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Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33136
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Fas and Fas-L have been shown to be important molecular effectors for the homeostatic control of the lymphoid system, including B cells (for review, see 14 , T cells (for reviews, see Refs. 15–17), and dendritic cells, and may also function as regulators of APCs (18). CD4+Th1 cells lyse normal but not Fas-deficient macrophages in an Ag-specific MHC-restricted reaction (19). A role for Fas and Fas-L in the control of tissue macrophages has been observed in the pathogenesis of arteritis in the MRL mouse (20). APCs are critical elements for T cell activation and for the generation of Ag-specific, MHC-restricted effector T cells of both the CD4+ and CD8+ phenotype. Activated Ag-specific CD4+ and CD8+ T cells can express Fas-L and other death receptors in addition to cytolytic granules containing perforin and granzymes (21, 22, 23, 24, 25). APCs expressing the appropriate Ag and MHC molecule are potential target cells for activated T cells and may be lysed by previously activated T cells through the perforin/granzyme or Fas-L/Fas pathway. Effector T cells therefore are capable of turning off the original antigenic stimulus by lysing APCs. This negative feedback control of Ag presentation may be necessary to limit T cell activation and avoid tissue destruction.
In this study, we ablated the two rapidly acting cytotoxic pathways, perforin and Fas-L, by cross-breeding of perforin-deficient with Fas-L-deficient mice. Double-deficient mice develop a spontaneous syndrome accompanied by tissue destruction due to infiltrating T cells and monocytes/macrophages, weight loss, and early death. We present evidence that the failure of activated T cells to lyse Ag-presenting monocytes/macrophages may be responsible for this syndrome. Cytotoxicity mediated by perforin thus may contribute to limiting T cell activation, in addition to controlling intracellular pathogens.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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P815 mastocytoma (H-2d), EL-4 (H-2b), L1210 (H-2d), and YAC-1 lymphomas and WEHI-164 fibrosarcoma (H-2d) were passaged in Iscove’s modified Dulbecco’s medium containing 10% heat-inactivated FCS.
Antibodies
Hamster anti-murine CD3 Ab 2C11, a gift of Dr J. A.
Bluestone, University of Chicago (Chicago, IL), was purified by passage
over protein G-Sepharose. For staining of membrane-associated TNF,
polyclonal rabbit anti-mouse TNF-
(IP-400) obtained from Genzyme
(Cambridge, MA) was used at a final concentration of 1:20, and detected
by fluoresceinated goat anti-rabbit IgG at 1:50 (Organon Technica,
West Chester, PA). All other Abs were from PharMingen (San Diego, CA).
Generation of perforin/Fas-L, cytotoxicity double-deficient (cdd) mice and source of other mouse strains
Female C57BL/6 perforin-deficient (PKO) mice, generated as described (10), were bred to C3H/HeJ-Faslgld and to C57BL/6gld males (The Jackson Laboratory, Bar Harbor, ME) under viral Ag-free conditions in the animal facilities at the University of Miami School of Medicine (Miami, FL). Heterozygous first generation (F1) mice were then brother-sister mated to obtain second generation (F2) mice that were screened for perforin and Fas-L deficiency by PCR (10) and ligase chain reaction (26), respectively, as described (27). bm1 mice were obtained from The Jackson Laboratory.
Flow cytometry
One million cells were incubated for 30 min in 50 µl hybridoma 2.4G2 anti-FcRIII Ab supernatant to block FcR. Cells were then incubated for 30 min with FITC- or phycoerythrin-conjugated Abs diluted to 5 µg/ml in PBS containing 0.5% BSA and 0.01% sodium azide. Cells were washed three times and analyzed in a FACScan flow cytometer (Becton Dickinson, Mountain View, CA).
Preparation of infiltrating cells
Pancreas and uterus were minced into small cubes and agitated for 1 h on ice in PBS, pH 7.2, containing 10 mM EDTA. Cells were then pipetted and filtered through wiremesh to obtain single cell suspensions. Single cell suspensions from the pancreas were also prepared by cannulating the main duct and injecting collagenase V (2 mg/ml) (Sigma, St. Louis, MO) in tissue culture medium. Cells were dispersed by 10-min incubation at 37° in medium containing 2 mg/ml collagenase V with constant agitation. Cells were washed several times, and infiltrating white cell elements were separated from other cells by gradient centrifugation using Lympholyte M (Accurate Biochemicals, Westbury, NY).
Carrageenan treatment
If cdd mice were to be used for breeding, carrageenan injection was started on days 35 to 40 with weekly i.p. injections of 100 µg carrageenan (Sigma) dissolved at 1 mg/ml in PBS, pH 7.2, until pregnancy was noted. In experiments measuring the effect of carrageenan on pancreatic infiltrating cells, injection was begun on day 70 and repeated once or twice at weekly intervals before analysis of infiltrating cells.
Cytotoxic T cell lines
CD8+CTL lines from C57BL/6, C57BL/6
gld/gld, C57BL/6 P0/0, or C57BL/6 cdd mice were
prepared by culturing 10 x 106 spleen cells with
10 x 106 irradiated (6000 rad) DBA-2 or
bm1 stimulator spleen cells in 4 ml Iscove’s modified
Dulbecco’s medium containing 10% heat-inactivated FCS and 50 µM
2-ME (basic medium). Spleen cells were restimulated weekly with 1
x 106 irradiated stimulator cells. After 3 wk, cells were
transferred to CTL medium (above medium plus 25 U/ml murine rIL-2,
2.5% rat spleen Con A supernatant, 20 mM
methyl--D-mannopyranoside) and maintained by weekly
restimulation with irradiated spleen cells. For short-term cultures,
CTL were tested for cytotoxicity 5 days after primary stimulation or
one restimulation.
Staphylococcal enterotoxin B (SEB)-specific CD4 CTL were generated by culturing 2 x 106 spleen cells/ml (C57BL/6) with 5 µg/ml SEB (Sigma) (28) for 5 days. Cytotoxicity assays were conducted against syngeneic cells pulsed with 5 µg/ml SEB.
Peritoneal macrophages used as targets for SEB-specific CD4+CTL or bm1-specific CD8+CTL were elicited in C57BL/6 or bm1 mice with thioglycolate, as described (29), and labeled with 51Cr for cytotoxicity assays.
Cytotoxicity assays
51Cr release assays were performed according to
standard protocols for 4 or 16 h. All assays were performed in
triplicate. For redirected lysis, anti-CD3 Ab at 1 µg/ml was
present throughout the assay. Inhibition of TNF activity was
accomplished by addition of neutralizing anti-TNF- antiserum
(IP-400; Genzyme) at the start of each assay at the indicated
concentrations.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To compare the influence of the MHC background on perforin/Fas-L
double deficiency, C3H (H-2a) and C57BL/6
(H-2b) gld/gld mice were interbred with
perforin-deficient C57BL/6 (PKO) mice under viral pathogen-free
conditions in appropriate facilities. Double heterozygous
F1 mice were interbred, and tail biopsies of the
F2 generation were screened by PCR for homozygous perforin
deficiency, detectable through the insertion of the neomycin resistance
gene into the perforin gene (10). The homozygous gld point
mutation (6) was screened by a ligase chain reaction assay (26), as
described previously (27). Animals homozygous for perforin and Fas-L
cdd were identified and set aside for further breeding.
Surprisingly, however, it soon became evident that cdd mice,
after thriving for about 8 wk of age, did not breed, became ill, lost
weight, and died usually by 15 wk (Fig. 1
, inset in A).
Death was unrelated to any detectable viral or bacterial infection and
occurred uniformly within a similar time period, regardless of
differences in the MHC background, pure H-2b, or mixed
H-2b x H-2a, suggesting that death was caused
by the cytotoxic double deficiency and unrelated to genetic background.
Male and female cdd mice are equally susceptible to disease
and early death. Female cdd mice were infertile, and no
pregnancy or delivery was observed even after mating with normal, not
immunodeficient C57BL/6 males. Male cdd mice, in contrast,
were fertile, but short lived. Mice homozygous for the gld
defect, but heterozygous at the perforin locus (P+/0, gld)
and expressing one functional perforin allele, were protected from
early death (Fig. 1). They were therefore used for breeding to generate
sufficient numbers of cdd mice for further study.
Heterozygous P+/0, gld mice reproduced normally; as
expected, the frequency of cdd offspring was 25%, while
50% of the litter remained perforin heterozygous. P+/0, gld
mice were used as controls for experiments with cdd animals.
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At autopsy, 11- to 14-wk-old cdd mice showed pronounced
splenomegaly, but only moderate to minimal lymph node enlargement in
peripheral and mesenteric nodes, which was similar to heterozygous
P+/0, gld controls. The size of the pancreas was
considerably reduced in cdd compared with P+/0,
gld mice. On microscopic examination, mild levels of
cellular infiltration were apparent in the liver, lung, and kidneys of
both cdd and P+/0, gld controls. However, a
striking difference was apparent in the pancreas, which in 20 of 20
cdd mice exhibited severe pancreatitis (Fig. 1
A,
right), whereas all P+/0, gld control pancreata
appeared normal (Fig. 1A, left). In
cdd mice, the pancreas contained extensive mononuclear
infiltrates, which were accompanied by a loss of exocrine acinar cells.
Despite the severity of the inflammatory response, secretory ducts were
unaffected and islets of Langerhans remained intact, as evidenced by
immunostaining for insulin and the absence of hyperglycemia (not
shown), even in terminally ill mice. Ovaries from cdd mice
were infiltrated by mononuclear cells, with a corresponding reduction
in the number of maturing follicles (Fig. 1B), and
infiltration of the uterus with mononuclear cells was severe when
compared with P+/0 gld controls (Fig. 1C).
Mac-1 (CD11b)-positive T cells and Mac-1-positive monocytes/macrophages infiltrate pancreas and uterus
The gld defect is associated with the expansion of a
B220-positive T cell subset in lymph node and spleen (8, 30) with
increased Fas expression (31). While gld mice show severe
lymphadenopathy usually after 6 mo, they do not develop weight loss or
pancreatitis later in life. To determine the nature of infiltrating
cells that may be responsible for pancreatitis and hysterosalpingitis
in cdd mice (P0/0, gld/gld), we compared them to
infiltrating pancreatic cells in perforin heterozygous,
gld/gld control mice (P+/0, gld) differing by one
functional perforin allele (Fig. 2).
Since perforin heterozygous gld mice had only few resident
white cells in the pancreas, it was necessary to pool the infiltrating
pancreatic white cells from three P+/0, gld mice controls
and compare them with each cdd mouse. P+/0, gld
mice had normal body weight without detectable lymphadenopathy, while
the cdd cells came from 70–100-day-old mice of about
20 g body weight, decreased from 26 g within the previous 2
wk. The analysis was repeated 12 times over a period of more than 1 yr,
with similar results using mice of pure H-2b (C57BL/6) or
mixed H-2b x H-2a (C57BL/6 x C3H)
background. In comparison with pancreatic infiltrating cells, data are
also presented for cdd spleen cells (n = 6),
cdd peripheral (n = 5) and mesenteric lymph
nodes (n = 3) together with P+/0, gld
controls (Fig. 2). The frequency of Mac-1-positive cells infiltrating
the pancreas depended on the stage of disease (see Fig. 5 below) and
increased with increasing age of the mice. Data of surface markers
(mean and SD) showing significant differences between P+/0,
gld, and cdd mice are shown.
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). Both Mac-1/CD3-positive T
cells and Mac-1/F4.80-positive macrophages are increased in
cdd pancreata when compared with the perforin
heterozygous gld state (Fig. 2). B220/CD3-positive
cdd T cells, on the other hand, are increased to a
lesser extent in the cdd pancreas than the P+/0
gld pancreas (Fig. 2). The increase of Mac-1/CD3-positive
cdd T cells, relative to P+/0, gld, is found to a
lesser extent in cdd peripheral lymph nodes (Fig. 3, A and B) and
spleens (Fig. 3C). In contrast, Mac-1/F4.80-positive
macrophages are not increased in spleen and lymph nodes of
cdd mice. Mesenteric and peripheral lymph nodes and spleens
of both cdd and P+/0 gld mice show increased
CD3/B220-positive T cells. cdd spleens are characterized by
an increase of T cell cellularity that may be responsible for the
enlarged spleens in cdd mice noted above.
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, A
and B). Mac-1-positive T cells, but not
monocytes/macrophages, are also found in cdd lymphoid
organs. A small number of Mac-1/CD3-positive cells is normally present
in healthy spleens, probably representing a subset of activated T cells
(Fig. 3C). This population is increased in the perforin
heterozygous gld state and quadruples in the spleen of
cdd mice (Fig. 3C).
Infiltrating mononuclear cells in the uterus of two cdd mice
analyzed likewise are characterized by Mac-1-positive T cells and
monocytes/macrophages (data not shown), suggesting a similar
pathogenetic mechanism for pancreatitis and hysterosalpingitis.
Moreover, the CD4 to CD8 ratio of infiltrating cells in both organs
undergoing tissue destruction in cdd disease was found to be
inverted, suggesting expansion of the CD8 subset over and above the CD4
subset (Fig. 4). The inversion of the
CD4/CD8 ratio was not found in cdd lymph nodes and spleen
cells of the same cdd animal (Fig. 4). Infiltrating T cells
are TCR ß positive and express high levels of Fas, and a
fraction is CD4/CD8 double negative (data not shown).
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The presence of monocytes/macrophages in pancreas and uterus of cdd mice suggests their participation in destruction of these organs either directly or through the activation and expansion of infiltrating CD8+ T cells. Thus, destruction of the pancreas and infertility of female cdd mice may be causally related to the presence of increased numbers of monocytes/macrophages. To test this hypothesis, monocytes/macrophages were inactivated in cdd mice by weekly i.p. carrageenan injection (100 µg in PBS), beginning on day 35 to 40 of their life.
Carrageenan injection improved the fertility of female cdd
mice to the extent that they became pregnant and delivered healthy
cdd litters (Fig. 5), while
untreated female cdd mice never became pregnant. About 70%
of treated mice became pregnant and remained healthy for up to 130
days, indicating that carrageenan treatment, possibly together with the
ensuing pregnancy, delayed onset of cdd disease. Male mice,
even when treated continuously by weekly carrageenan injections, showed
only a comparatively small benefit when compared with female mice
in disease onset and survival (Fig. 5, upper panel).
Weekly carrageenan injection also delayed pancreatic disease. The
extent of pancreatic infiltration by Mac-1-positive cells, including
both T cells and monocytes/macrophages, over time increases steadily
from 20% on day 60 to 80% by day 100 and remains constant thereafter
in the few mice surviving beyond this time. If a regimen of weekly
carrageenan injection is implemented on day 70 at a time when the mice
are beginning to lose weight, the infiltration of Mac-1-positive cells
in the pancreas is halted and appears to be reversed to levels of less
than 10% in some animals (Fig. 5, lower panel).
Mac-1-positive cells include both T cells and monocytes/macrophages,
indicating that infiltration of both cell types is reversed by
carrageenan. Since carrageenan affects only macrophages, this finding
suggests that expansion of Mac-1-positive T cells is secondary to
monocyte/macrophage presence in the tissues undergoing destruction.
cdd CTL are unable to lyse monocyte/macrophage targets
Allospecific CD8+CTL lines (H-2b,
anti-H-2d) were generated from spleens of
cdd mice in parallel with control CTL lines from C57BL/6,
PKO, B6 gld/gld mice and compared for their ability to lyse
allospecific (H-2d) tumor targets in a standard 4-h
51Cr release assay (Fig. 6A). Wild-type B6 CTL and
gld CTL exhibited a high level of cytotoxicity against P815
targets, while killing by PKO CTL was significantly reduced.
cdd CTL, in contrast, were completely unable to lyse P815
targets in 4 h. Similar results were obtained using primary
allospecific CTL generated in 5-day MLC from cdd and control
mice (not shown). cdd CTL remained incapable of P815 lysis
even when redirected by anti-CD3 (2C11) Ab (Fig. 6B).
Similarly, Fas transfection of P815 was also incapable of rendering
targets susceptible to 4-h lysis by cdd CTL (Fig. 6C), further demonstrating loss of the Fas-L- and
perforin-killing pathways.
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D). Lysis was completely inhibited by neutralizing
anti-TNF- antiserum.
The inability of cdd CTL to lyse target cells in 4-h assays
using the perforin or the Fas-L effector pathway suggested a mechanism
by which expansion of monocytes/macrophages in the pancreas and uterus
of cdd mice could take place. Assuming that resident tissue
macrophages present Ag and activate cognate T cells, ensuing T cell
activation coupled to the expression of Fas-L and perforin will result
in the generation of cytotoxic T cells that are capable of eliminating
APCs through one or both of the major cytolytic pathways. The lytic
action of CTL is expected to limit monocyte/macrophage action, thereby
down-regulating further T cell activation. To test this hypothesis,
CD4+ cdd CTL were generated by addition of SEB
to B6 gld or B6 cdd spleen cells and cultured for
5 days. Thioglycolate-elicited macrophages from normal B6 mice were
pulsed with SEB and used as targets (Fig. 6F). CD8+cdd and gld CTL were generated in MLC
against bm1 targets (H-2b with a mutation in
Kb) and tested against bm1 peritoneal
macrophages (Fig. 6E). While gld CTL of the CD4
or CD8 phenotype were able to lyse the appropriate targets in 4 h,
cdd CTL were completely unable to lyse peritoneal
macrophages, indicating that perforin is essential for lytic activity
in the gld state in this system and that cdd T
cells are unable to eliminate cognate Ag-presenting macrophages.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Early death and generalized lymphoproliferation are also seen in CTLA-4-deficient mice with a predilection for severe pancreatitis and myocarditis (33, 34). While mechanistically clearly different from CTLA4 deficiency, our study supports the concept of organ-specific protection against lymphocyte damage.
Mechanistically, we propose that perforin and Fas-L down-regulate Ag
presentation by killing APCs via either the perforin- or the
Fas-L-mediated mechanism. Continued survival of APCs in the face of
activated T cells may result in continuous restimulation and expansion
of both CTL and APCs, ultimately leading to organ destruction by
perforin- and Fas-L-independent mechanisms. This explanation of the
pathogenetic mechanism of cdd disease implies that activated
cytotoxic T cells control their own down-regulation by a negative
feedback loop, eliminating the original antigenic stimulus through
lysis of the APCs (Fig. 7). If this
negative feedback loop is inactivated through the ablation of perforin
and Fas-L gene expression, autoimmunity ensues. This disease mechanism
also implies that cdd T cells are able to mediate tissue
destruction.
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and
TNF, may exert cytotoxic functions via TRAIL (35, 36, 37, 38, 39, 40), the
ligand for DR4 to DR7, or DR3-ligand (41, 42, 43, 44, 45). cdd CTL, in
addition to producing TNF (Fig. 6 (27)), express high levels of TRAIL
mRNA (data not shown). In addition to the demonstration of expanded monocyte/macrophage populations in affected tissues, the postulated pathogenetic mechanism of cdd disease is supported by the dramatic effect of carrageenan treatment on cdd mice. Carrageenan, a monocyte/macrophage toxic agent, delays and reverses tissue expansion of both monocytes/macrophages and T cells, restores fertility in female mice, and significantly delays autoimmune disease onset and death. Apparently, the elimination of functional monocytes/macrophages in vivo by carrageenan can partially replace the defect in cytotoxicity normally responsible for control of APCs. cdd mice generated by Braun et al. (46) also died relatively early, but survived and bred for 120 to 150 days without treatment in facilities that, unlike ours, were not reported to be viral Ag free (46). It is possible that pathogen exposure is beneficial in cdd disease and delays onset of disease, reminiscent of the effect of carrageenan. Our results show that cdd T cells are capable of mediating tissue damage directly or through activation of other cells. In ongoing studies, we have found that cdd T cells can cause lethal graft versus host disease in allogeneic recipients if precautions are taken against rejection of the graft. The effector mechanisms of cdd graft versus host disease and tissue destruction are under analysis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Eckhard R. Podack, Department of Microbiology and Immunology (R-138), University of Miami School of Medicine, P. O. Box 016960, Miami, FL 33136. E-mail address:
3 Abbreviations used in this paper: Fas-L, Fas-ligand; cdd, cytotoxicity double-deficient; SEB, staphylococcal enterotoxin B.
Received for publication May 19, 1998. Accepted for publication August 28, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in CD8+ cytotoxic T lymphocyte-mediated lysis. J. Immunol. 150:4303.[Abstract]
B. Immunity 7:831.[Medline]
B pathway. Immunity 7:821.[Medline]
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 L. Mincheva-Nilsson, O. Nagaeva, K.-G. Sundqvist, M.-L. Hammarstrom, S. Hammarstrom, and V. Baranov {gamma}{delta}T cells of human early pregnancy decidua: evidence for cytotoxic potency Int. Immunol., May 1, 2000; 12(5): 585 - 596. [Abstract] [Full Text] [PDF]
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M. J. Kaplan, D. Ray, R.-R. Mo, R. L. Yung, and B. C. Richardson TRAIL (Apo2 Ligand) and TWEAK (Apo3 Ligand) Mediate CD4+ T Cell Killing of Antigen-Presenting Macrophages J. Immunol., March 15, 2000; 164(6): 2897 - 2904. [Abstract] [Full Text] [PDF]
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M. R. M. van den Brink, E. Moore, K. J. Horndasch, J. M. Crawford, J. Hoffman, G. F. Murphy, and S. J. Burakoff Fas-Deficient lpr Mice Are More Susceptible to Graft-Versus-Host Disease J. Immunol., January 1, 2000; 164(1): 469 - 480. [Abstract] [Full Text] [PDF]
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 S. E. Stepp, R. Dufourcq-Lagelouse, F. L. Deist, S. Bhawan, S. Certain, P. A. Mathew, J. Henter, M. Bennett, A. Fischer, G. d. S. Basile, et al. Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis Science, December 3, 1999; 286(5446): 1957 - 1959. [Abstract] [Full Text]
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