marrow, thymus, and
peripheral blood of HIV-seropositive individuals (2, 14, 15, 16,
23, 26, 29, 32, 48, 56, 57). Recent studies with the murine model
have demonstrated that gastrointestinal epithelium can function as an
extrathymic site for T-cell differentiation and maturation (41,
42). There is no information available, however, on the effects
of HIV infection on T-cell maturation or differentiation and progenitor
cell frequency in intestinal epithelium. The intestinal epithelium,
like the thymic epithelium, has been shown to be capable of supporting
T-cell differentiation and maturation (36) and also of
carrying out negative and positive selection of T cells (42). Since gastrointestinal lymphoid tissue harbors more
than 90% of the total lymphocytes in the body, a high level of T-cell turnover may occur at this site. The development and maturation of T
cells from tissue progenitors that might have migrated into the
gastrointestinal epithelium may be one of the mechanisms for maintaining T-cell homeostasis at these sites. Progenitor cells capable
of generating mature T cells have been isolated from cryptopatches of
the mouse intestinal epithelium (45). Murine intestinal
epithelial cells were shown to secrete the c-kit ligand
called stem cell factor (SCF), which supports T-cell differentiation
(7, 9). Since HIV infection can cause severe
CD4+ T-cell depletion, lymphopoiesis in the
gastrointestinal epithelium may be involved in maintaining T-cell
homeostasis. No information is available on the effects of HIV
infection on lymphopoiesis in the intestinal epithelium. These studies
have been limited by the inability to obtain sufficient amounts of
intestinal tissue samples in early stages of HIV infection.
Simian immunodeficiency virus (SIV)-infected rhesus macaques provide a
suitable animal model to determine the effect of HIV infection on the
lymphopoietic potential of the gastrointestinal epithelium. Our
previous studies have demonstrated that intestinal lymphoid tissue is
an early target organ for SIV (20, 21, 34, 49). Severe
depletion of CD4+ T cells coinciding with an increase in
CD8+ T cells was detected in both intestinal
intraepithelial lymphocytes and lamina propria during primary SIV
infection (34, 46). The early depletion of intestinal
CD4+ T cells was characterized by an attempt to maintain
homeostasis by constantly replenishing the depleted T-cell pool, as was
evidenced by the fact that there was an increase in CD8+ T
cells following infection (34, 51). The intestinal
epithelium may play an important role in this process. The potential of
the immune system to generate T cells to maintain T-cell homeostasis during the course of HIV infection has been demonstrated (1, 33). One of the mechanisms may involve differentiation and
maturation from T-cell precursors at thymic and extrathymic sites such
as the gastrointestinal epithelium.
Based on the above-described findings, we hypothesized that the
gastrointestinal epithelium may be an active site for the prevalence of
progenitor cells and that HIV infection leads to an alteration in the
phenotypic profile of these progenitor cells present in the
gastrointestinal epithelium. We used SIV-infected rhesus macaques to
enumerate and characterize the phenotype and frequency of
CD34+ progenitor cells in the gastrointestinal epithelium
and to determine whether SIVmac251 infection has an effect on the
phenotype and frequency of these CD34+ progenitor cells.
Viral loads in intestinal tissue during primary SIV infection.
Our previous studies have demonstrated that lymphocytes located in the
gastrointestinal epithelium were infected with SIV early during the
course of SIV infection, which resulted in severe changes in their
phenotypic and functional profiles (34). Higher numbers of
SIV-positive cells were detected during the primary acute and terminal
stages than during the asymptomatic stage of SIV infection. These
infected cells were strongly positive for SIV nucleic acids, indicating
that they may support active viral replication (34, 46). The
viral burden in intestinal tissue samples was measured by the branched
DNA signal amplification assay as previously described by Pachl et al.
(40) and Harris et al. (19). High copy numbers of
SIVmac251 RNA were detected in intestinal tissue samples during primary
SIV infection between 1 and 2 weeks postinfection (p.i.). At 2 weeks
p.i., the SIV RNA copy numbers in jejunum and colon tissues ranged from
423,000 to 596,000 and 410,000 to 674,000 per 25 mg of tissue,
respectively. The viral burden steadily increased, and by 4 weeks p.i.,
copy numbers ranged from 1,717,000 to 21,997,000 and 1,095,000 to
2,230,000 per 25 mg of tissue in jejunum and colon tissues,
respectively. The high viral loads, accompanied by severe
CD4+ T-cell depletion during early SIV infection, may have
a significant impact on the homeostatic mechanisms that operate in this
extensive and severely affected lymphoid compartment.
Unlike in the thymus, the frequency of CD34+
progenitors did not decline in the gastrointestinal epithelium during
primary SIV infection.
The frequency of CD34+
progenitors was determined by flow cytometry, using freshly isolated
mononuclear cells from jejunum and colon epithelium and thymus tissue
and peripheral blood from rhesus macaques (n = 4) 1 to
4 weeks after SIV infection. The cell isolation procedures and flow
cytometric analysis were performed as previously described (34,
46). The frequencies of CD34+ progenitors in the
intestinal epithelia of SIV-infected animals were compared with those
of uninfected control animals. A minor proportion of mononuclear cells
within the jejunum and colon epithelia of uninfected rhesus macaques
expressed the CD34 antigen, whereas the thymus tissues was found to
contain a higher proportion of CD34+ progenitors (Fig.
1a). The frequency of CD34+
progenitors in the colon epithelium increased at 1 to 2 weeks following
SIV infection (Fig. 1a) but returned to preinfection levels at 4 weeks
p.i. The percentages of CD34+ cells in the jejunal
epithelium did not show any decline and remained similar to the
preinfection values during primary SIV infection (Fig. 1a). The CD34
antigen has been shown to be expressed by a minor population of
mononuclear cells in the bone marrow which exhibit multilineage
progenitor cell activity in vitro (10, 11, 50). Previous
studies have shown that the CD34+ bone marrow cells were
enriched for primitive hematopoietic stem cells and may reconstitute
long-term multilineage hematopoiesis in nonhuman primates (5,
6). In the murine model, progenitor cells were found to be
present within the crypts found at the base of the villus epithelium
(45). Further, gastrointestinal intraepithelial lymphocytes
from humans (30) and mice (17) have been shown to
express RAG-1 (recombination activation gene 1), suggesting that the
intestinal epithelium may support extrathymic T-cell differentiation
and maturation. It is difficult to determine at this point why the
increase in CD34+ progenitors was more prominent only in
the colon epithelium. It may be possible that the unique
microenvironments of the jejunum and colon may play a role in this
process and may contribute to the differences observed in the
prevalence of CD34+ cells following SIV infection.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Gastrointestinal Epithelium Is an Early Extrathymic
Site for Increased Prevalence of CD34+ Progenitor Cells
in Contrast to the Thymus during Primary Simian Immunodeficiency
Virus Infection
ABSTRACT
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FIG. 1.
Alterations in the prevalence of CD34+
progenitor cells in the gastrointestinal epithelium during primary SIV
infection. Freshly isolated mononuclear cells from the jejunum and
colon epithelium and thymus tissues of uninfected control and
SIV-infected rhesus macaques at 1 to 2 weeks and 4 weeks p.i. were
stained with CD34 and CDw90 (Thy-1) or CD117 (c-kit
receptor) and analyzed by flow cytometry. Negative-control samples were
stained with matched-isotype control antibodies. The frequencies of
CD34+ (a), CD34+ Thy-1+ (b), and
CD34+ c-kit+ (c) cells were
determined as percentages of gated mononuclear cells.
|
The prevalence of primitive CD34+ progenitors expressing Thy-1 and the c-kit receptor increased in the gastrointestinal epithelium during primary SIV infection. The frequencies of CD34+ Thy-1+ progenitors were determined by flow cytometry, using freshly isolated mononuclear cells from jejunum and colon epithelium and with thymus tissue and peripheral blood from rhesus macaques (n = 4) at 1 to 4 weeks after SIV infection and compared to those from uninfected controls (Fig. 1b). A subpopulation of CD34+ cells in the gastrointestinal epithelium of uninfected control animals was found to express Thy-1, indicating that a subset of CD34+ progenitor cells in the intestinal epithelium consisted of primitive precursor cells. Studies have shown that the most primitive progenitor subsets of human bone marrow CD34+ cells were characterized by the expression of Thy-1 (4, 12, 18, 39). Further, these studies have demonstrated that Thy-1 antigen was expressed by a population of CD34high, CD45RAlow, and HLA-DRlow cells and that this population of cells was found to harbor high-proliferative-potential hematopoietic precursor cells and long-term-culture-initiating cells. Murray et al. (39) have demonstrated that the CD34+ Thy-1+ subset of peripheral blood stem cells is enriched for primitive stem cells. The frequencies of CD34+ Thy-1+ progenitors increased in both jejunum and colon epithelium at 1 and 2 weeks p.i. relative to those of uninfected controls (Fig. 1b) but returned to preinfection levels at 4 weeks p.i. In contrast to the case in the gastrointestinal epithelium, the frequency of CD34+ Thy-1+ progenitors in the thymus declined at 1 (n = 2) and 2 (n = 2) weeks p.i. and then increased to preinfection levels at 4 (n = 2) weeks p.i. (Fig. 2), suggesting that regeneration of CD34+ cells in the thymus was characterized by an increase in the frequency of CD34+ Thy-1+ progenitors. No significant differences in the levels of Thy-1 expression in intestinal epithelium and thymus tissues were observed between SIV-infected animals and control animals.
The primitive CD34+ progenitor cells have been shown to be enriched for the c-kit receptor. We determined the frequencies of CD34+ c-kit+ progenitors in freshly isolated mononuclear cells from jejunum and colon epithelium and in thymus and peripheral blood of rhesus macaques at 1 to 4 weeks after SIV infection and compared them with those of uninfected controls (Fig. 1c). The frequency of CD34+ c-kit+ cells was found to increase in the colon epithelium at 1 and 2 weeks p.i. but returned to preinfection levels at 4 weeks p.i. No decline was evident in the frequency of CD34+ c-kit+ cells within the jejunum epithelium relative to uninfected controls during primary SIV infection. Thymus was found to contain only a minor proportion of CD34+ c-kit+ progenitors (~1 to ~2%), which increased to ~6 to ~8% at 2 weeks p.i. and then returned to uninfected control levels at 4 weeks p.i. The c-kit receptor (CD117) is a tyrosine kinase-containing receptor that binds to SCF. Puddington et al. (43) have reported that the interactions between murine SCF and the c-kit receptor may play an important role in maintaining homeostasis in the gastrointestinal mucosa. Kanamori et al. (24) have identified tiny clusters of cells in the murine intestinal crypts. A large proportion of these cells expressed c-kit, the interleukin-7 receptor, Thy-1, and lymphocyte function-associated antigen 1 and were CD3
, T-cell
receptor 
and 
negative, soluble immunoglobulin M negative,
and B220, indicating that the crypts may be the
extrathymic site where the development of T and/or B progenitors takes
place and that they may be a source of extrathymic T cells. Briddell et
al. (8) have reported that in humans the c-kit
receptor is expressed on both primitive and more differentiated
hematopoietic progenitor cells.
Our results demonstrated that the frequency of CD34+
Thy-1+ and CD34+ c-kit+
primitive precursors in the gastrointestinal epithelium increased early
in SIV infection. Klimpel et al. (25) demonstrated that the
production of SCF was enhanced in the intestine following Salmonella infection and suggested that intestinal
epithelial cells may be the major producer of SCF. It is likely that
enhanced secretions of SCF may be observed following SIV infection.
Serum SCF levels were found to be elevated in HIV-infected patients (31). As SCF has been shown to increase the colony-forming
potential of hematopoietic progenitors obtained from HIV-infected
individuals (35, 52), secreted SCF may play an important
role in the differentiation of progenitor cells expressing the
c-kit receptor and thereby contributing to the maintenance
of homeostasis in the intestinal immune system. The role of cell
trafficking in increasing the prevalence of CD34+ cells in
the gastrointestinal epithelium cannot be completely ruled out.
However, as there were no major changes in the frequency of
CD34+ cells in peripheral blood during early infection,
cell traffic may play only a minor role in this process. On the other
hand viral infection may play a role in increasing the frequency of these subpopulations of precursor cells in the gastrointestinal epithelium. Hillyer et al. (22) have shown that the
percentage of bone marrow CD34+ progenitors increased
during primary SIV infection. Our data show that changes in the
CD34+ progenitor cell percentages in intestine are similar
to those observed in bone marrow during primary infection.
CD34+ progenitors coexpressing CD4 undergo a dramatic depletion in the gastrointestinal epithelium during primary SIV infection. A heterogeneous population of committed progenitor cells positive for CD4 antigen was detected in the gastrointestinal epithelium. We determined the effect of primary SIV infection on the frequency of CD34+ CD4+ cells. In uninfected control samples, the frequency of CD34 gated cells expressing CD4 antigen was found to be about 15 to 16% in the jejunum epithelium and 13 to 28% in the colon epithelium, whereas ~28 to ~39% of CD34 gated cells were found to coexpress CD8 antigen. Following SIV infection, the frequency of CD34+ CD4+ precursors was found to decline dramatically at 1 to 2 weeks p.i. in both jejunum and colon epithelium (~2 to ~5%) and remained low even at 4 weeks p.i. In contrast, the frequency of CD34+ progenitors coexpressing CD8 was found to increase at 1 to 2 weeks p.i. (~59 to ~79%) relative to values for uninfected controls and then to decrease to ~48 to ~50% at 4 weeks p.i. These changes in the phenotype and prevalence of this progenitor cell population following SIV infection suggest that the progenitor cells may play a major role in maintaining tissue homeostasis at intestinal lymphoid sites. Our previous studies have shown that the immunophenotypic profiles of IEL and LPL were significantly altered during primary SIV infection, which was not reflected in peripheral blood (34, 46). The frequency of the CD3+ CD4+ single-positive (~0 to ~5%) and CD3+ CD4+ CD8+ double-positive (~2 to ~5%) T-cell subsets declined in the jejunum epithelium as early as 2 weeks p.i. compared to the frequency of CD3+ CD4+ single-positive (~8 to ~20%) and CD3+ CD4+ CD8+ double-positive (~5 to ~13%) T-cell subsets in uninfected control animals. A similar decline was observed in the frequency of CD3+ CD4+ single-positive (~0 to ~1%) and CD3+ CD4+ CD8+ double-positive (~2 to ~5%) T-cell subsets in the colon epithelia compared to the frequency of CD3+ CD4+ single-positive (~3 to ~42%) and CD3+ CD4+ CD8+ double-positive (~8 to ~17%) T-cell subsets in the colon epithelium of uninfected animals. No major changes were observed in the frequency of CD3+ CD4+ single-positive (~54 to ~58%) and CD3+ CD4+ CD8+ double-positive (~1 to ~2%) T cells in the peripheral blood of SIV-infected animals at 4 weeks p.i. compared to uninfected control animals. An increase in the proportion of CD3+ CD8+ T cells coincided with CD4+ T-cell depletion, suggesting that homeostatic mechanisms may operate in the gastrointestinal epithelium to maintain T-cell numbers, as previously reported (34). The frequency of CD3+ CD8+ T cells increased from ~39 to ~75% in both the jejunum and the colon of uninfected control animals to >77% at 2 weeks p.i. It is possible that the selective increase in the frequencies of various primitive and committed subsets of progenitors coinciding with the dramatic changes observed in the gastrointestinal epithelium early in infection may be a mechanism for maintaining T-cell homeostasis in the gastrointestinal epithelium. Our results were found to support this hypothesis. Following SIV infection, the severe depletion may be the frequency of CD34+ cells coexpressing CD4 antigen was found to coincide with the severe depletion of CD4+ T cells. The levels of CD4+ T cells remained low throughout infection, suggesting that the depletion of progenitor CD34+ CD4+ cells may be a factor contributing to the failure of replenishment of CD4+ T cells in the intestinal epithelium. In mice, pluripotent hematopoietic stem cells and T-cell lineage precursors have been shown to express CD4 (53, 54). Low levels of CD4 antigen were shown to be expressed on subsets of human CD34+ cells (28), and a majority of the CD34+ CD4+ cells isolated from human peripheral blood was found to express the fusin receptor (13), indicating that these cells are susceptible to HIV infection. On the other hand, the increased frequency of CD34+ cells coexpressing CD8 antigen during primary SIV infection may be one of the mechanisms for the increased prevalence of CD8+ cells in the intestinal epithelium. The majority of the CD34+ progenitor cells in the thymus were found to coexpress both CD4 and CD8 antigens prior to and after SIV infection, indicative of their immature phenotype.
In conclusion, our study has drawn attention to the role of extrathymic sites such as the gastrointestinal epithelium during primary SIV infection. We observed contrasting changes in the frequency of progenitor cells during primary SIV infection which may have significant implications in understanding how these lymphopoietic sites may contribute to maintenance of tissue homeostasis during primary HIV and SIV infection. Taken together our results clearly demonstrate that in contrast to the thymus, the gastrointestinal epithelium is an early site for the increased prevalence of CD34+ Thy-1+ and CD34+ c-kit+ progenitor cells during primary SIV infection and may play an important role in the maintenance of T-cell homeostasis.| |
ACKNOWLEDGMENTS |
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This work was supported by grants from the National Institutes of Health (R01-DK43183, R01-AI43274, and RR-00169) and the Universitywide AIDS Research Program, University of California.
We are thankful to Linda Hirst, Ross Tarara, and Don Canfield at the California Regional Primate Research Center for valuable assistance in this project.
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Infectious Diseases, Room 3143, Tupper Hall, School of Medicine, University of California Davis, Davis, CA 95616. Phone: (530) 752-3542. Fax: (530) 752-8692. E-mail: sdandekar{at}ucdavis.edu.
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Journal of Virology, May 1999, p. 4518-4523, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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