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Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden
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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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We have used the CTL response of B64 mice against cells of BALB.B origin to investigate the mechanisms of immunodominance. This is an established model of CTL responses to multiple minor H Ags, comprising at least 40 different Ags (32). The term minor was originally used for these Ags, because graft rejection in the murine models studied was slower than that for MHC-mismatched grafts. However, it has now become clear that CTL recognition of minor H Ags can cause strong transplantation reactions in man and mouse (16, 33, 34, 35). Minor H Ags have been defined as MHC-presented peptides (36), and a number of minor H MHC class I-presented peptides recognized by CD8+ T cells have been identified (37, 38, 39, 40, 41, 42, 43, 44). Minor H Ags with limited tissue expression have been suggested as targets in T cell immunotherapy of, e.g., leukemic cells (45, 46).
CTL in the B6 anti-BALB.B response focus on a few MHC class
I-restricted determinants: in our hands three immunodominant epitopes
as defined by elution and HPLC fractionation of peptides. In addition
to these immunodominant epitopes, nondominant epitopes associated with
the BALB.B alleles H-8c, H-19c,
and H-25c were defined. The nondominant epitopes
elicit a CTL response when present alone in spleen cells from B6 minor
H congenic mice, while they do not elicit a CTL response when present
in BALB.B spleen cells also carrying the dominant epitopes. The
nondominant epitopes were nevertheless found to be processed and loaded
in MHC class I molecules of BALB.B spleen cells (15). A summary of this
response pattern is provided, as a presentation of the experimental
system used (Table I
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The inbred mouse strain BALB.B (H-2b) was bred and maintained at the MTC, Karolinska Institute (Stockholm, Sweden). The inbred mouse strain C57BL/6By (H-2b) and C57BL/6By minor H congenic strains were purchased (The Jackson Laboratory, Bar Harbor, ME) and further bred and maintained at the MTC, Karolinska Institute. The congenic strains were: B6.C-H-8c/By, -H-19c/By, -H-25c/By, and -H-28c/aBy.
Cell lines
RMA-S is a TAP-2 deficient tumor cell line with low levels of unstable "empty" MHC class I molecules on the cell surface. It is derived from the Rauscher leukemia virus-induced mouse T cell lymphoma RBL-5 of C57BL/6 origin (H-2b) (48). The cells were grown in RPMI 1640 medium supplemented with penicillin-streptomycin and 5% FCS in 50-ml cell culture flasks at 37°C and 5% CO2.
Generation of Con A-activated T cell blasts
Spleen cells were incubated for 48 h at 2 x
106 cells/ml in 
-MEM medium supplemented with
penicillin-streptomycin, 10% FCS, 10 mM HEPES, 3 x
10-5 M 2-ME, and 3 µg/ml of Con A (Sigma, St. Louis,
MO). Before use as targets in a standard 4-h 51Cr
cytotoxicity assay, dead cells were removed by centrifugation on a
Lymphoprep gradient (Nycomed, Oslo, Norway).
Acid elution of naturally processed peptides from cell lysates and from intact cells
Splenocytes (109) were washed three times in PBS, lysed in 10 ml of distilled water containing 1% trifluoroacetic acid (TFA), and sonicated for 1 min. The lysates were centrifuged at 14,000 rpm for 30 min using a Sorvall RC-5C centrifuge and a SS-34 rotor (DuPont, Wilmington, DE), after which the supernatant was recovered. The supernatants were filtered sequentially through Microsep microconcentrators (Filtron Technology, Northborough, MA) with cut-off limits of 30 and 10 kDa. All work was performed at 4°C. For eluates from intact cells, 109 splenocytes were incubated for <1 min in 10 ml of ice-cold PBS containing 0,1% TFA. The eluates were subsequently treated as described above.
Separation by reverse phase HPLC
The filtered eluates were separated using the protocol of Wallny and co-workers (36). Briefly, the separations were performed on a reverse phase Superpac Pep-S column (C2/C18, 5-µm particles, 4.0 x 250 mm; Pharmacia LKB, Uppsala, Sweden) using Pharmacia LKB equipment. The elution procedure was as follows: solution A, 0.1% TFA in H2O; solution B, 0.1% TFA in acetonitrile; 0 to 40 min, linear increase to 60% solution B; 40 to 45 min, 60% solution B; 45 to 50 min, linear decrease to 0% solution B. The flow rate was 1 ml/min. Elution was monitored by measuring UV light absorption at 214 nm in a continuous flow detector. Forty 1-ml fractions were collected in the interval from 0 to 40 min. Individual fractions were dried by vacuum centrifugation.
Generation of bone marrow-derived DC
Bone marrow-derived DC were obtained using the protocol of Inaba et al. (49) with minor modifications. Bone marrow cells were cultured in DMEM containing 10% supernatant from the granulocyte-macrophage CSF-secreting cell line X63 (a gift from Dr. D. Gray through Dr. C. Watts, University of Dundee, Dundee, U.K.) and 20% FCS. The culture medium was replaced every third day, and the cells were replated on day 7.
In vivo priming
B6 mice were immunized with three weekly s.c. inoculations of 50 x 106 (20 Gy) irradiated splenocytes or with one s.c. inoculation of 5 x 105 live bone marrow-derived DC.
In vitro restimulation
Single cell suspensions of spleens from immunized or nonimmunized mice were prepared. Effector cells (20 x 106) were incubated with 10 x 106 irradiated (20 Gy) splenocytes in 15 ml of RPMI 1640 medium supplemented with penicillin-streptomycin, 10% FCS, 3 x 10-5 M 2-ME, 1 mM sodium pyruvate, 0,1 mM nonessential amino acids, and 2 mM L-glutamine at 37°C and 5% CO2 for 5 days.
In vitro interference experiments
Responder cells (8 x 106) were restimulated with 8 x 106 stimulator cells in 4 ml of medium. For interference experiments, 8 x 106 second party splenocytes, primed or unprimed, were added to the cultures. Cultures with and without added second party splenocytes were prepared in parallel. Responder cells were counted only in the cultures to which no second party splenocytes had been added and were diluted to the indicated E:T cell ratios. Cultures with added second party splenocytes were diluted identically, without counting the cells, thus allowing a comparison of the total cytotoxic activity generated in the cultures.
Generation of CTL lines
B6 mice were immunized in vivo with either DC or splenocytes. Splenocytes from immunized mice were restimulated every 10th day. The T cell lines used had been restimulated between two and five times.
In vitro cytotoxicity assay
Target cells were labeled with 51Cr and resuspended in cell culture medium. Target cells (5 x 103) were added to each well followed by addition of effector cells. The cells were incubated for 4 h at 37°C, and supernatants were harvested. Radioactivity was measured in a Pharmacia LKB gamma counter, and specific lysis was calculated: [(cpm released with effector cells - cpm released without effector cells)/(cpm released by detergent - cpm released without effector cells)] x 100. Experiments with >30% spontaneous lysis were discarded.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One explanation for the failure of BALB.B cells to elicit CTL
against the nondominant Ags could be the lack of expression by BALB.B
APC. To investigate this, DC from BALB.B mice were used as targets for
CTL lines directed against the nondominant epitope
H-19c. The specificity of the CTL lines was
confirmed by their ability to kill Con A blasts from
H-19c, but not B6, mice (data not shown). Such
H-19c-specific CTL lines killed DC from BALB.B mice,
while DC from B6 mice were not killed (Fig. 1A). The same result was seen
with CTL lines obtained after immunization with either splenocytes or
live DC from H-19c mice.
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B). The same result was seen for
the nondominant epitope associated with H-25c (data
not shown). These results demonstrate that these nondominant epitopes
are functionally expressed on APC, even if the APC also express
dominant epitopes. Nondominant minor H Ags are presented at the surface of BALB.B cells in amounts sufficient to elicit a CTL response
Although nondominant epitopes were found to be presented by BALB.B
APC, the quantity may not be sufficient to elicit a CTL response.
However, the quantity presented by cells congenic for single
nondominant minor H Ags is sufficient, since the latter can elicit a
CTL response. Therefore, we compared the amount of nondominant epitopes
presented at the cell surface by BALB.B and minor H congenic cells, as
measured by recognition of the nondominant epitopes in cell surface
eluates from these cells. Cell surface eluates were prepared by mild
acid elution (which keeps the cells intact, as measured by retention of
trypan blue and 51Cr; data not shown), followed by HPLC
separation and loading of individual fractions on TAP-deficient RMA-S
target cells. Ag-specific CTL recognized the relevant epitopes in HPLC
fractions no 20 (H-8c), no 23
(H-19c), and no 28 (H-25c) in
cell surface eluates of cells from both the congenic strains carrying
the relevant nondominant epitope and from BALB.B cells (Fig. 2, A and B, and
data not shown). Lysis levels of RMA-S cells loaded with eluates from
BALB.B and congenic cells did not differ significantly. Furthermore,
there was no significant difference in CTL recognition of serial
dilutions of surface eluates from the two cell types under conditions
where the CTL could detect a twofold difference in amount of Ag (Fig. 2, C and D). This suggests that BALB.B and minor
H congenic cells present similar amounts of the nondominant epitopes at
the cell surface.
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Our data suggested that the failure of the nondominant epitopes to
elicit CTL after immunization with BALB.B cells cannot be explained by
the lack of presentation of these epitopes in the presence of the
dominant epitopes. We speculated that immunodominance in this system is
determined independently of the APC, e.g., in an interaction between
responding CTL. The same pattern of immunodominance should then also
occur if dominant and nondominant epitopes are presented on separate
cells. However, CTL responses to nondominant epitopes could be obtained
after in vivo immunization with mixtures of splenocytes from
H-19c and BALB.B mice. In contrast, when dominant
and nondominant epitopes were present on the same cell, as on BALB.B
cells or even on cells from F1 mice between a congenic
strain carrying a nondominant epitope and BALB.B mice, no reactivity to
the nondominant epitopes could be observed (Table II). Hence, separation of APC for
nondominant and dominant epitopes could break immunodominance. The same
result has previously been obtained for immunodominance of BALB.B minor
H Ags expressed in cells from recombinant inbred strains (50) and
subdominance of the H-Y Ag (51, 52).
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Taken together, the data obtained suggested that the mechanism for
immunodominance of certain minor H Ags is not determined solely at the
level of epitope presentation. Nevertheless, presentation of epitopes
by the same APC appears to be an important factor for immunodominance.
To investigate whether an immune response against dominant epitopes
could affect the immune response against nondominant epitopes, we
established an in vitro model where splenocytes separately primed
against dominant and nondominant epitopes were restimulated on the same
APC. Indeed, B6 splenocytes primed against dominant BALB.B epitopes
markedly decreased the CTL response against the nondominant epitope
associated with H-19c when both CTL populations were
restimulated on BALB.B splenocytes. This effect was not the result of
unspecific crowding in the MLC, since addition of the same number of
unprimed B6 splenocytes did not affect the cytotoxicity against
H-19c (Fig. 3A). (The cytotoxicity in this
control experiment was not due to a novel activity mediated by the B6
cells, since such naive cells stimulated in vitro with BALB.B cells
yielded no response (data not shown).) Activation in the MLC of the B6
anti-BALB.B effectors was necessary, since restimulation of B6
anti-BALB.B and B6 anti-H-19c with
H-19c splenocytes (i.e., expressing only the
nondominant epitope) did not result in any interference of the
cytotoxic response against H-19c (Fig. 3B). Addition of B6 anti-BALB.B effectors also
interfered with the CTL response against the nondominant epitopes
associated with H-8c and H-25c,
respectively (data not shown).
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C)
when restimulation was performed with BALB.B cells that express both
epitopes, demonstrating that an immune response against a single
dominant epitope is sufficient for this interference effect. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The recognition of BALB.B DC demonstrated that the nondominant epitopes were presented by these cells. Our experiments demonstrate that the presence of dominant epitopes does not influence the cell surface presentation of nondominant epitopes in a heterogeneous splenocyte population. Peptide elution demands high numbers of cells; therefore, it was not possible to use this technique to directly quantify the amount of peptide presented by DC. When considering the methodology used, it should be noted that the CTL recognition of nondominant epitopes from the two different strains should only be influenced by the loaded peptide eluates, since the CTL population and the target cells used were identical. Furthermore, even if a difference between cells from the two strains could have been masked by cytotoxicity at a maximum plateau level, such a difference should have been revealed in the titration of the eluates. Levels of cytotoxicity have been shown to directly correlate with the amount of presented peptide at lysis and peptide levels below a saturation level (26). Although the methods used for epitope quantification do not determine the absolute amount of the epitopes, there was no systematic difference observed in recognition of the nondominant epitopes between the two cell types compared: immunogenic (congenic cells) or nonimmunogenic (BALB.B cells) for the nondominant epitope. Significant differences would be expected if the main reason for quenching the CTL response against the nondominant epitopes in this system was due to inhibition of determinant selection within the APC in the presence of the immunodominant epitopes. This in line with conclusions based on a study of presentation of nondominant epitopes in SV40 (7).
The nondominant minor H epitopes studied can hence be classified as subdominant according to a terminology proposed by Vitiello et al. (8). It is important to stress that the experiments in this study did not address differences in presentation between dominant and subdominant epitopes with respect to, e.g., MHC affinity or proportion of MHC molecules binding the epitope. Dominant epitopes have been shown to be better presented than subdominant epitopes in several studies (8, 9, 17, 26). The important conclusion from the present study is that despite similar expression of the subdominant epitope in cells of two genotypes, the CTL response against them differed significantly depending on the absence or the presence of dominant epitopes. This suggested a role for mechanisms of immunodominance acting exterior of the APC, i.e., at the responding T cell level. We have recently observed immunodominance between synthetic peptide epitopes where events postdeterminant selection also appear to play a major role (53).
Immunodominance in the system studied here nevertheless appeared to depend on a process involving the APC, since it was possible to prime the same mouse simultaneously for nondominant and dominant epitopes by immunization with the epitopes presented on separate cells. The same result has previously been obtained for immunodominance of BALB.B minor H Ags expressed in cells from recombinant inbred strains (50) and subdominance of the H-Y Ag (51, 52). We hypothesized that immunodominance in this system could be determined in the interaction between the responding T cells and the APC, such that some T cell responses are favored when different epitopes are presented by the same cell. This could be due to competition for APC surface (e.g., costimulatory or MHC molecules) or APC-derived factors (e.g., cytokines), T cell-mediated elimination of APC or signaling between T cells brought together around one APC (so-called bystander suppression) (54, 55). Indeed, addition of T cells responding to dominant Ags substantially reduced the in vitro CTL response against the subdominant epitopes. This interference was not due to nonspecific crowding, since addition of unprimed splenocytes did not affect the response. Furthermore, addition of the same interfering T cell population primed to dominant Ags had no effect when T cells were restimulated on APC presenting only the subdominant Ag. An important finding from this study is thus that inhibition of the secondary CTL response in vitro to a subdominant epitope can be obtained by T cells responding to a dominant epitope presented by the same APC. Deng et al. have suggested that the presence of immunodominant epitopes suppresses the CD8+ T cell response to nondominant epitopes (10). The suggestion was based on the finding that deletion of an immunodominant epitope rescued the CTL response to a nondominant epitope without affecting the presentation of the nondominant epitope. This could occur through several mechanisms, e.g., by peptide antagonism. To our knowledge, the present study is the first to directly demonstrate that an ongoing immune response against a dominant epitope can inhibit the immune response against a nondominant epitope. It is not yet known whether this in vitro observation appropriately reflects the mechanisms for immunodominance in vivo. Consumption of or competition for APC constituents may, for example, be more pronounced in an in vitro system.
With this reservation, it is pertinent to briefly discuss the regulation of responses within T cell/APC clusters (56, 57) and the possible mechanisms for T cell interference around the APC. T cell responses are initiated in aggregations of T cells around APC in the lymph node, where each such cellular conglomerate may be regarded as a separate microenvironment in terms of availability of critical factors such as cytokines and costimulatory molecules. If multiple T cell clones responding to different epitopes presented by the same APC influence this microenvironment, each response will not only depend on intrinsic properties of that particular epitope-T cell combination. This may be compared with the previously described suppression mediated by anergic cells around an APC (58), also proposed as a mechanism for infectious tolerance (59, 60). In that model, anergic cells bind to the APC by virtue of their capacity to recognize Ag. By being present but doing nothing at the site of action, they not only fail to respond themselves, they also prevent others from acting efficiently.
Neither infectious tolerance, bystander suppression, nor the interference phenomenon described by us requires Ag-specific interference. For example, T cells primed to the single dominant Ag H-28c also inhibited the response to the subdominant H-19c, an Ag that the T cells of the H-28c-primed mice had not been confronted with previously. The key factor determining specificity appears to be the APC; the interference can affect T cell responses directed against nonrelated Ags, provided that they are presented by the same APC. Such competition at the microenvironmental level would be in line with the idea that T cell dynamics at various levels (differentiation, selection, responses, and survival) (61) "do not rely only on the interactions of each T cell with their respective ligands, but also on the nature and number of other competing cells" (62).
Why do some T cells dominate over others? If the APC is a limiting factor, the simplest possibility is that the T cells first arriving at the APC become dominating. In the antigenic system that we are studying, the CTL response against dominant epitopes is faster than the CTL response against nondominant epitopes (E. Z. Wolpert, unpublished observations). We do not know whether this reflects a difference in precursor frequencies in the unprimed animal, a difference in kinetics between the two responses, or other factors. Some investigators report lower frequencies of T cells reacting to subdominant than to dominant epitopes in animals after challenge with the complete Ag (31) or after challenge with the nominal epitopes (53), while other investigators do not see such a difference (52). Other potential influencing factors include characteristics of individual responding T cells. In one case, TCRs specific for a dominant epitope were more heterogeneous and had lower affinity for their peptide/MHC complex than the TCRs specific for a subdominant epitope (28).
In further studies it will be important to investigate the mechanism of T cell interference at the microenvironmental level as well as its role in immunodominance in vivo. Major questions concern the fate of the APC during T cell activation and the rules determining why one T cell response dominates over another when epitopes for both CTL populations are expressed. By applying the in vitro model described in this study to other systems where the epitopes are defined as specific peptides, it may be possible to dissect the importance of APC peptide ligand density, numbers of responding T cells, TCR-MHC affinity, and T-APC avidity for the interference phenomenon. Further understanding of the immunodominance phenomenon will teach us more about the regulation and control of immune responses, knowledge that can have broad implications in vaccination, transplantation, and autoimmune disease.
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Acknowledgments |
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Footnotes |
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2 E.Z.W. and P.G. contributed equally to this paper.
3 Address correspondence and reprint requests to Dr. Elisabeth Z. Wolpert, Microbiology and Tumor Biology Center, Box 280, S-171 77 Stockholm, Sweden. E-mail address:
4 Abbreviations used in this paper: B6, C57BL/6; H, histocompatibility; TFA, trifluoroacetic acid; DC, dendritic cells.
Received for publication March 5, 1998. Accepted for publication June 22, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) were
tested for lysis by a CTL line directed against
H-19c. One experiment of four is shown.
B, B6 mice were immunized with splenocytes from
H-19c; responder spleens were split in three and
restimulated with splenocytes from BALB.B (•),
H-19c (
), or B6 (
) or from H-8c splenocytes (
).
B, The same experiment was performed as in
A, with H-25c splenocytes instead
of H-8c splenocytes. C, Cell
surface eluates from BALB.B (•) or H-8c (