| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Although many Ags carry several potential CTL epitopes, only one or a few are selected by the immune response in vivo, a phenomenon known as immunodominance (17). The major epitope(s) chosen by T cells in complex Ags are called immunodominant. Apart from the dominant epitope(s), complex Ags such as proteins, cells, or micro-organisms harbor a hierarchical array of subdominant and/or cryptic epitopes (17, 18, 19, 20, 21, 22, 23). Both of these terms have been used operationally to define intrinsically immunogenic epitopes that fail to induce a response when introduced within a more complex antigenic challenge (17, 19, 21). According to a recent mechanistic classification proposed for class I-presented peptides, the term subdominant refer to epitopes that are processed and presented; they can elicit a response, but fail to do so in the presence of other "dominant" epitopes (22, 23). The term cryptic is then reserved for epitopes that are not presented. This may be accounted for by any of a number of mechanisms operating at the level of intracellular Ag processing. Peptide selection for cell surface expression can thus be influenced by proteasomal cleavage specificity (24, 25, 26) and protein sequences flanking the potential epitopes (27), as well as TAP-peptide transport preferences (28, 29, 30, 31) and peptide competition for binding to the MHC class I molecule (21). The life span of MHC-peptide complexes, after they have arrived at the cell surface, influences the immunogenicity of potential epitopes (32). However, immunodominance can also be influenced by the available T cell repertoire (33, 34, 35) and the cytokine milieu (36).
A major limitation in the development of peptide vaccines is the extensive polymorphism in the human MHC loci. Additionally, immunity to antigenic variants and strains of pathogens may not be achieved using a single peptide. Thus, effective coverage of the human population will most probably need the inclusion of several epitopes. After good candidate peptides have been identified, the vaccine can be delivered loaded on APC, mixed with adjuvant, or as lipopeptides. Recently, peptides loaded on dendritic cells (DC)3 has proved particularly efficient in the induction of protective CTL immunity (12, 13).
To address the mechanisms of immunodominance in MHC class I-restricted T cell responses, as well as the functionality of multiepitope peptide vaccines, we analyzed the CTL response to mixtures of five well-characterized H-2Kb-restricted epitopes, each of which has been described as immunodominant within its antigenic system (11, 37, 38, 39, 40, 41). Clear patterns of dominance among the five epitopes were observed, and the dominance was abrogated when DC were employed for Ag delivery. Our results have important implications for the understanding of immunodominance in T cell responses and for future vaccine development.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
C57BL/6 (B6) mice were bred and maintained at the Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden. Animal care was in accordance with institutional guidelines. Mice were used at 6 to 10 wk of age. The RMA-S cell line, a TAP2-deficient derivative of the Rauscher virus-induced T cell lymphoma RBL-5 of B6 (H-2b) origin (42), was maintained at 37°C and 5% CO2 in RPMI 1640 tissue culture medium supplemented with 5% FCS, 50 µg streptomycin/ml, 100 µg penicillin/ml, and 2 mM L-glutamine.
Synthetic peptides
Synthetic peptides corresponding to the following epitopes were synthesized by the solid phase method using F-moc chemistry, purified by reverse phase HPLC, and analyzed by electrospray mass spectrometry: vesicular stomatitis virus (VSV) NP52–59 RGYVYQGL (37); Sendai virus (SV) NP324–332 FAPGNYPAL (11, 38); mink cell focus-inducing murine leukemia virus (MCF) 1233 env574–581 KSPWFTTL (39); mutated Ras (mRas) 59–67 AGLEEYSAM (40); and OVA257–264 SIINFEKL (41).
Generation of bone marrow-derived dendritic cells
Bone marrow-derived DC were obtained from B6 mice using the protocol of Inaba et al. (43) with the following alterations. 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.
Peptide immunization and generation of peptide-specific CTL
B6 mice were immunized through one of three different routes. 1) 0.1 µmol (approximately 100 µg) peptide was dissolved in 0.1 ml distilled water, mixed with 0.1 ml IFA by sonication, and injected s.c. in the base of the tail (44, 45). 2) 10 x 106 B6 spleen cells were incubated at 37°C with 10 µM of relevant peptides for 2 h in serum-free RPMI 1640, washed twice, irradiated with 2000 rad, and inoculated i.v. (46). 3) 1 x 105 B6 DC were incubated at 37°C with 30 µM of relevant peptides for 2 h in serum-free DMEM, washed twice, and injected s.c. (13). Nine to twelve days after immunization through the IFA and DC routes or 3 wk after immunization through the splenocyte route, 25 x 106 immune spleen cells were cocultured with 25 x 106 irradiated B6 spleen cells in the presence of 0.1 µM of relevant peptides in 12 ml of complete medium (RPMI 1640 supplemented with 10% FCS, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 5 x 10-5 M 2-ME, 2 mM L-glutamine, 50 mg streptomycin/ml, and 100 mg penicillin/ml) at 37°C and 5% CO2. Five days later, these cells were used as effectors in a 51Cr release CTL assay (see below).
Limiting dilution assay for CTL frequency in vivo
At 9 to 12 days after immunization with peptide in IFA, immune B6 splenocytes were titrated in U-bottom 96-well plates using 60 wells at each dilution, together with 105 2000 rad-irradiated B6 splenocytes and 0.1 µM peptide. Medium was supplemented with 20 IU/ml IL-2 and 5% MLC supernatant. An 8-h 51Cr release assay was performed after 6 days, at which time RMA-S target cells coated with peptide were added to 40 wells and RMA-S without peptide were added to 20 wells to measure the nonspecific release. Positive wells were defined as those wells for which 51Cr release levels exceeded the mean nonspecific release level by more than three times its SD. The in vivo CTL frequency was estimated by linear regression calculation (47).
H-2Kb peptide stabilization assay
RMA-S cells were incubated overnight at 26°C in complete medium with titrated concentrations of peptide followed by a 45-min chase at 37°C. Cells were then stained with FITC-conjugated anti-H-2Kb Ab AF6-88.5 (PharMingen, San Diego, CA) and analyzed for H-2Kb expression by flow cytometry using a FACScan flow cytometer and the CellQuest program (Becton Dickinson, Sunnyvale, CA) (48, 49). Relative fluorescence was calculated according to the following formula: relative fluorescence = mean fluorescence for RMA-S with specific peptide - mean fluorescence for RMA-S without peptide.
CTL assay
CTL activity was measured in a standard 51Cr release assay. Briefly, peptide-coated target cells were prepared by incubating cells with 30 µM of peptide for 1 h at 37°C. Coated cells were labeled with 100 µl 1 mCi/ml 51Cr for 1 h at 37°C. Titrated numbers of restimulated effector cells were incubated with 3 x 103 51Cr-labeled target cells for 4 h at 37°C in 5% CO2. After incubation, released radioactivity was measured, and specific lysis was calculated according to the formula: % specific release = ((experimental release - spontaneous release)/(maximum release - spontaneous release)) x 100.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To examine the CTL response to multiple MHC class I
restricted epitopes, five well-characterized peptide epitopes were
chosen, each known to be H-2Kb restricted and
immunodominant in the CD8+ T cell responses to their
complex Ags (Table I
). The VSV
NP52, SV NP324, and MCF env574 are
dominant in the CTL-mediated clearance of the corresponding viral
infections, while OVA257 and mRas59 are in the
focus of the CTL response to OVA and mutant Ras-protein, respectively.
To compare the magnitude of the CTL response to each of these five
epitopes as single peptides, groups of B6 mice were immunized with the
peptides in IFA. Immunogenicity was assessed as number of responding
mice (Table I) and mean level of CTL activity in responding mice (Fig. 1). Three of these five epitopes, SV
NP324, VSV NP52, and the OVA257,
reproducibly elicited strong CTL responses. The MCF env574
epitope induced an intermediate response, while in our hands, the
mRas59 was only weakly immunogenic. The overall pattern was
similar when mice were immunized with peptide-loaded live DC or
irradiated splenocytes, although the DC route generally generated
weaker CTL activity.
|
|
and Figure 1 with mice immunized
with single epitopes dissolved in IFA, or loaded on irradiated
splenocytes or live DC, a hierarchical pattern of CTL reactivity is
evident, with SV NP324, VSV NP52, and
OVA257 being the most immunogenic, followed by MCF
env574 and mRas59 in descending order. Superdominance in the complex CTL response to five "immunodominant" synthetic peptide epitopes
With knowledge of the strength of the five CTL epitopes at hand,
we wanted to investigate the simultaneous response to mixtures of these
epitopes. When all five peptides were coinjected dissolved in adjuvant,
the CTL response focused on the SV NP324 and VSV
NP52 determinants; both of these epitopes elicited vigorous
CTL responses (Fig. 2). The
immunodominance of these two epitopes in the complex CTL response
against the set of dominant epitopes was termed "superdominance."
The mRas59-specific response was weak but in the same range
as against the single mRas59 epitope (Fig. 2 and Fig. 1, respectively). Surprisingly, the OVA257 and MCF
env574 epitopes now generated only very weak CTL responses,
and we therefore termed these epitopes subdominant in the CTL response
to the complex mixture.
|
), i.e.,
the VSV NP52 and SV NP324 epitopes were
dominant and OVA257 and MCF env574 were
subdominant, while the mRas59 epitope was virtually
nonimmunogenic. Peptide administration on DC reverts superdominance
Since bone marrow-derived DC have proved powerful in the delivery
of MHC class I-restricted peptides for induction of immunity against
tumors, for example (12, 13), we tested this mode of Ag delivery in
relation to the superdominance among multiple dominant epitopes. B6
mice injected s.c. with DC pulsed with the five peptides responded
vigorously to the SV NP324, VSV NP52,
OVA257, and MCF env574 epitopes, while
mRas59 elicited only a very weak CTL response (Fig. 2).
Thus, the subdominance of OVA257 and MCF env574
observed when the peptide mixture was injected in IFA or loaded on
irradiated splenocytes was broken when peptides were presented in vivo,
loaded on live DC.
The presence of several epitopes potentiate the CTL response against each Ag when loaded on DC
As shown above, the CTL response against the complex mixture of
peptides dissolved in IFA focused on two epitopes, SV
NP324 and VSV NP52. In most experiments,
however, these dominant epitopes also elicited lower CTL activity in
the mixture than when they were injected as single epitopes (Fig. 3, upper panel). In
contrast, CTL responses against all peptides were boosted when the
mixture was injected loaded on DC compared with single peptides loaded
on DC (Fig. 3, lower panel). Thus, the DC route of Ag
challenge not only reverted the subdominance of the OVA257
and MCF env574 epitopes, but also enhanced CTL responses
against all components in the complex mixture.
|
Since MHC class I binding affinity has proved to strongly
influence peptide immunogenicity and determinant selection (21, 50, 51), we investigated whether the patterns of immunodominance observed
in the peptide mixture correlated with differences in peptide affinity
for class I. The stability of complexes between H-2Kb
and each of the five peptides was tested by stabilizing "empty"
cell surface Kb molecules on the TAP2-deficient cell line,
RMA-S. Peptides were added to cultures of RMA-S maintained at 26°C
overnight, followed by a 45-min chase at 37°C. The SV
NP324, OVA257, VSV NP52, and MCF
env574 epitopes all formed stable complexes with
H-2Kb at high peptide concentrations (Fig. 4). At lower concentrations, the
subdominant OVA257 was in fact more efficient at
stabilizing Kb, indicating a higher affinity. On the other
hand, mRas59 stabilized Kb poorly, indicating a
lower class I affinity. Taken together, these data indicate that the
superdominance of SV NP324 and VSV NP52 and
subdominance of OVA257 and MCF env574 in the
complex mixture is probably not directly related to MHC binding
affinity, while the low immunogenicity of mRas59 may depend
on weak MHC class I binding.
|
The results described above suggested that dominance in the CTL
response against the peptide mixture was not determined at the level of
processing or binding to the restriction element, but rather at the T
cell level. To address this possibility, we performed limiting dilution
analysis with splenocytes from mice primed in vivo with the single
peptides (Fig. 5). On days 9 through 12
after priming, the in vivo frequency of specific CTL differed markedly
between the epitopes. The dominant epitopes SV NP324
and VSV NP52 both elicited CTL at a frequency 
1/25,000
splenocytes, while the OVA257 and MCF env574
frequencies were 3.5-fold lower. Thus, the superdominance of the SV
NP324 and VSV NP52 epitopes in the peptide
mixture correlated with higher numbers of CTL at days 9 through 12 in
the single peptide-immunized mice.
|
T cell clones of different specificities may display different
avidities for their specific ligands as an imprint of the selection
process, which is likely to affect the specificities selected as
dominant during a peripheral immune response. CTL generated against the
single peptides were therefore tested against target cells loaded with
titrated amounts of the specific peptides. CTL specific for the SV
NP324, VSV NP52, OVA257, and
MCF env574 required similar doses of peptide (0.05 nM)
for half-maximal lysis (Fig. 6,
upper panel). Furthermore, these four CTL responses
required similar overall amounts of peptide (1 nM) during the 5-day
in vitro restimulation (Fig. 6, lower panel). T cells
specific for SV NP324 were activated at a somewhat lower
peptide concentration both at the target cell level and during in vitro
culture, suggesting a slightly elevated T cell avidity. However, there
was no clear-cut difference between the dominant VSV NP52
epitope and the subdominant OVA257 and MCF
env574 epitopes.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Since the peptide epitopes were injected or loaded on APC in a preprocessed form, epitope selection at the level of intracellular Ag processing can be excluded as the cause of the observed immunodominance. Competition for binding to the MHC is a major factor influencing epitope selection and dominance patterns in CTL responses against complex Ags (21, 50, 51), although it is clear that peptide immunohierarchy in T cell responses does not always correlate with binding affinity to the restriction element (52). In the present study, the subdominance of OVA257 and MCF env574 could not be attributed to lower affinity to the MHC, since they stabilized H-2Kb equally as well as the dominant SV NP324 and VSV NP52. A previous study indicated that SV NP324, OVA257, and VSV NP52 have similar affinities for Kb, which supports this conclusion (53). The dominance patterns can probably be explained, therefore, by mechanisms operating at the T cell level. Indeed, the subdominance of both MCF env574 and OVA257 correlated with lower CTL frequency on days 9 through 12 after immunization, and that of MCF env574 also correlated with slightly lower intrinsic immunogenicity. Peptide dose titrations both at the target cell level and upon restimulation in vitro suggest generally similar dosage requirements in dominant and subdominant responses, although a slightly higher T cell avidity for Ag was seen in the dominant SV NP324-specific response.
These results, together with the observation that delivery of Ags loaded on cultured DC could break dominance, are consistent with a model for immunodominance based on T cell competition for APC capacity. In this model, APC capacity is limiting in a competition between T cell clones. As a result of this competition, epitopes that are recognized by less frequent T cells may not be detected by a sufficient number of cells to elicit a response, even if these epitopes bind MHC molecules and are presented equally as well as Ags recognized by more frequent T cells. Inoculation of Ag loaded on 1 x 105 live DC could render APC capacity nonlimiting, since at a given time point after immunization, such mice would be likely to have a larger population presenting Ag in secondary lymphoid organs, compared with the natural recruitment of APC from the skin at the site of IFA injection. The differences in CTL frequencies were observed on days 9 through 12 after immunization and may reflect the number of T cell precursors before immunization, but we cannot exclude the fact that other factors influencing clonal expansion postimmunization contribute to the observed differences in CTL frequency as well as to the immunodominance patterns.
Cellular competition among CD8+ T cells has been discussed in relation to several steps of T cell differentiation (54, 55, 56, 57). Features of Ag presentation that could sharpen the competition and thus restrict diversity of T cell responses include numbers of APC, total APC surface available, and availability of cytokines. One good candidate cytokine that could regulate competition is IL-12. In fact, IL-12, recently shown to modulate immunodominance among HIV-1 epitopes (36), is produced by DC upon Ag-specific interaction with T cells (58) through ligation of cell surface CD40 (59). The latter observation can also explain our result that the presence of several epitopes on inoculated DC tend to potentiate responses against each Ag. Another candidate is TGF-ß, since it can have both T cell-stimulatory (60) and -inhibitory (61) effects depending on the state of cell activation (62). Experiments to investigate the importance of cytokines in immunodominance are currently underway in our laboratory. We have recently observed immunodominance in a system based on minor histocompatibility Ags, in which events occurring postdeterminant selection appear to play a major role (our manuscript in preparation).
Our results show that immunodominance is not an absolute feature. Novel hierarchies emerge in the response against multiple dominant epitopes that do not necessarily reflect determinant selection within the APC. CTL responses against complex Ags harboring multiple epitopes that are equally well presented by the same MHC class I molecule may be balanced by differences in T cell availability and limitations in APC capacity.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Johan Sandberg, Microbiology and Tumor Biology Center, Karolinska Institute, Box 280, S-171 77 Stockholm, Sweden. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cell; MCF, mink cell focus-inducing murine leukemia virus; mRas, mutant ras protein; SV, Sendai virus; VSV, vesicular stomatitis virus.
Received for publication June 18, 1997. Accepted for publication December 4, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production by T helper 1 cells. Eur. J. Immunol. 26:659.[Medline]
This article has been cited by other articles:
|
|
 |
|
  H. R. Fryer, A. Scherer, A. Oxenius, R. Phillips, and A. R. McLean No evidence for competition between cytotoxic T-lymphocyte responses in HIV-1 infection Proc R Soc B, December 22, 2009; 276(1677): 4389 - 4397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Huang, Y.-J. Wang, A. P. White, J.-Z. Meng, G.-R. Liu, S.-L. Liu, and Y.-D. Wang Salmonella expressing a T-cell epitope from Sendai virus are able to induce anti-infection immunity J. Med. Microbiol., September 1, 2009; 58(9): 1236 - 1242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Riedl, A. Wieland, K. Lamberth, S. Buus, F. Lemonnier, K. Reifenberg, J. Reimann, and R. Schirmbeck Elimination of Immunodominant Epitopes from Multispecific DNA-Based Vaccines Allows Induction of CD8 T Cells That Have a Striking Antiviral Potential J. Immunol., July 1, 2009; 183(1): 370 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Turnbull, M. Wong, S. Wang, X. Wei, N. A. Jones, K. E. Conrod, D. Aldam, J. Turner, P. Pellegrino, B. F. Keele, et al. Kinetics of Expansion of Epitope-Specific T Cell Responses during Primary HIV-1 Infection J. Immunol., June 1, 2009; 182(11): 7131 - 7145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Dzutsev, I. M. Belyakov, D. V. Isakov, D. H. Margulies, and J. A. Berzofsky Avidity of CD8 T cells sharpens immunodominance Int. Immunol., April 1, 2007; 19(4): 497 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. A. York, M. A. Brehm, S. Zendzian, C. F. Towne, and K. L. Rock Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance PNAS, June 13, 2006; 103(24): 9202 - 9207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Foulds and H. Shen Clonal Competition Inhibits the Proliferation and Differentiation of Adoptively Transferred TCR Transgenic CD4 T Cells in Response to Infection. J. Immunol., March 1, 2006; 176(5): 3037 - 3043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Newberg, K. J. McEvers, D. A. Gorgone, M. A. Lifton, S. H. C. Baumeister, R. S. Veazey, J. E. Schmitz, and N. L. Letvin Immunodomination in the Evolution of Dominant Epitope-Specific CD8+ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys J. Immunol., January 1, 2006; 176(1): 319 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hayakawa, V. Screpanti, H. Yagita, A. Grandien, H.-G. Ljunggren, M. J. Smyth, and B. J. Chambers NK Cell TRAIL Eliminates Immature Dendritic Cells In Vivo and Limits Dendritic Cell Vaccination Efficacy J. Immunol., January 1, 2004; 172(1): 123 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. S. Liu, Y. Xu, L. Hardy, V. Khammanivong, W. Zhao, G. J. P. Fernando, G. R. Leggatt, and I. H. Frazer IL-10 Mediates Suppression of the CD8 T Cell IFN-{gamma} Response to a Novel Viral Epitope in a Primed Host J. Immunol., November 1, 2003; 171(9): 4765 - 4772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Malkevitch, L. J. Patterson, K. Aldrich, E. Richardson, W. G. Alvord, and M. Robert-Guroff A Replication Competent Adenovirus 5 Host Range Mutant-Simian Immunodeficiency Virus (SIV) Recombinant Priming/Subunit Protein Boosting Vaccine Regimen Induces Broad, Persistent SIV-Specific Cellular Immunity to Dominant and Subdominant Epitopes in Mamu-A*01 Rhesus Macaques J. Immunol., April 15, 2003; 170(8): 4281 - 4289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Stober, I. Jomantaite, R. Schirmbeck, and J. Reimann NKT Cells Provide Help for Dendritic Cell-Dependent Priming of MHC Class I-Restricted CD8+ T Cells In Vivo J. Immunol., March 1, 2003; 170(5): 2540 - 2548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Chen, J. R. Bennink, P. A. Morton, and J. W. Yewdell Mice Deficient in Perforin, CD4+ T Cells, or CD28-Mediated Signaling Maintain the Typical Immunodominance Hierarchies of CD8+ T-Cell Responses to Influenza Virus J. Virol., September 11, 2002; 76(20): 10332 - 10337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schirmbeck, D. Stober, S. El Kholy, P. Riedl, and J. Reimann The Immunodominant, Ld-Restricted T Cell Response to Hepatitis B Surface Antigen (HBsAg) Efficiently Suppresses T Cell Priming to Multiple Dd-, Kd-, and Kb-Restricted HBsAg Epitopes J. Immunol., June 15, 2002; 168(12): 6253 - 6262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Palmowski, E. M.-L. Choi, I. F. Hermans, S. C. Gilbert, J.-L. Chen, U. Gileadi, M. Salio, A. Van Pel, S. Man, E. Bonin, et al. Competition Between CTL Narrows the Immune Response Induced by Prime-Boost Vaccination Protocols J. Immunol., May 1, 2002; 168(9): 4391 - 4398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rice, T. Elliott, S. Buchan, and F. K. Stevenson DNA Fusion Vaccine Designed to Induce Cytotoxic T Cell Responses Against Defined Peptide Motifs: Implications for Cancer Vaccines J. Immunol., August 1, 2001; 167(3): 1558 - 1565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Loirat, F. A. Lemonnier, and M.-L. Michel Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization J. Immunol., October 15, 2000; 165(8): 4748 - 4755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Rawson, I. F. Hermans, S. P. Huck, J. M. Roberts, H. Pircher, and F. Ronchese Immunotherapy with Dendritic Cells and Tumor Major Histocompatibility Complex Class I-derived Peptides Requires a High Density of Antigen on Tumor Cells Cancer Res., August 1, 2000; 60(16): 4493 - 4498. [Abstract] [Full Text]
|
|
|
|
|
|
J. K. Sandberg, L. Franksson, J. Sundback, J. Michaelsson, M. Petersson, A. Achour, R. P. A. Wallin, N. E. Sherman, T. Bergman, H. Jornvall, et al. T Cell Tolerance Based on Avidity Thresholds Rather Than Complete Deletion Allows Maintenance of Maximal Repertoire Diversity J. Immunol., July 1, 2000; 165(1): 25 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q.-J. Zhang, S. S. Chen, C.-A. Saari, M. G. Massuci, F. Tufaro, and W. A. Jefferies Evidence of Selective Processing of Immunodominant Epitopes in Virally Infected Cells J. Immunol., May 1, 2000; 164(9): 4513 - 4521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yang, D. Kittlesen, C. L. Slingluff Jr., C. E. Vervaert, H. F. Seigler, and T. L. Darrow Dendritic Cells Infected with a Vaccinia Vector Carrying the Human gp100 Gene Simultaneously Present Multiple Specificities and Elicit High-Affinity T Cells Reactive to Multiple Epitopes and Restricted by HLA-A2 and -A3 J. Immunol., April 15, 2000; 164(8): 4204 - 4211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Wilson, W. C. Olson, T. Tuting, C. R. Rinaldo, M. T. Lotze, and W. J. Storkus HIV-1-Specific CTL Responses Primed In Vitro by Blood-Derived Dendritic Cells and Th1-Biasing Cytokines J. Immunol., March 1, 1999; 162(5): 3070 - 3078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Z. Wolpert, P. Grufman, J. K. Sandberg, A. Tegnesjo, and K. Karre Immunodominance in the CTL Response Against Minor Histocompatibility Antigens: Interference Between Responding T Cells, Rather than with Presentation of Epitopes J. Immunol., November 1, 1998; 161(9): 4499 - 4505. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
