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*
Departments of Medicine and Microbiology, Dartmouth Medical School, Hanover NH 03755; and
Laboratoire Associé Institut National de la Recherche Agronomique d’Immunologie Parasitaire, Faculté de Pharmacie, Tours, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß and are at least partially dependent upon
the presence of TCR-
/
T cells in the host. Endogenous production
of the pivotal cytokine, IFN-, is essential for host immunity. These
findings demonstrate that gut-derived IEL represent a potentially
important mechanism to provide long term immunity to the
host. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Intraepithelial lymphocytes (IEL) are located among the epithelial
cells that line the lumen of the gut (2, 3). The IEL and epithelial
cells are continually exposed to pathogens and important arbitrators of
host immunity to infection (4, 5). IEL from the small intestine are
unique in cellular composition and development compared with other
peripheral T cells. The IEL are comprised of few B cells and are
predominantly CD3+, with CD8+ more prevalent
than CD4+. Approximately 60% of the CD8 population bears
homodimeric -chains. Of the CD8/ population, approximately
40% is TCR-/+, and 20% is TCR-/ß. The
remainder of the CD8 population is comprised of - and ß-chains and
express TCR-/ß. IEL of all subsets contain intracytoplasmic
metachromatic granules and are rich in granzymes and perforin,
consistent with their cytotoxic function (6, 7). IEL participate in
modulating host immunity through the release of various cytokines,
including IL-2, IL-3, IL-5, TNF-, TGF-ß, and, most apparent,
IFN- (8).
Adoptive transfer of primed CD8+ IEL can protect against
acute, orally acquired infection with T. gondii (9). The
Ag-primed IEL exhibit MHC-restricted cytotoxicity against both
parasite-infected enterocytes and macrophages (10). These cells produce
significant quantities of IFN-, which is essential for both acute
and long term host immunity against this opportunistic pathogen (11, 12). Depletion of IFN- in mice that have received Ag-primed IEL
reverses protection (9). These results suggest that IEL are an
important primary barrier against acute infection with T.
gondii. Moreover, the ability of these IEL to protect the host is
dependent upon the induction of IFN-, although the source for this
cytokine is uncertain.
Primary infection with T. gondii confers long term
protection in the immunologically competent host (11). In mice,
spleen-derived CD8+ T cells are essential for host immunity
(13). These CD8+ T cells are Ag specific, exhibit cytotoxic
activity against parasite-infected target cells, and produce IFN- in
response to Ag stimulation (14). The majority of IEL exhibit the
morphology and phenotypic characteristics associated with
memory/activated cells, including the absence of CD62L (L-selectin),
down-regulation of the CD45 RB determinant expressed by naive CD4 and
CD8 T cell, and up-regulation of the specific activation marker CD69
(15, 16, 17, 18). Recently, the Ly-6C marker has been identified on
CD8+ memory T cells (19). In this report we explore the
ability of IEL isolated from the intestine of orally infected mice to
provide long term host immunity to this pathogen and examine the
requirement for these primed IEL to produce the essential Th1 cytokine,
IFN-.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female 8- to 10-wk-old inbred CBA/J (H-2k) and
C57BL/6 (H-2b) mice were obtained from The Jackson
Laboratory (Bar Harbor, ME). Mice were housed under approved conditions
of the Animal Research Facility at Dartmouth Medical School. Female
IFN--KO mice (C57BL/6-Ifgtm1Ts) that have a targeted deletion of the
IFN- gene were utilized. IEL isolated from these mice failed
to produce detectable quantities of IFN-. Female TCR-/-KO mice
(C57BL/6-Tcrdtm1 Mom) have a targeted mutation and lack expression of
/ T cell receptor in all adult lymphoid and epithelial organs.
These mice failed to express TCR-/ on IEL.
The 76K strain of T. gondii was used in this study. This strain, isolated by Laugier and Quilici (20), produces large numbers of cysts containing bradyzoites in the brains of infected mice. Mice were infected orally by intragastric gavage of cysts collected from the brains of infected mice. Cysts are maintained by passage every 2 mo into naive mice.
Brain tissue containing strain 76K cysts was suspended in saline
buffer, and the suspension was adjusted to contain 10 or 100 cysts in
each 0.5-ml dose to infect the donor mice, respectively C57BL/6 or
CBA/J. The recipient mice were challenged with either 40 or 100 cysts,
except as otherwise noted. As donor mice, IFN--KO mice were infected
orally with five cysts. As recipient, both IFN--KO and
TCR-/-KO mice received 40 cysts as a challenge dose. The cysts
were administrated intragastrically to each animal by gavage.
Isolation of IEL and subset purification
IEL were isolated as previously described with modifications (21). The small intestine was flushed with PBS and cut into 2-mm sections. After removal of Peyer’s patches and fat, the intestine was divided longitudinally. The mucosa were scraped and dissociated by mechanical disruption on a stirring platform for 15 min in RPMI 1640 containing 4% FCS and 1 mM dithioerythitol. Tissue debris and cell aggregates were removed by passage over a glass-wool column in RPMI 1640/4% FCS. The lymphocytes were obtained by centrifugation on a Ficoll layer (density = 1.077), and the cells were suspended in complete medium.
IEL were resuspended in RPMI with 4% FCS and washed before separation. Thirty million cells were incubated with rat anti-mouse CD8ß mAb (PharMingen, San Diego, CA) for 30 min at 4°C, followed by 15-min incubation at 4°C with goat anti-rat IgG microbeads. The complexes were applied to a prewashed miniMACS (Miltenyi Biotec, Auburn, CA) column in PBS and 10% FCS. Both positive and negative IEL fractions were assayed; cells were stained with FITC-conjugated rat anti-CD8ß mAb and analyzed by FACS. This purification procedure resulted in a highly pure CD8ß+ population (>98%).
Immunofluorescence staining and cytokine depletion
Cell suspensions containing 2 x 106 cells were
added to 96-well plates and washed twice in PBS. The cells were
resuspended in 50 µl of normal rabbit serum for 10 min at room
temperature to prevent nonspecific Ab staining. The cells were then
incubated for 1 h on ice in the presence of 50 µl of rat mAb
(1/50 dilution) directed at CD19, CD8, CD8ß, TCR-/ß,
TCR-/, and Ly-6C. After washing, the cells were fixed with 1%
paraformaldehyde in PBS and analyzed by FACScan (Becton Dickinson,
Mountain View, CA) the following day.
For in vivo depletion of IFN-, mice were treated with 3 mg of rat
anti-mouse IFN- (XMG6, American Type Culture Collection,
Manassas, VA) 1 day before challenge with T. gondii 76K
cysts. Control mice were treated with a similar volume of rat IgG Ab
(Sigma, St. Louis, MO).
Adoptive transfer and parasite challenge
For the short term study, primed IEL were purified on days 3, 6, 9, 11, 13, 16, and 28 postinfection (p.i.) along with the control population obtained from uninfected mice. Mice were challenged with cysts 4 days following the adoptive transfer of cells except as otherwise noted.
For analysis of long term immunity, primed IEL were purified from the donor mice on day 6 after infection in C57BL/6 and on day 11 in CBA mice. IEL (2 x 106) were transferred into naive syngenic recipients that were challenged at different times after the transfer (days 4, 7, 15, 30, and 60). The protection was assessed by the decrease in mortality rate and the brain cyst load of the survivors. The IEL collected were assayed for parasite contamination in two ways. First, IEL from either infected or naive mice were cultured in vitro with human fibroblasts (HF) at a ratio of 1:5 (one HF to five IEL). As a control, tachyzoites were used to infect an HF monolayer at a ratio of 5:1 and analyzed for lysis. Two days p.i. the fibroblast monolayer had been completely destroyed by the proliferating parasite. There was no observable evidence of parasite infection in the fibroblast cultures inoculated with either primed or unprimed IEL. During the next 14 days, there was no evidence of parasite infection in the HF monolayer. The second assay for determining contamination in the IEL population involved transfer of primed IEL into naive recipients and assay of their sera 2 wk later for Ab production. No significant amount of anti-T. gondii-specific IgG could be detected in the blood of mice transferred with primed IEL, suggesting that the primed IEL are parasite free.
Cyst enumeration
Protection in both strains of mice was assessed by enumeration of brain cysts in the survivors. For cyst enumeration, mice were sacrificed 45 days after the challenge. The brain was isolated and homogenized in 5 ml of PBS. The mean number of cysts per brain was determined microscopically by counting 10 samples (10 µl each) of each homogenate. The results are expressed as the mean ± SD for each group. The results are representative of at least two separate experiments.
Statistical analysis
Statistical differences between various groups were assessed using analysis of variance (significance set at 0.05).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Since susceptibility is genetically determined, two different
mouse strains were assayed for IEL production in response to infection.
C57BL/6 (highly susceptible) and CBA (highly resistance) were infected
by oral gavage with either 10 or 100 cysts, respectively. At increasing
time points p.i. IEL were enumerated (Fig. 1
). The number of IEL that were isolated
was mouse strain dependent. The resistant CBA/J strain mice had the
greatest number of IEL elicited on day 11 p.i. Thereafter, the
cell count gradually returned to 50% over baseline. For C57BL/6 mice,
the highest increase was observed on day 6. Thereafter, the cell count
returned to either baseline or below. On day 11 p.i. in CBA mice
and on day 6 p.i. in C57BL/6 mice phenotypical analysis revealed
in both strains that primed and unprimed IEL are comprised of 87%
CD8+, 0.5% CD19+, and about 15%
CD4+. At these times, compared with unprimed IEL, there was
a potent increase in CD8ß+-primed cells (from 30% in
unprimed to 62% in primed population) and in TCR-/ß-primed cells
as well (from 28% in the unprimed to 65% in the primed population).
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To determine the optimal time for induction of IEL that were protective, a time-course study was performed using C57BL/6 and CBA/J mice. IEL were isolated and adoptively transferred via the tail vein into syngenic recipient mice. Four days after the transfer, the recipients were challenged. A definite correlation between infection and ability to confer resistance was observed.
In C57BL/6 mice, IEL isolated on day 3 p.i. were partially
protective (75% survival rate in transferred recipients). The highest
level of protection was achieved when IEL were isolated on either day 6
or day 9 p.i. (Fig. 2A).
Thereafter, the ability of IEL to protect declined further from the day
of challenge to the day when cells were isolated. By day 28
p.i., there is no difference in the ability to protect between unprimed
and Ag-primed IEL. Almost all the recipients from these two groups died
by day 20 postchallenge.
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B). IEL from both day 16 and day 28 also
reduced cysts burden, but to a much lesser extent
(p > 0.05; error bars are present in Fig. 2 but are too small to be seen).
To determine whether the ability of IEL to protect was limited to mouse
strain, CBA/J mice were evaluated. Since CBA/J mice are highly
resistant to parasite infection, morbidity is best quantified by
enumeration of brain cyst load. As shown in Figure 3, IEL that were isolated between days 3
and 11 p.i. conferred an average decrease of 50% in cyst number
compared with that in the control group receiving unprimed IEL. There
was no significant difference in the ability of IEL to protect when
recovered between days 3 and 11. IEL isolated on day 13 p.i.
reduced cyst burden by 80% (p < 0.0001). IEL
isolated from day 13 p.i. mice were the most efficient at
protecting against challenge. By day 28 the IEL were no longer able to
confer protection when challenged.
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Previous studies in CBA mice indicated that CD8ß+
were responsible for protective immunity (9). IEL on day 6 p.i.
were isolated from C57BL/6 mice and separated by affinity into a
CD8ß+ and a CD8ß- population. These IEL
were adoptively transferred into naive mice, and the mice were
challenged with a lethal dose of cysts. In this experiment the
CD8ß+ population of primed IEL conferred 100% protection
against lethal challenge (Fig. 4).
Furthermore, these CD8ß+-primed cells were able to
slightly reduce cyst burden in the adoptively immunized mice (200
± 15 cysts) compared with that in the primed IEL population (300
± 25). Neither the Ag-primed CD8ß- population nor the
unprimed IEL from uninfected mice could transfer immunity.
CD8ß+-primed population was comprised of 68% TCR-/ß
cells, whereas CD8ß- cells are mainly TCR-/ cells
(75%). Therefore, CD8ß+ TCR-/ß-primed IEL could
account for the protection.
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/ T cells play an important accessory role in host
immunity
Previous studies from our laboratory indicate a potentially
important role for / T cells in early host immunity parasite. To
establish whether host cell populations were important for host
immunity, CD8ß+ (68% TCR-/ß) IEL were isolated from
C57BL/6 mice on day 6 p.i. and adoptively transferred into
/-KO recipient mice (Fig. 5). Four
days after transfer, the mice were challenged. Transfer of Ag-primed
CD8ß+ IEL into the parental C57BL/6 mice prevented
mortality following challenge. Adoptive transfer of these primed
CD8ß+ IEL into TCR-/-deficient mice conferred
partial protection against lethal challenge by a 50% increase in
resistance. Furthermore, these cells reduced cyst burden in both
strains of mice, although to a lesser extent in the
TCR--/- mice (p < 0.001).
This observation suggests that TCR-/ plays an important role in
host immunity to this parasite.
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To determine whether IEL can stimulate long term protective
immunity, Ag-primed IEL were collected from either C57BL/6 on day 6 or
CBA/J mice on day 13 from orally infected mice and adoptively
transferred into recipient mice. The mice were challenged 4, 7, 15, 30,
and 60 days post-transfer. Control mice were immunized with unprimed
IEL at the same time points. Mice receiving Ag-primed IEL were more
resistant and had fewer brain cysts than mice immunized with control
IEL. As shown in Figure 6, except for one
mouse from the group challenged on day 7 after transfer, which died,
all the C57/BL6 mice receiving primed IEL survived, whereas mice
receiving control IEL died (by day 10 postchallenge). The C57BL/6
survivors had a significant reduction in the number of brain cysts
compared with mice that received a nonlethal challenge (compare to Fig. 2B). There was a uniform decrease in mortality and morbidity
(cyst number) independent of the time post-transfer. Mice challenged on
either day 4 or day 60 had a similar survival rate (
100%) and a
similar number of intracerebral cysts. The ability of the IEL to
protect long term against parasite challenge was independent of mouse
strain.
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Protection is independent of IEL IFN- production
The importance of IFN- in host resistance to T.
gondii infection is well documented. We have demonstrated
previously that primed IEL synthesize IFN- and that protection by
primed IEL is dependent on IFN-. To determine whether production of
this cytokine by the IEL is essential to their protective capacity,
adoptive transfer studies were performed using mice that are
genetically deficient in the production of this cytokine.
IFN--/- and their parental C57BL/6 mice were orally
infected with 10 cysts. Six days later their IEL were isolated and
adoptively transferred into naive recipients. Four days
postimmunization with IEL, the mice were challenged with 40 cysts. As
illustrated in Figure 7, adoptive
transfer of primed IEL from infected IFN--KO mice was protective.
Moreover there was only a slight, but nonsignificant, difference
(p > 0.05) in the brain cyst load of the
recipients of primed wild-type IEL and primed IFN--KO IEL. Transfer
of either C57 or IFN--KO unprimed IEL failed to protect against
challenge. This observation suggested that the protection induced by
IEL is independent of their IFN- production.
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is essential to the immunity of these
cells, IEL were purified from either IFN--KO or the parental C57BL/6
mice on day 6 p.i. These cells were adoptively transferred into
C57BL/6 recipient mice. Three days after the adoptive transfer, the
mice were treated with rat anti-mouse IFN- mAb, and the
following day they were challenged. Treatment of mice with
anti-IFN- mAb completely abrogated the protection conferred by
immunization with primed IEL. A similar response was observed
regardless of whether the IEL were from IFN--KO or C57BL/6 mice
(data not shown). IFN- depletion by Ab led to the death of all mice
within 10 days postchallenge.
To confirm the importance of endogenous IFN- in host immunity, IEL
were isolated from C57BL/6 mice on day 6 p.i. and adoptively
transferred into IFN--KO recipient mice. Four days after transfer,
the mice were challenged. Although adoptive transfer of Ag-primed IEL
protected the C57BL/6 mice, these cells could not prevent death in the
IFN--/- mice. This observation indicates that
endogenous IFN- production of the recipient mice, not IFN-
production of IEL, is essential for protection (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in the recipient mice but independent
of IFN- production by the IEL. A kinetic analysis demonstrates that the protective IEL are elicited at a specific time p.i. This time p.i. varies with mouse strain. Optimal activity was observed when the IEL were harvested on day 9 for C57BL/6 mice and on day 13 for CBA/J mice. C57BL/6 mice are more susceptible to infection with T. gondii (22). These mice usually succumb to infection within 15 days after the infection. We observed that in C57BL/6 mice infected with 10 cysts, maximum protection was transferred when the fewest number of IEL were isolated from the intestine (D9). Similarly, IEL isolated from CBA/J mice were equally protective when isolated on day 13 pi. The specificity of the time interval for the induction of a protective phenotype would suggest that these IEL develop Ag specificity and memory during this period. When adoptively transfered into naive mice and upon Ag re-exposure, these cells become responsive. Isolation of the IEL either before the specific time interval (before day 6) or after (after day 9 for C57BL/6 and D16 CBA/J) results in an inadequate number of protective IEL.
This loss of protective capacity may be associated with lymphocyte trafficking. Although the origin of IEL remains uncertain, these cells do exhibit migratory activity in vivo (23). Immune induction occurs principally within the Peyer’s patch. Luminal Ags cross the intestinal mucosa via M cells that are in close proximity to the Peyer’s patch. Within the Peyer’s patch, Ag is presented to both T and B cells, resulting in activation and regulation of lymphocyte-homing receptors. The activated cells traffic to the general circulation and home to the gut (3). It has now been demonstrated that Ag presentation in the epithelium can activate CD8 cells in the mesenteric lymph nodes that migrate to the intestine (24). Thus, migration of the primed IEL from the gut to other organs once the priming Ags are no longer evident could explain the absence of a protective population on day 28 p.i. Consistent with this hypothesis is the observation that IEL isolated on day 6 (C57BL/6) or day 13 (CBA/J) p.i. induce long-lasting immunity in the recipient mice. The Ly-6C memory phenotype has also been observed to be up-regulated on CD8+ T cells involved in organ-specific homing (19, 25). In addition to the up-regulation of this phenotype on the isolated IEL in the current study, we have further information that adoptively transferred IEL home to the gut within hours after transfer. At least in C57BL/6 mice, these cells cannot be detected in the gut 24 h after transfer, but reappear in the gut when the mice are challenged with parasites (D. Buzoni-Gatel, manuscript in preparation). Taken together, these data provide evidence that Ag-specific IEL can persist in the host for prolonged periods of time and probably become activated upon Ag re-exposure.
The role of IFN- in protection against T. gondii is well
established. The mechanism by which IFN- protects is not fully
appreciated. IFN- stimulates oxidative killing of the parasite by
macrophages through increased production of reactive oxygen metabolites
(26). Alternatively, in association with a costimulatory molecule such
as TNF-, it can induce the production of nitric oxide (27, 28).
Nitric oxide has both a microbiocidal effect as well as a deleterious
effect on the host in certain species of mice (29). Interestingly, the
source of IFN- in these studies suggest that it is the endogenous
production of IFN- by the host, not the IEL from the
parasite-infected donor, that is involved in protective immunity.
CD8+ T cells exert differential effects on Th1 and Th2
CD4+ T cell development (30) and may have an early
immunoregulatory function that can lead to an increase in the capacity
of Th1 cell to produce IFN-. IFN- enhances endothelial activation
(ICAM-1 expression) and thus may promote cellular extravasation from
the bloodstream to sites of inflammation (31). IFN- may also be
involved in up-regulation of specific homing receptors on IEL and
facilitate localization in the gut. It is uncertain whether TCR-/ß
CD8+ IEL need contact with APC to be stimulated after the
transfer. Gut epithelial cells express both MHC class I and II surface
molecules and may also present Ag to CD8+ T cells in the
context of CD1 molecule, a nonclassical MHC (32, 33). These
interactions between epithelial cells and gut IEL may lead to
activation of the IEL as well as to killing of the infected epithelial
cells by cytotoxic mechanisms that have been previously described in
vitro (10).
The induction of protective IEL appears to be at least partially
dependent upon the stimulation of an effective TCR-/ cell
response in the host. Previous observations in our laboratory and
others indicate that / T cells are stimulated early in response
to both oral and i.p. infection with T. gondii (34, 35). In
this study mice deficient in TCR-/ that received Ag-primed IEL
were only partially protected against challenge, whereas their parental
controls were completely protected. Moreover, the surviving mice had a
significant increase in the number of intracerebral cysts. Whether the
TCR-/+ CD8+ cells have a regulatory role
in the gut is poorly understood at present (36, 37, 38, 39). The absence of
TCR-/ cells in the gut results in a variety of immune
deficiencies, including decreased MHC class II expression by intestinal
epithelial cell (40), reduced IgA production in the lamina propria (41, 42), and alterations in tissue maintenance and repair (40, 43).
Moreover, several studies have provided strong evidence that
TCR-/+ CD8+ T cells may fulfill a
down-regulatory role on immune responses by inhibiting cell-mediated
immunity (44, 45). During infection with Eimeria vermiformis
it has been shown that mice lacking / T cells display exaggerated
intestinal damage, apparently due to failure to regulate the
consequences of the /ß T cell response (46). Thus, TCR- IEL
subpopulation may have a dual role in the IEL-mediated immunity. They
could regulate the inflammation that occurs in the gut after the
infection. Different cytokines are thought to play a critical role in
the down-regulation of gut immunity. It would be of particular interest
to determine the level of TGF-ß (47, 48, 49) produced by IEL after
T. gondii infection. Studies are currently underway to
explore this potentially important regulatory mediator in the gut
(A. C. Lepage, manuscript in preparation).
A long term protective role of gut-derived IEL may be critical for host
immunity to this opportunistic pathogen. Whether these cells are the
primary barrier against recurrent disease upon parasite re-exposure in
the host or are involved in immune surveillance remains uncertain.
There does appear to be an essential role for endogenous IFN- in
regulating this CD8+-mediated event. The mechanism by which
these IEL home to the appropriate organ is not known, and whether these
IEL are involved in the pathogenesis of acute inflammatory bowel
disease associated with this infection is 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. Lloyd H. Kasper, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756. E-mail address:
3 Abbreviations used in this paper: GALT, gut-associated lymphoid tissue; IEL, intraepithelial lymphocytes; KO, knockout; p.i., postinfection; HF, human fibroblasts.
Received for publication April 16, 1998. Accepted for publication June 25, 1998.
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C. Zaph, K. A. Rook, M. Goldschmidt, M. Mohrs, P. Scott, and D. Artis Persistence and Function of Central and Effector Memory CD4+ T Cells following Infection with a Gastrointestinal Helminth J. Immunol., July 1, 2006; 177(1): 511 - 518. [Abstract] [Full Text] [PDF]
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C. E. Egan, J. E. Dalton, E. M. Andrew, J. E. Smith, M.-J. Gubbels, B. Striepen, and S. R. Carding A Requirement for the V{gamma}1+ Subset of Peripheral {gamma}{delta} T Cells in the Control of the Systemic Growth of Toxoplasma gondii and Infection-Induced Pathology J. Immunol., December 15, 2005; 175(12): 8191 - 8199. [Abstract] [Full Text] [PDF]
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L. H. Kasper and D. Buzoni-Gatel Ups and Downs of Mucosal Cellular Immunity against Protozoan Parasites Infect. Immun., January 1, 2001; 69(1): 1 - 8. [Full Text] [PDF]
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F. Velge-Roussel, P. Marcelo, A. C. Lepage, D. Buzoni-Gatel, and D. T. Bout Intranasal Immunization with Toxoplasma gondii SAG1 Induces Protective Cells into Both NALT and GALT Compartments Infect. Immun., February 1, 2000; 68(2): 969 - 972. [Abstract] [Full Text] [PDF]
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