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*
Department of Microbiology and Immunology, Emory University; and
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
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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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Despite the widespread use of DO11.10 TCR transgenic mice, a detailed analysis of the T cell epitope has not been reported (13, 14). Grey and coworkers (15) characterized an N-terminal epitope of OVA323–339 recognized by many T cells and identified residues 327–333 as critical for peptide binding to I-Ad by comparing the affinity of OVA323–339 to a series of truncated peptides and single amino acid substitutions. These early findings are supported by the recently published crystal structure of OVA323–339 bound to I-Ad, which reveals the positioning of residues 324–332 within the binding groove of the MHC molecule (4). However, Shimonkevitz et al. (13) showed that DO11.10 T cells are much less sensitive to OVA323–336 compared with OVA323–339, despite the observation that these peptides have equal affinities for I-Ad (15). Similarly, it has recently been demonstrated that tetrameric complexes of OVA328–338 bound to I-Ad can be used to detect DO11.10 T cells, suggesting that DO11.10 recognizes a carboxy-terminal region of the peptide (16). Collectively, these studies indicate that multiple epitopes within OVA323–339 can be presented by I-Ad, a possibility supported by the lack of strong MHC anchor residues observed in the crystallized OVA323–339:I-Ad molecule (4, 14, 15, 16).
In this study the T cell epitopes recognized by the OVA323–339-specific DO11.10 (H-2d) and OT-II (H-2b) TCR transgenic mice were mapped using a series of OVA323–339 analogue peptides. Amino- and carboxy-terminal truncations were used to find the approximate ends of the T cell epitopes, and single amino acid substitutions were used to identify critical TCR contact residues. Our analysis demonstrates that DO11.10 and OT-II T cells recognize the same 9-aa core epitope (329–337) located in the C-terminal end of the OVA peptide; however, the importance of secondary TCR contact residues and peptide flanking residues differs between the cells. Because the epitope recognized by DO11.10 and OT-II was not the epitope seen in the OVA323–339:I-Ad crystal structure (4), additional OVA-specific clones were generated and analyzed. These clones were specific for other areas of the peptide, indicating that OVA323–339 contains multiple T cell epitopes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DO11.10 TCR transgenic mice (H-2d) were generated by Murphy et al. (14), and the DO11.10 recombination activating gene-deficient (RAG-/-)3 mice were a gift from Terrence Barret (17). OT-II TCR transgenic mice (H-2b), originally generated by Barnden et al. (18), were obtained from Dr. Judith A. Kapp (Emory University). BALB/CAnNCr (H-2d) and C57BL/6NCr (H-2b) mice were purchased from the National Cancer Institute (Frederick, MD). All mice were housed and maintained in the Emory University Department of Animal Resources facility.
Cells and reagents
Transgenic T cell lines were obtained by stimulating spleen cells from DO11.10 RAG-/- or OT-II mice with either 0.1 µM or 1 µM chicken OVA peptide 323–339 (ISQAVHAAHAEINEAGR), respectively. Other T cells were generated by s.c. priming BALB/c mice with 10 µg OVA protein (Sigma, St. Louis, MO) in CFA (Difco, Detroit, Michigan). Draining lymph nodes were removed after 9 days, and T cells were cloned by limiting dilution upon stimulation with 0.3 µM OVA323–339 peptide and gamma-irradiated syngeneic splenocytes (2000 rad). T cell lines and clones (2 x 105/well) were restimulated every 2 wk in a 24-well plate with appropriate peptide and 5 x 106 gamma-irradiated splenocytes (2000 rad) from either BALB/c or C57BL/6 mice along with 50 U of IL-2 obtained from the culture supernatants of IL-2-secreting P815 cells (19). Cell culture media consisted of RPMI 1640 supplemented with 2 mM L-glutamine, 0.01 M HEPES buffer, 100 µg/ml Gentamycin (Mediatech, Herndon, VA), 10% FBS (Atlanta Biologicals, Norcross, GA), and 2 x 10-5 M 2-ME (Sigma). All peptides were synthesized using florenyl methoxycarbonyl chemistry on a Symphony/Multiplex Peptide Synthesizer and were analyzed by HPLC (Rainin Instruments, Woburn, MA).
Proliferation assay
T cells (3 x 104/well) were incubated with the indicated peptide and 5 x 105 irradiated syngeneic spleen cells in duplicate in a 96-well plate. Proliferating cells were labeled after 48 h with 0.4 µCi/well of [3H]thymidine, and after another 18 h, the assays were harvested and analyzed on a Matrix 96 Direct Beta Counter (Packard, Meriden, CT). Data shown represent one of at least three similar experiments performed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DO11.10 (H-2d) and OT-II
(H-2b) CD4+ T cells were
originally generated by priming either a BALB/c or a C57BL/6 mouse,
respectively, with OVA protein (18, 20). Responses of
these T cells are OVA323–339-specific even
though the MHC backgrounds of the primed mice are different (13, 18). In fact, DO11.10 and OT-II T cells can respond to
OVA323–339 presented by
I-Ad and I-Ab (Refs.
20, 21 and our unpublished data). Despite the
widespread use of these T cell systems, the fine specificities of the
epitopes recognized by the cells are unknown. A panel of N- and
C-terminal truncations of the OVA peptide 323–339 was used to find the
approximate ends of the DO11.10 and OT-II T cell epitopes (Fig. 1
and summarized in Table I). The stepwise removal of amino acids
from the N-terminal end of the OVA peptide has little or no effect on
the DO11.10 response until amino acids 327 and 328 are deleted. These
truncations cause a substantial decrease in DO11.10 proliferation,
indicating that these amino acids are located on the N-terminal edge of
the DO11.10 T cell epitope. The response of OT-II is similarly affected
by the removal of amino acid 328. Truncations from the C-terminal side
of OVA323–339 reveal that amino acids 337 and
336 are important to DO11.10, whereas the removal of 338 and 339 have
minimal effect on T cell proliferation. OT-II is dependent on residues
337 and 338, indicating that these amino acids mark the C-terminal edge
of the OT-II epitope. Because T cells can differ in their dependency on
residues flanking the core 9 aa (9, 10), truncated
peptides cannot be used to determine the precise boundaries of the
epitopes, yet our data indicate that DO11.10 and OT-II T cells
recognize a C-terminal region of the OVA323–339
peptide (Fig. 1 and Table I).
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To further map the OVA epitope recognized by DO11.10 and OT-II,
the residues important to the T cell response were identified by
measuring proliferation of the cells to peptides with an alanine (or
serine if the original amino acid was an alanine) substituted at each
position of OVA323–339. Proliferation of DO11.10
to these "alanine scan" peptides on I-Ad
depended on the conservation of amino acids 331, 333, and 335 (Fig. 2A). The epitope recognized by
OT-II on I-Ab was similarly mapped and residues
331, 333, and 336 were identified as being important to T cell
recognition (Fig. 2B). These results confirmed the data
obtained using truncated peptides, locating the core epitope for
DO11.10 and OT-II in the C terminus of
OVA323–339.
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for T cell recognition were further analyzed using
analogue peptides substituted at these residues with each amino acid.
DO11.10 T cells were tolerant of only one very conservative
substitution at 333, whereas five were accepted at amino acid 331 (Fig. 3, A and B) and the
majority of substitutions were accepted at residue 335 (data not
shown). The response of OT-II was similar to that of DO11.10 with only
one conservative amino acid substitution allowed at amino acid 333,
whereas 
10 substitutions were tolerated at residue 331 (Fig. 3, C and D) and four were allowed at 336 (data not
shown). These results indicate that the primary TCR contact residue
(P5) for both DO11.10 and OT-II is amino acid 333 with the core 9-aa
epitope spanning peptide residues 329–337. The two T cells vary in
their recognition of important secondary TCR contact residues (residue
335 vs 336; Fig. 2) and peptide flanking residues (Fig. 1 and Table I),
which is expected because each uses a different TCR (18, 20). These results demonstrate that the OVA epitope 329–337
recognized by DO11.10 and OT-II T cells is presented by both
I-Ad and I-Ab MHC
molecules, which provides an explanation for why these cells are able
to respond to OVA presented by either MHC molecule.
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DO11.10 recognition of a C-terminal epitope within
OVA323–339 agrees with data published by the
labs of Kappler and Marrack and others studying DO11.10 T cells
(13, 14, 16). However, reports of an N-terminal epitope
suggest that OVA323–339 can be presented by
I-Ad in multiple binding registers (4, 15). To investigate OVA323–339
presentation by I-Ad, a panel of T cells specific
for OVA323–339 was generated by cloning T cells
from an OVA protein-primed BALB/c mouse (H-2d).
The epitope recognized by each T cell was identified using truncations
and substitutions of the wild-type OVA323–339
peptide (Figs. 4 and
5). The response of these clones is
vastly different from those of DO11.10 and OT-II, indicating that
OVA323–339 contains at least three different T
cell epitopes. Two clones reacted similarly, with no reduction in
proliferation in response to any of the C-terminal truncations.
However, their response was greatly reduced upon removal of just one or
two amino acids from the N-terminal side of the peptide (Fig. 4, A, B, D, and E). Amino acid
328 is crucial for these T cells, whereas other secondary T cell
contact residues vary between clones, establishing that the core 9-aa
epitope spans 324–332 (Fig. 5A). This is the binding
register found in the crystallized
OVA323–339:I-Ad complex
(4). Analysis of the data from another T cell clone, A1,
shows that this T cell recognizes a different epitope located in the
center of OVA323–339 (Figs. 4 and 5). The
truncations and single amino acid substitutions reveal that this
epitope spans from amino acid 327–335 with 331 as the primary
TCR contact residue. Other important secondary TCR contact residues for
this T cell clone are found at 328 and 333 (Figs. 4, C and
F, and 5B).
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All peptide:MHC class II crystal structures, including the
OVA324–332:I-Ad structure,
have shown MHC anchor residues located at positions 1, 4, 6, and 9 of
the core 9-aa epitope (4, 5, 6, 8). The identification of
residue 333 as the primary TCR contact residue for DO11.10 predicts
that amino acids 329A, 332A, 334I, and 337A (positions 1, 4, 6, and 9)
are the MHC anchor residues for the epitope recognized by DO11.10 (Fig. 6). MHC anchor residues are typically
identified using peptide binding assays, which analyze the role of each
amino acid residue in peptide affinity for the MHC (7, 15, 23, 24). However, we have shown that
OVA323–339 contains at least three distinct T
cell epitopes, each of which should correspond to a unique MHC binding
register (Fig. 6). Because of this, traditional peptide binding assays
cannot be used to identify MHC anchor residues. The effect of altering
a single MHC anchor residue for one epitope may have little or no
effect on overall peptide affinity for I-Ad
because binding in other registers may compensate for any loss of
binding of one epitope. Therefore, the influence of single amino acid
changes on peptide binding would be inconclusive.
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). Substituted peptides
were made in which amino acids 329A, 332A, 334I, and 337A (positions 1,
4, 6, and 9) were replaced with the corresponding anchor residues from
the high-affinity sperm whale myoglobin (SWM) peptide 106–118 (329E,
332I, 334V, 337S) and the lower-affinity MHC class II-associated
invariant chain peptide (CLIP) 85–99 (329 M, 332A, 334P, 337 M) (Fig. 7 and Refs. 24, 25). As
expected, proliferation of DO11.10 was unaffected by the anchor swap
peptide containing high-affinity anchor residues from SWM, yet the
weaker-affinity CLIP anchors decreased the dose-response curve 10- to
100-fold (Fig. 7). These data suggest that positions 1, 4, 6, and 9,
corresponding to amino acids 329, 332, 334, and 337, are the MHC anchor
residues for the epitope recognized by DO11.10.
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Our data suggest that at least three different epitopes are being
presented simultaneously during a T cell response to
OVA323–339 (Fig. 6). To manipulate the ratio of
ligands to favor presentation of one epitope over another, we designed
altered peptides with a large biotinylated anchor residue to hinder
binding in the small MHC binding pockets revealed by the
I-Ad crystal structure. For instance, a
biotinylated lysine residue substituted at amino acid 337 (position 9
of the C-terminal register and position +5 for the N-terminal register;
Fig. 6) decreases the proliferation of DO11.10 T cells by more than
10-fold (Fig. 8). In contrast,
stimulation of DO11.10 with OVA 324K-biotin, which affects the
N-terminal register (position 1) without changing the C-terminal
epitope (position -5), yields a 10-fold increase in T cell sensitivity
as well as a stronger peak proliferative response. These data
demonstrate that an alteration outside of the core 9-aa epitope and its
flanking residues can have significant affects on a T cell’s response
when multiple epitopes are presented.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). DO11.10 and OT-II T
cells recognize the same C-terminal epitope spanning amino acids
329–337. Residue 333 is the primary TCR contact for both cells;
however, the importance of secondary TCR contact residues and peptide
flanking residues varies between the cells. T cells specific for the
N-terminal epitope seen in the
OVA323–339:I-Ad crystal
structure as well as for an epitope located in the center of the
peptide were also found.
Earlier analysis of two well-documented
OVA323–339-specific T cell hybridomas by Sette
et al. (15) also used truncations and single amino acid
substitutions to map the requirements for peptide interaction with
I-Ad. These analyses can be reexamined to
determine the epitope specificities of the studied T cell hybridomas.
The 8DO-51.15 T cell hybridoma was dependent on the first five
N-terminal amino acids and had important TCR contact residues at amino
acids 325, 328, and 331, indicating that this T cell recognized the
N-terminal OVA323–339 epitope seen in the
crystal structure and recognized by our clones A6 and A7 (Fig. 6). The
3DO54.8 T cell hybridoma did not require the first several N-terminal
amino acids and had critical TCR contact residues at amino acids 328,
329, 331, and 333, consistent with recognition of the central
OVA323–339 epitope also seen by our clone A1
(Fig. 6).
Unlike CD8+ T cell epitopes, all
CD4+ epitopes examined thus far have conformed to
the same general structure, with major MHC anchor residues at positions
1, 4, 6, and 9, a primary TCR contact residue at position 5, and
secondary TCR contact residues at 2, 3, 7, and/or 8
(4, 5, 6, 7, 8). In some cases, position 7 has been shown to
interact with the MHC molecule (6, 8). Crystallized
peptide:MHC class II complexes have revealed that this core 9-aa
epitope is always located within the MHC binding groove (4, 5, 6, 8). The finding of three overlapping epitopes within
OVA323–339 indicates that there are also
multiple binding registers. Early binding studies by Grey and coworkers
(15) identified residue 332 as one of the most important
I-Ad binding residues, a finding which supports
our argument of multiple binding registers because this amino acid is
an MHC anchor residue for all three epitopes described here (Fig. 6).
The crystal structures of OVA323–339 and
hemagglutinin (HA)126–138 bound to
I-Ad published by Wilson and coworkers
(4) reveals several unique characteristics that define
peptide binding to I-Ad. For instance, peptide
binding to I-Ad does not require the insertion of
large polar or charged peptide anchor residues into MHC pockets. The
anchor residues for HA126–138 and
OVA323–339 are mostly small- to medium-sized
nonpolar amino acids like alanine and valine. Additionally, the
majority of hydrogen bonds between I-Ad and a
bound peptide are to the peptide backbone, allowing binding to be
virtually sequence-independent. These characteristics led the authors
to predict that OVA may be able to bind to I-Ad
in multiple registers that all have a similar pattern of small anchor
residues (4). We have shown that one of the two
alternative registers suggested by Wilson and coworkers
(4) is recognized by DO11.10 and OT-II T cells (
Figs. 1–3
and 7). We did not identify any T cells specific for the second
predicted register centered at amino acid 330, although the examination
of additional clones may lead to their discovery. The existence of the
central epitope recognized by the A1 clone was not predicted, most
likely due to the asparagine located at position 9, which does not
conform to the observed preference for alanine at this position.
However, according to our data (Fig. 7), DO11.10 T cells are able to
respond to OVA peptides with vastly different MHC anchor residues,
suggesting that the I-Ad binding motif is not
simply restricted to small, nonpolar amino acids. In fact, the SWM
peptide 106–118, which has a very high affinity for
I-Ad (Fig. 7), has a large negatively charged
residue (glutamic acid) at position 1 (24).
Other molecules in the murine I-A and human HLA-DQ families are structurally similar to I-Ad, and therefore, the characteristics of the MHC binding pockets and peptide-MHC interactions should be comparable (4). The relative absence of dominant MHC anchors may allow for the presentation of a single peptide on multiple MHC molecules. For instance, OVA323–339 is known to bind I-Ab, I-Au, and I-As as well as MHC molecules from other species (20, 21, 25, 26, 27). The bovine RNase peptide 90–105 has also been shown to be presented by multiple MHC class II alleles (28). We expect that further analysis of other I-A binding peptides will demonstrate similar promiscuity of MHC binding, and other nested sets of epitopes as described for OVA323–339. The close proximity of these three T cell epitopes may explain the prevalence of T cells generated in an OVA protein-primed mouse, which are specific for OVA323–339 (13). A single epitope within this peptide may not be a better ligand than an epitope found elsewhere in the protein, but the concentration of epitopes within this sequence makes OVA323–339 a "hotspot" of T cell reactivity (13). Peptides with a nested set of epitopes like OVA323–339 have advantages over single-epitope peptides because the potential pool of responding T cells is multiplied for each epitope.
Altering the effective concentration of a ligand when using a nested
set of epitopes as observed with OVA323–339
could be an effective mechanism for controlling the immune response.
Several groups have demonstrated that the phenotype of a Th cell can be
influenced by Ag dose (29, 30). We were able to change the
effective dose of the C-terminal OVA epitope by two methods. First, the
affinity of this OVA epitope was modulated by swapping its MHC anchor
residues with those from other peptides with a desired affinity for MHC
such as SWM or CLIP (Fig. 7). DO11.10 proliferation to OVA-CLIP was
decreased by 10- to 100-fold (Fig. 7). In the second method, a single
anchor residue of the N-terminal register was altered, decreasing the
affinity of this epitope and consequently increasing presentation of
the C-terminal epitope as measured by the response of DO11.10 T cells
(Fig. 8). Both of these techniques affect T cell proliferation in a
manner consistent with the expected availability of the
OVA329–337:I-Ad ligand and
could be used to favor the presentation of any given epitope over
another.
One of the goals of research using altered peptide ligands is to develop in vivo therapies designed to control T cell populations in disorders such as autoimmunity or graft rejection (22). The presentation of multiple epitopes from peptides such as OVA323–339 may make it difficult to manipulate the bulk T cell response in this manner because the TCR contact residues will vary depending on the epitope recognized. However, it is interesting that amino acid 331 is an important TCR contact residue for each of the analyzed T cell clones despite their recognition of different epitopes. Amino acid substitutions of the OVA323–339 peptide at this residue may yield partial agonist and antagonist peptides able to control the responses of all OVA323–339-reactive T cells (22). In contrast, substitutions at amino acid 335 or 336 would be expected to only affect T cells such as DO11.10 and OT-II, which recognize the C-terminal epitope.
Note added in proof:
Since the submission of this manuscript, McFarland et al. (31) have biochemically confirmed the existence of the central I-Ad binding register recognized by clone A1 and the DO54.8 hybridoma.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Brian D. Evavold, Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, GA 30322.
3 Abbreviations used in this paper: RAG, recombination activating gene; CLIP, class II-associated invariant chain peptide; SWM, sperm whale myoglobin; HA, hemagglutinin.
Received for publication June 15, 1999. Accepted for publication February 16, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and ß-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76:34.[Medline]
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 J. A. Tobar, L. J. Carreno, S. M. Bueno, P. A. Gonzalez, J. E. Mora, S. A. Quezada, and A. M. Kalergis Virulent Salmonella enterica Serovar Typhimurium Evades Adaptive Immunity by Preventing Dendritic Cells from Activating T Cells. Infect. Immun., November 1, 2006; 74(11): 6438 - 6448. [Abstract] [Full Text] [PDF]
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K. C. McKenna and J. A. Kapp Accumulation of Immunosuppressive CD11b+ Myeloid Cells Correlates with the Failure to Prevent Tumor Growth in the Anterior Chamber of the Eye J. Immunol., August 1, 2006; 177(3): 1599 - 1608. [Abstract] [Full Text] [PDF]
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P. G. Thomas, S. A. Brown, W. Yue, J. So, R. J. Webby, and P. C. Doherty An unexpected antibody response to an engineered influenza virus modifies CD8+ T cell responses PNAS, February 21, 2006; 103(8): 2764 - 2769. [Abstract] [Full Text] [PDF]
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J. Arends, J. Wu, J. Borillo, L. Troung, C. Zhou, N. Vigneswaran, and Y.-H. Lou T Cell Epitope Mimicry in Antiglomerular Basement Membrane Disease J. Immunol., January 15, 2006; 176(2): 1252 - 1258. [Abstract] [Full Text] [PDF]
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 D. A. Hokey, A. T. Larregina, G. Erdos, S. C. Watkins, and L. D. Falo Jr. Tumor Cell Loaded Type-1 Polarized Dendritic Cells Induce Th1-Mediated Tumor Immunity Cancer Res., November 1, 2005; 65(21): 10059 - 10067. [Abstract] [Full Text] [PDF]
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S.-D. Chou, A. N. H. Khan, W. J. Magner, and T. B. Tomasi Histone acetylation regulates the cell type specific CIITA promoters, MHC class II expression and antigen presentation in tumor cells Int. Immunol., November 1, 2005; 17(11): 1483 - 1494. [Abstract] [Full Text] [PDF]
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 A. L. Mora, J. LaVoy, M. McKean, A. Stecenko, K. L. Brigham, R. Parker, and M. Rojas Prevention of NF-{kappa}B activation in vivo by a cell-permeable NF-{kappa}B inhibitor peptide Am J Physiol Lung Cell Mol Physiol, October 1, 2005; 289(4): L536 - L544. [Abstract] [Full Text] [PDF]
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J. Sun, B. Tumurbaatar, J. Jia, H. Diao, F. Bodola, S. M. Lemon, W. Tang, D. G. Bowen, G. W. McCaughan, P. Bertolino, et al. Parenchymal Expression of CD86/B7.2 Contributes to Hepatitis C Virus-Related Liver Injury J. Virol., August 15, 2005; 79(16): 10730 - 10739. [Abstract] [Full Text] [PDF]
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N. Nath, S. Giri, R. Prasad, M. L. Salem, A. K. Singh, and I. Singh 5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2005; 175(1): 566 - 574. [Abstract] [Full Text] [PDF]
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B. A. Rabinovich, J. Li, R. Hurren, and R. G. Miller Immunosynapse formation coincides with rapid activation of NK cells by syngeneic T cells and correlates with clustering of MHC class I Int. Immunol., June 1, 2005; 17(6): 671 - 676. [Abstract] [Full Text] [PDF]
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R. Maehr, H. C. Hang, J. D. Mintern, Y.-M. Kim, A. Cuvillier, M. Nishimura, K. Yamada, K. Shirahama-Noda, I. Hara-Nishimura, and H. L. Ploegh Asparagine Endopeptidase Is Not Essential for Class II MHC Antigen Presentation but Is Required for Processing of Cathepsin L in Mice J. Immunol., June 1, 2005; 174(11): 7066 - 7074. [Abstract] [Full Text] [PDF]
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D. Palliser, E. Guillen, M. Ju, and H. N. Eisen Multiple Intracellular Routes in the Cross-Presentation of a Soluble Protein by Murine Dendritic Cells J. Immunol., February 15, 2005; 174(4): 1879 - 1887. [Abstract] [Full Text] [PDF]
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T. Ghansah, K. H. T. Paraiso, S. Highfill, C. Desponts, S. May, J. K. McIntosh, J.-W. Wang, J. Ninos, J. Brayer, F. Cheng, et al. Expansion of Myeloid Suppressor Cells in SHIP-Deficient Mice Represses Allogeneic T Cell Responses J. Immunol., December 15, 2004; 173(12): 7324 - 7330. [Abstract] [Full Text] [PDF]
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M. Gunzer, C. Weishaupt, A. Hillmer, Y. Basoglu, P. Friedl, K. E. Dittmar, W. Kolanus, G. Varga, and S. Grabbe A spectrum of biophysical interaction modes between T cells and different antigen-presenting cells during priming in 3-D collagen and in vivo Blood, November 1, 2004; 104(9): 2801 - 2809. [Abstract] [Full Text] [PDF]
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W. S. Park, Y. Bae, D. H. Chung, Y.-L. Choi, B. K. Kim, Y. C. Sung, E. Y. Choi, S. H. Park, and K. C. Jung T cell expression of CIITA represses Th1 immunity Int. Immunol., October 1, 2004; 16(10): 1355 - 1364. [Abstract] [Full Text] [PDF]
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A. L. Mellor, P. Chandler, B. Baban, A. M. Hansen, B. Marshall, J. Pihkala, H. Waldmann, S. Cobbold, E. Adams, and D. H. Munn Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase Int. Immunol., October 1, 2004; 16(10): 1391 - 1401. [Abstract] [Full Text] [PDF]
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N. Parameswaran, D. J. Samuvel, R. Kumar, S. Thatai, V. Bal, S. Rath, and A. George Oral Tolerance in T Cells Is Accompanied by Induction of Effector Function in Lymphoid Organs after Systemic Immunization Infect. Immun., July 1, 2004; 72(7): 3803 - 3811. [Abstract] [Full Text] [PDF]
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R. L. Sparks-Thissen, D. C. Braaten, S. Kreher, S. H. Speck, and H. W. Virgin IV An Optimized CD4 T-Cell Response Can Control Productive and Latent Gammaherpesvirus Infection J. Virol., July 1, 2004; 78(13): 6827 - 6835. [Abstract] [Full Text] [PDF]
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T. F. Rowley and A. Al-Shamkhani Stimulation by Soluble CD70 Promotes Strong Primary and Secondary CD8+ Cytotoxic T Cell Responses In Vivo J. Immunol., May 15, 2004; 172(10): 6039 - 6046. [Abstract] [Full Text] [PDF]
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D. M. Richards, S. L. Dalheimer, B. D. Ehst, T. L. Vanasek, M. K. Jenkins, M. I. Hertz, and D. L. Mueller Indirect Minor Histocompatibility Antigen Presentation by Allograft Recipient Cells in the Draining Lymph Node Leads to the Activation and Clonal Expansion of CD4+ T Cells That Cause Obliterative Airways Disease J. Immunol., March 15, 2004; 172(6): 3469 - 3479. [Abstract] [Full Text] [PDF]
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N. Bertho, J. Cerny, Y.-M. Kim, E. Fiebiger, H. Ploegh, and M. Boes Requirements for T Cell-Polarized Tubulation of Class II+ Compartments in Dendritic Cells J. Immunol., December 1, 2003; 171(11): 5689 - 5696. [Abstract] [Full Text] [PDF]
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E. Sawicka, C. Zuany-Amorim, C. Manlius, A. Trifilieff, V. Brinkmann, D. M. Kemeny, and C. Walker Inhibition of Th1- and Th2-Mediated Airway Inflammation by the Sphingosine 1-Phosphate Receptor Agonist FTY720 J. Immunol., December 1, 2003; 171(11): 6206 - 6214. [Abstract] [Full Text] [PDF]
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K. Teramoto, K. Kontani, Y. Ozaki, S. Sawai, N. Tezuka, T. Nagata, S. Fujino, Y. Itoh, O. Taguchi, Y. Koide, et al. Deoxyribonucleic Acid (DNA) Encoding a Pan-Major Histocompatibility Complex Class II Peptide Analogue Augmented Antigen-specific Cellular Immunity and Suppressive Effects on Tumor Growth Elicited by DNA Vaccine Immunotherapy Cancer Res., November 15, 2003; 63(22): 7920 - 7925. [Abstract] [Full Text] [PDF]
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Z. Guo, E. Kavanagh, Y. Zang, S. M. Dolan, S. J. Kriynovich, J. A. Mannick, and J. A. Lederer Burn Injury Promotes Antigen-Driven Th2-Type Responses In Vivo J. Immunol., October 15, 2003; 171(8): 3983 - 3990. [Abstract] [Full Text] [PDF]
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A. E. Oran and H. L. Robinson DNA Vaccines, Combining Form of Antigen and Method of Delivery to Raise a Spectrum of IFN-{gamma} and IL-4-Producing CD4+ and CD8+ T Cells J. Immunol., August 15, 2003; 171(4): 1999 - 2005. [Abstract] [Full Text] [PDF]
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M. L. Ford and B. D. Evavold Regulation of Polyclonal T Cell Responses by an MHC Anchor-Substituted Variant of Myelin Oligodendrocyte Glycoprotein 35-55 J. Immunol., August 1, 2003; 171(3): 1247 - 1254. [Abstract] [Full Text] [PDF]
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A. L.-D. de Cerio, J. J. Lasarte, N. Casares, P. Sarobe, M. Ruiz, J. Prieto, and F. Borras-Cuesta Engineering Th determinants for efficient priming of humoral and cytotoxic T cell responses Int. Immunol., June 1, 2003; 15(6): 691 - 699. [Abstract] [Full Text] [PDF]
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B. A. Rabinovich, J. Li, J. Shannon, R. Hurren, J. Chalupny, D. Cosman, and R. G. Miller Activated, But Not Resting, T Cells Can Be Recognized and Killed by Syngeneic NK Cells J. Immunol., April 1, 2003; 170(7): 3572 - 3576. [Abstract] [Full Text] [PDF]
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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]
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Y. Zhan, J. F. Purton, D. I. Godfrey, T. J. Cole, W. R. Heath, and A. M. Lew Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation PNAS, February 4, 2003; 100(3): 1197 - 1202. [Abstract] [Full Text] [PDF]
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V. I. Mallet-Designe, T. Stratmann, D. Homann, F. Carbone, M. B. A. Oldstone, and L. Teyton Detection of Low-Avidity CD4+ T Cells Using Recombinant Artificial APC: Following the Antiovalbumin Immune Response J. Immunol., January 1, 2003; 170(1): 123 - 131. [Abstract] [Full Text] [PDF]
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F. G. Gao, V. Khammanivong, W. J. Liu, G. R. Leggatt, I. H. Frazer, and G. J. P. Fernando Antigen-specific CD4+ T-Cell Help Is Required to Activate a Memory CD8+ T Cell to a Fully Functional Tumor Killer Cell Cancer Res., November 15, 2002; 62(22): 6438 - 6441. [Abstract] [Full Text] [PDF]
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A. M. Kalergis and J. V. Ravetch Inducing Tumor Immunity through the Selective Engagement of Activating Fc{gamma} Receptors on Dendritic Cells J. Exp. Med., June 17, 2002; 195(12): 1653 - 1659. [Abstract] [Full Text] [PDF]
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B. V. Stern, B. O. Boehm, and M. Tary-Lehmann Vaccination with Tumor Peptide in CpG Adjuvant Protects Via IFN-{gamma}-Dependent CD4 Cell Immunity J. Immunol., June 15, 2002; 168(12): 6099 - 6105. [Abstract] [Full Text] [PDF]
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T. Nakayama, D. J. Kasprowicz, M. Yamashita, L. A. Schubert, G. Gillard, M. Kimura, A. Didierlaurent, H. Koseki, and S. F. Ziegler The Generation of Mature, Single-Positive Thymocytes In Vivo Is Dysregulated by CD69 Blockade or Overexpression J. Immunol., January 1, 2002; 168(1): 87 - 94. [Abstract] [Full Text] [PDF]
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T. M. C. Hornell, S. M. Martin, N. B. Myers, and J. M. Connolly Peptide Length Variants p2Ca and QL9 Present Distinct Conformations to Ld-Specific T Cells J. Immunol., October 15, 2001; 167(8): 4207 - 4214. [Abstract] [Full Text] [PDF]
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I. Takahashi, H. Kosaka, K. Oritani, W. R. Heath, J. Ishikawa, Y. Okajima, M. Ogawa, S.-i. Kawamoto, M. Yamada, H. Azukizawa, et al. A New IFN-Like Cytokine, Limitin Modulates the Immune Response Without Influencing Thymocyte Development J. Immunol., September 15, 2001; 167(6): 3156 - 3163. [Abstract] [Full Text] [PDF]
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F.-D. Shi, M. Flodstrom, S. H. Kim, S. Pakala, M. Cleary, H.-G. Ljunggren, and N. Sarvetnick Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase J. Immunol., September 1, 2001; 167(5): 3000 - 3006. [Abstract] [Full Text] [PDF]
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D. Bumann In Vivo Visualization of Bacterial Colonization, Antigen Expression, and Specific T-Cell Induction following Oral Administration of Live Recombinant Salmonella enterica Serovar Typhimurium Infect. Immun., July 1, 2001; 69(7): 4618 - 4626. [Abstract] [Full Text] [PDF]
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S. P. Deshpande, S. Lee, M. Zheng, B. Song, D. Knipe, J. A. Kapp, and B. T. Rouse Herpes Simplex Virus-Induced Keratitis: Evaluation of the Role of Molecular Mimicry in Lesion Pathogenesis J. Virol., April 1, 2001; 75(7): 3077 - 3088. [Abstract] [Full Text]
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