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Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, and could mediate
strong protection against L. monocytogenes when
transferred to infected mice. Macrophages pulsed with heat-killed
Listeriae presented Ag to the clone in a TAP-independent
manner. Both TAP-independent and -dependent processing occurred in
vivo, as TAP-deficient mice infected with L.
monocytogenes were partially protected by adoptive transfer of
the clone. This is the first example of CD8+ T
cell-mediated, TAP-independent protection against a pathogen in vivo,
confirming the importance of alternative MHC class I processing
pathways in the antibacterial immunity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(3). Accordingly,
mice deficient in ß2-microglobulin are hindered
in their ability to control L. monocytogenes infection
(4, 5). H2-M3 is a nonclassical MHC class Ib molecule that can present pathogen-derived epitopes to CD8+ T cells during the infection of mice with L. monocytogenes (6, 7). Several features distinguish H2-M3 from classical MHC class Ia molecules. First, H2-M3 exhibits minimal polymorphism. Only seven different forms of H2-M3 are known, and the vast majority of laboratory mice express the same form, which is designated H2-M3wt (8). Second, H2-M3 has a remarkable preference for binding formylated peptides (9), a phenomenon that is now understood at the molecular level (10). In eukaryotic cells, formyl groups are only found on 13 mitochondrial proteins, whereas all prokaryotic protein synthesis initiates with a formyl methionine group. Thus, it has been hypothesized that H2-M3 is specialized for the presentation of bacteria-derived formylated epitopes (9, 11).
Recently, several Listeria-derived epitopes that are presented by H2-M3 to CD8+ T cells have been identified (12, 13, 14). In this study we have used one of these epitopes, fMIGWII, to investigate the protective function of H2-M3 restricted T cell responses during L. monocytogenes infection. An H2-M3-restricted cytotoxic CD8+ T cell clone was generated that could mediate protection following adoptive transfer to Listeria-infected mice. Partial protection was also observed following transfer to TAP1-/- recipients, indicating that an unconventional Ag processing pathway was operative in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 mice were obtained from the Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin (Berlin, Germany), and were used between 6 and 8 wk of age. TAP1-/- mice were provided by Dr. S. Tonegawa (Massachusetts Institute of Technology, Cambridge, MA) and backcrossed six times to the C57BL/6 background. All mice were bred under specific pathogen-free conditions.
Materials
The formylated peptide fMIGWII (12) was synthesized by Jerini BioTools (Berlin, Germany). L. monocytogenes strain EGD Sv1/2a was originally obtained from G. B. Mackaness (Trudeau Institute Saramac Lake, NY) and grown in tryptic soy broth (Difco, Detroit, MI). Stocks were stored at -70°C until use. Heat-killed L. monocytogenes (HKL)2 was prepared by incubating bacteria at 70°C for 1 h. Effective killing was confirmed by incubating an aliquot of HKL overnight in tryptic soy broth. The HKL preparation did not contain peptides capable of binding directly to H2-M3 as verified using the H2-M3 peptide binding assay previously described by Vyas et al. (15) (data not shown).
Cells
EL4 and L929 cells were cultured in RPMI medium supplemented with 10% FCS (Sigma, St. Louis, MO), 1 mM L-glutamine, 10 mM HEPES, 5 x 10-5 M 2-ME, 1 mM sodium pyruvate, 100 µg/ml penicillin, and 100 U/ml streptomycin. This medium was designated RP10. Bone marrow cells were harvested from the tibia and femur of C57BL/6 mice and seeded into 90-mm bacterial grade petri dishes (Greiner, Frickenhausen, Germany). Bone marrow-derived macrophage (BMM) medium was DMEM supplemented with 10% FCS, 5% horse serum, 1 mM glutamine, 10 mM HEPES, 1 mM sodium pyruvate, and 20% L929 cell-conditioned medium. The cells were cultured at 37°C in a humidified atmosphere containing 7% CO2. All tissue culture reagents were obtained from Biochrom (Berlin, Germany) unless otherwise stated.
Peptide immunization
fMIGWII (2 mg/ml in PBS) was emulsified in a 1:1 mix with IFA (Organon Teknika, Durham, NC). Mice were immunized twice at 10-day intervals with 100 µg peptide s.c. at the base of the tail. Control mice received PBS emulsified with IFA. Ten days after the second immunization, groups of mice were either challenged with 5 x 103 CFU L. monocytogenes or sacrificed to determine the efficacy of peptide immunization.
Generation of T cell lines
To generate H2-M3-restricted CTL lines specific for fMIGWII, C57BL/6 mice were infected with 5 x 103 CFU L. monocytogenes i.v., and the spleens were collected 6 days later. Single cell suspensions were prepared by passing the spleens through a metal sieve, followed by lysis of the erythrocytes with ammonium chloride lysis buffer. Forty million L. monocytogenes-immune spleen cells were cultured with the same number of stimulator cells in RP10. Stimulator cells were prepared by incubating irradiated (2000 rad) C57BL/6 spleen cells at 37°C for 1 h in the presence of 10-7 M fMIGWII. The stimulator cells were washed twice before being added to the Listeria-immune spleen cells. The fMIGWII-specific T cell lines were cultured in RP10 and restimulated on a weekly basis by the addition of fresh stimulator cells pulsed with fMIGWII. After the second in vitro stimulation the cells were sustained by twice weekly addition of fresh RP10 containing 7% supernatant from Con A-stimulated spleen cells.
For some experiments CD8+ T cell lines or clones of irrelevant Ag specificity were used as a negative control. T cell lines specific for OVA257–264 (H2-Kb) (16) and LLO91–99 (H2-Kd) (17) were cultured in the same way as 3C8 cells, using peptide-loaded irradiated spleen cells as control. Alternatively a CD8+ T cell clone specific for the adenovirus type 5 E1A gene (H-2Db) was cultured as described (18).
Cloning of fMIGWII-specific T cell lines
fMIGWII-specific T cell lines were cloned by limiting dilution. Briefly, T cells were cultured in 96-well round bottom plates (Nunc, Roskilde, Denmark) at a density of 0.3 cells/well and stimulated with 5 x 104 irradiated, fMIGWII-coated APC per well (prepared as described above). Cultures were conducted in RP10 supplemented with 7% Con A supernatant. Clones were expanded by weekly restimulation with peptide-coated APC and by twice weekly addition of fresh Con A supernatant. One clone, 3C8, was further expanded in six-well plate (Nunc) cultures for in vivo studies.
Cytotoxic T lymphocyte assay
Target cells were BMM infected with L. monocytogenes at an moi of 10 for a period of 6 h. During the final 90 min, the cells were labeled with 100 µCi 51Cr. Alternative targets were EL4 cells labeled with 50 µCi 51Cr and 10-6 M fMIGWII. The targets were washed three times and 5 x 103 targets/well were added, together with 3C8 cells at a range of E:T ratios. After a 4-h incubation, 80 µl supernatant was collected and 51Cr activity was determined. Percentage of specific lysis was determined as (experimental value - spontaneous release)/(maximum release - minimum release).
Stimulation with HKL
BMM from C57BL/6 and TAP1 -/- mice were
plated out at 5 x 104 cells per well in
flat-bottom 96-well plates and allowed to adhere overnight.
104 3C8 cells/well in 100 µl RP10 were cultured
together with 108/ml HKL. Supernatant was
collected after 24 h, and IFN- was measured by ELISA.
Adoptive transfer
For adoptive transfer experiments, clone 3C8 was harvested 8–10 days following previous Ag stimulation and washed twice in PBS before i.v. administration in 200 µl PBS. Mice were infected i.v. 30–60 min later with 105 L. monocytogenes. Three days following infection, the mice were killed and bacterial load in the liver and spleen were determined as described previously (4).
Cytokine assays
IFNg, IL-4, IL-6, and IL-10 were measured by standard capture
ELISA, using R4–6A2, 11B11, 20F3, and JES5–2A57 as capture Abs and
biotinylated XMG1.2, BVD6–24G2, 32C11, and SXC-1 as detection Abs,
respectively. For measurement of TNF, an L929 cell bioassay was
performed. Briefly, 5 x 104 L929 cells were
cultured overnight in a flat-bottom 96-well plate (Nunc). Samples were
diluted 2-fold across the plate, and actinomycin D (Sigma) was added to
a final concentration of 2 µg/ml. After a 24-h incubation the cells
were fixed with 5% formaldehyde, stained with crystal violet, and
washed gently in water. After addition of 33% acetic acid, the plates
were read at 595 nm. The results were measured against a recombinant
TNF-
standard (Genzyme, Cambridge, MA).
Inguinal lymph nodes were collected from immunized mice, and
peptide reactivity was determined by IFN- enzyme-linked
immunospot (ELISPOT). ELISPOT plates (Millipore, Bedford, MA) were
coated with 4 µg/ml anti-IFN- Ab (R4–6A2) in 0.05 M carbonate
buffer, pH 9.6 at 4°C overnight. The plates were washed once and
blocked with PBS-1% BSA for 2 h at 37°C. After 2 washes,
varying numbers of lymph node cells, together with
105 control or fMIGWII-coated
(10-6 M; 37°C incubation for 1 h) EL4
cells were incubated in RP10 for 24 h. The plates were washed
extensively, and 0.25 µg/ml biotinylated anti-IFNg Ab (XMG1.2)
was added. After a 2-h incubation at 37°C, the plates were washed and
alkaline phosphatase-conjugated streptavidin (Dianova, Hamburg,
Germany) was added for a further 1 h incubation. The plates were washed
and color was developed for 15 min by addition of
5-bromo-4-chloro-3-indolylphosphate/nitro blue tetrazolium alkaline
phosphatase substrate (Sigma). Spots were counted under a dissecting
microscope.
Statistics
CFU data were analyzed using a two-tailed Mann-Whitney U test. Differences were considered significant when p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Three Listeria-derived peptide epitopes that are
presented by H2-M3 to CD8+ T cells have been
described: fMIGWII (12), fMIVIL (13), and
fMIVTLF (14). To investigate the protective capacity of
H2-M3-restricted T cell responses during Listeria infection,
peptide immunization with fMIGWII was undertaken. C57BL/6 mice were
immunized s.c. with 100 µg fMIGWII, followed by a booster
immunization 10 d later. After another 10 days, draining lymph
nodes and spleen cells were collected from one group of mice and tested
for reactivity to fMIGWII in an IFN- ELISPOT. Significant T cell
priming was detected in peptide-immunized mice, but not in mice
receiving IFA alone (Fig. 1
). The
remaining immunized mice were infected i.v. with 5 x
103 CFU L. monocytogenes. As a
positive control, mice infected with 103 CFU
L. monocytogenes i.v. 20 days previously were also
challenged with Listeria. At days 2 (data not shown) and 4
(Table I) following infection, groups of
four mice were sacrificed and bacterial loads in the liver and spleen
were determined. In contrast to mice that had been previously infected
with Listeria, mice immunized with fMIGWII were not
protected against Listeria challenge infection (Table I). In
a subsequent experiment, we attempted to improve immunization efficacy
by immunizing mice with a mix of 100 µg of both fMIGWII and another
H2-M3 binding epitope from L. monocytogenes, fMIVIL.
However, no protection was observed following challenge with
Listeria (data not shown).
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Resistance to Listeria infection involves numerous arms
of the immune response, and it is perhaps not surprising that
immunization with a single H2-M3-restricted CTL epitope was not
sufficient to induce protection. As an alternative approach to peptide
immunization, T cells specific for fMIGWII were generated and
characterized with respect to protective function. To generate
H2-M3-restricted T cells, Listeria-immune spleen cells
obtained 7 days following sublethal Listeria infection were
stimulated with irradiated spleen cells pulsed with
10-7M fMIGWII, as described in Materials
and Methods. The resulting cell line was cytotoxic and produced
IFN- (data not shown). The line was cloned by limiting dilution, and
one clone, 3C8, was expanded for further in vitro and in vivo
analysis.
Characterization of the H2-M3-restricted clone 3C8
The 3C8 clone was CD8+, ß
TCR+ (data not shown) and was able to lyse
targets pulsed with fMIGWII (Fig. 2A) as well as
Listeria-infected targets (Fig. 2B). To
characterize the cytokines produced by clone 3C8, 5 x
104 3C8 cells (10 days after the last Ag
stimulation) were cultured with 5 x 105
control or fMIGWII-pulsed APC, prepared as described in Materials
and Methods. Culture supernatant was collected after 48 h and
IFN-, TNF, IL-4, IL-6, and IL-10 were measured. Essentially no
cytokine was produced by unstimulated 3C8 cells, whereas IFN-, TNF,
and IL-6 were detected in the peptide-stimulated cultures (Table II). IL-4 and IL-10 were not detected.
Neither could IL-4 be detected in the more sensitive ELISPOT assay
(data not shown). Thus, 3C8 cells are associated with a typical type 1
cytokine pattern (19).
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To investigate the role of H2-M3-restricted T cells in protection
against Listeria infection, adoptive transfer experiments
were performed. C57BL/6 mice were given 107 3C8
cells i.v. in 200 µl PBS or PBS alone and then infected i.v. with a
high dose of L. monocytogenes (105
CFU). Three days later, bacterial load in the liver and spleen were
determined. Bacterial titers in the spleen (p
< 0.02) and liver (p < 0.01) were
substantially reduced in those mice that had received 3C8 cells
compared with control mice (Table III).
In all experiments, 3C8 cells were more active in reducing bacterial
load in the liver than in the spleen. As a further control, in one
experiment 107 CD8+ cells
specific for SIINFEKL presented by H2-Kb were
transferred to Listeria-infected C57BL/6 mice. These cells
were cultured using the same conditions as 3C8 cells, but did not
influence the course of Listeria infection (data not
shown).
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). Thus, H2-M3-restricted T cells can
protect mice from a lethal Listeria infection.
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The pathway by which Ag is processed and presented by H2-M3 is at
least partially distinct from the conventional MHC class I processing
pathway. Earlier studies indicated that exogenous HKL can be processed
by macrophages and presented via H2-M3, and that such processing is at
least partially TAP independent (12). Using IFN-
production as a readout, presentation of HKL-derived Ag by macrophages
to 3C8 cells could be demonstrated (Fig. 4). 3C8 cells also recognized HKL-pulsed
TAP1-/- macrophages, although IFN-
production was consistently reduced compared with 3C8 cells stimulated
with HKL-pulsed C57BL/6 macrophages. Thus, processing of exogenous Ag
by macrophages for presentation to 3C8 cells by H2-M3 was at least
partially TAP independent, confirming previously published data
(12). Nonspecific stimulatory effects of HKL were excluded
by showing that CD8+ T cell lines specific for
(and capable of producing IFN- in response to) the
H2-Kd-restricted LLO91–99
epitope or the H2-Kb-restricted
OVA257–264 epitope (16) did not
produce IFN- in response to HKL-pulsed macrophages (data not
shown).
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To test the in vivo relevance of TAP-independent presentation of HKL to 3C8 cells, adoptive transfer experiments in Listeria-infected TAP1-/- mice were performed. Our preliminary experiments had indicated that transfer of CD8+ T cells of irrelevant Ag specificity had no influence on Listeria infection. However, for this experiment we used an irrelevant CD8+ T cell clone as an additional control. The reason for this is that the activity of the 3C8 clone in TAP1-/- mice was considerably reduced compared with C57BL/6 mice (see below), and it was considered important to include this control to rigorously confirm the findings.
Adoptive transfer of 3C8 cells to Listeria-infected
TAP1-/- mice significantly reduced bacterial
load in the liver (p < 0.05) and spleen
(p < 0.05; Fig. 5) in comparison to mice receiving a
clone of irrelevant specificity. The ability of 3C8 cells to lower
bacterial burden, at least in the liver, was considerably lower in
TAP1-/- recipients compared with C57BL/6
recipients (p < 0.05 in the liver). The
irrelevant CD8+ clone, specific for the
adenovirus E1A gene, did not affect bacterial load in the liver or
spleen in C57BL/6 or TAP1-/- mice
(p > 0.05 in each case; Fig. 5). We conclude
that H2-M3-restricted T cells can participate in protection and that
this is, in part, TAP independent.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this paper we have addressed the protective ability of H2-M3-restricted T cell responses during Listeria infection. Our first approach was to examine whether immunization with peptides restricted by H2-M3 could protect against Listeria infection. Peptide immunization successfully primed H2-M3-restricted responses, albeit quite weakly, but had no influence on the course of infection following challenge with Listeria. fMIGWII-specific responses could also be primed following transfer of irradiated syngeneic spleen cells or dendritic cells pulsed with fMIGWII, but neither protocol protected mice from subsequent challenge (M. S. Rolph and S. H. E. Kaufmann, unpublished data). The immune response to Listeria infection is multifaceted and it is perhaps not surprising that immunization with a single peptide epitope is not sufficient to induce protection. Indeed, previous studies aiming to demonstrate the protective capacity of a CD8+ T cell response to a single epitope have mostly resorted to adoptive transfer (21). It is also interesting to note that for Listeria infection, H2-M3-restricted memory responses may not be as strong as MHC class Ia-restricted memory responses (22).This phenomenon could also potentially contribute to the lack of protection observed with our immunization protocol.
To further examine the protective potential of H2-M3-restricted
responses, a CD8+ T cell clone specific for
fMIGWII was generated. The clone was strongly cytotoxic and produced
high levels of IFN- and TNF. Substantial protection was observed
following transfer of 3C8 cells to Listeria-infected mice.
Similar results were obtained by Nataraj et al. using an
H2-M3-restricted clone generated following in vitro stimulation with
HKL (23). The strength of the protection mediated by 3C8
cells was further demonstrated by the ability to rescue mice from a
lethal infection. Our results, using a clone of defined specificity
(fMIGWII), demonstrate that H2-M3-restricted responses contribute to
protection against Listeria infection.
A recent study has addressed the role of MHC class Ib-restricted responses during Listeria infection. Mice deficient for MHC class Ia molecules (H2-Kb x H2-Db double knockout mice) controlled infection as efficiently as wild-type mice, and this was associated with measurable induction of CD8+ T cell responses restricted by H2-M3 and another MHC class Ib molecule, Qa1b (24). In contrast, mice deficient in ß2-microglobulin are more susceptible to Listeria infection (4, 5). Thus, CD8+ T cell responses restricted by MHC class Ib molecules, at least in mice of the H2b background, are important in the control of Listeria infection.
Conventional MHC class I Ag processing involves degradation of
polypeptides within the cytoplasm, followed by TAP-mediated transport
to the endoplasmic reticulum (ER). In the ER, the peptides form a
stable complex with MHC class I and
ß2-microglobulin before being transported to
the cell surface (25). Exogenous Ags do not readily gain
access to the MHC class I pathway, although exceptions have been noted
(26). For H2-M3, presentation of endogenous self
(mitochondrial) peptides appears to follow the conventional pathway and
is TAP dependent (27, 28). However, exogenous Ags can
readily access the H2-M3 presentation pathway. This is illustrated by
the ability of HKL-pulsed macrophages to present epitopes via H2-M3
(Fig. 4
; Refs. 12, 20, 23) but only minimally via MHC
class Ia molecules such as H2-Kd (17, 20). The mechanism by which HKL enters the H2-M3 presentation
pathway is not known. Peptide regurgitation, as described by Pfeifer et
al. (29) for MHC class Ia, is not likely as bystander
cells are not loaded with peptide when cultured together with
HKL-pulsed macrophages (30). Presentation of HKL by H2-M3
does require active processing (30, 31) but is not greatly
influenced by the presence or absence of TAP (Fig. 4; Ref.
30). It is probable that formylated peptides located
within the phagosome load H2-M3 molecules, which may access the
phagosomal compartment either from the cell surface or en route to the
cell surface from the ER (26, 30).
The extent to which TAP-independent presentation of HKL by BMM reflects events that occur in vivo during L. monocytogenes infection is not clear. To test this, 3C8 cells were transferred to Listeria-infected C57BL/6 and TAP1-/- mice. The results revealed that during Listeria infection, H2-M3-restricted, TAP-independent presentation to CD8+ T cells occurs, and that this pathway is sufficient to mediate substantial protection against Listeria infection. However, the protective efficiency of 3C8 cells was markedly less in TAP1-/- than in C57BL/6 hosts, indicating that TAP plays a role during in vivo L. monocytogenes infection in presentation via H2-M3. This probably indicates that in C57BL/6 mice, the endogenous MHC class I presentation pathway, in which peptides are transported from the cytosol to the ER by TAP, was also operative (2, 32). The suboptimal protection observed in TAP1-/- mice could also reflect a relative paucity of H2-M3 molecules available for peptide binding. In the absence of TAP, few H2-M3 molecules would be expected to leave the ER. If peptide binding occurs after H2-M3 molecules have left the ER (e.g., in the phagosome), then the absence of TAP may influence the magnitude of presentation.
It will be important to further elucidate the processing pathway for presentation of both exogenous and endogenous foreign antigen by H2-M3. The recent development of a mAb specific for H2-M3 (28) should greatly facilitate such analysis. Here we have shown that in vivo, in the absence of TAP, Listeria-derived peptides can still be presented in sufficient quantity to provide substantial protection following transfer of a specific CD8+ T cell clone. Indeed, to our knowledge this is the only example of CD8+ T cell-mediated, TAP-independent protection against a pathogen in vivo.
L. monocytogenes is the only pathogen known to induce H2-M3-restricted T cells and it will be of great interest to determine whether other bacterial pathogens can do so. Early studies identified apparently MHC-unrestricted CD8+ T cell responses during infection of mice with Mycobacterium bovis bacille Calmette Guérin (33), which probably reflects restriction by a nonpolymorphic presenting molecule such as H2-M3. The ability of H2-M3 to present Ag via both conventional (TAP-dependent) and unconventional (TAP-independent) processing pathways suggests that it may be particularly well suited for presentation of Ag derived from vacuolar bacterial pathogens such as Mycobacterium tuberculosis or Salmonella typhimurium.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: HKL, heat-killed L. monocytogenes; BMM, bone marrow-derived macrophage; ELISPOT, enzyme-linked immunospot; ER, endoplasmic reticulum.
Received for publication January 10, 2000. Accepted for publication July 27, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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