| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,§,§
*
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115;
Molecular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
Laboratory of Molecular Medicine, Department of Medicine, The Children’s Hospital, Howard Hughes Medical Institute, Boston, MA 02115;
§
Department of Molecular and Cellular Biology, Harvard University, Howard Hughes Medical Institute, Cambridge, MA 02138;
¶
Structural Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and
||
Instiut de Recherches Cliniques de Montréal, Laboratoire d’Immunologie, Montreal, Quebec, Canada
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
High resolution MHC/peptide/TCR structures have been determined for two human TCRs (A6 and B7) that are specific for an immunodominant HTLV-I Tax peptide bound to HLA-A2 (10, 11). A similar diagonal binding mode of the TCR has been observed for these two human complexes and a murine MHC/peptide/TCR complex (10, 11, 12). The diagonal binding mode buries most of the peptide in the MHC class I/TCR complex and allows the flat TCR surface to interact with the peptide by fitting down between the highest points of the MHC helixes. These crystal structures as well as mutagenesis experiments with murine MHC class I- and class II-restricted TCRs indicate that the diagonal binding mode may be general (13, 14).
The structures of A6 and B7 TCRs demonstrate how different TCRs
recognize the same MHC/peptide complex (10, 11). The surface
chemistries of the two TCRs are different, since only one of the 17
contact residues of the B7 TCR with the HLA-A2/Tax complex is identical
with the A6 TCR. Nevertheless, the same general binding mode is
observed, with a certain degree of rotation and tilt of the V domains.
The Vß domain of B7 is rotated about 10° counterclockwise relative
to the A6 TCR and is tipped closer to the MHC molecule. Smaller
differences are observed in the position of the V
domains.
In the A6 structure, the CDR1 and CDR3 loops of both V and Vß
contact the Tax11–19 peptide. The CDR1 loop of is
positioned over the peptide N-terminus, while the CDR1 loop of ß is
positioned over the C-terminal end of the peptide. A tyrosine at
position 5 of the Tax peptide is bound in a deep pocket at the center
of the TCR that is shaped by the CDR3 loops of both and ß. The
CDR2 loops of V and Vß are positioned over the helixes of the 2
and 1 domains of the MHC molecule, respectively.
In the A6 and B7 structures, substantial TCR contacts are only
made to residues Y5 and Y8 of the Tax peptide. Also, the total TCR
contact surface with the peptide is relatively small, approximately
one-third of the total TCR contact surface with the MHC/peptide complex
(
326 Å2 of 998 Å2). These observations
raise the following questions. 1) Which structural features contribute
to the specificity of these TCRs for the HLA-A2/Tax peptide complex? 2)
How different are these CTL clones in their fine specificity? 3) To
what extent can the peptide surface that is contacted by these TCRs be
modified?
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Single amino acid analogue peptides of Tax11–19 (LLFGYPVYV) were synthesized on pins on a 1-mg scale by Chiron Mimotopes (San Diego, CA). All other peptides were synthesized by Quality Controlled Biochemicals (Hopkinton, MA). These peptides were subjected to quality control by reverse phase HPLC and mass spectrometry. Peptides were dissolved in DMSO and diluted in medium, resulting in a final DMSO concentration of <1%.
Cytotoxicity assay
Human HLA-A2/Tax11–19-specific T cell clones 2G4 and B7 were previously described (15). Cytotoxicity was quantitated in a chromium release assay with HLA-A2-transfected Hmy2.C1R cells as targets at an E:T cell ratio of 10:1. Briefly, 106 target cells were labeled with 100 µCi of [51Cr]sodium chromate (New England Nuclear, Boston, MA) for 2 h, washed three times, and plated in RPMI/10% FCS at 5 x 103 cells/well in a 96-well U-bottom plate in triplicate. After addition of peptide, 5 x 104 T cells were added per well to a final volume of 200 µl. Following 4 h of incubation at 37°C, 100 µl of supernatant was taken, and radioactivity was quantitated in a gamma counter (Wallac, Gaithersburg, MD). The supernatant from 5 x 103 labeled target cells alone with or without the addition of 1% Triton X-100 (Sigma, St. Louis, MO) represented the total and spontaneous release, respectively. Specific lysis was determined as (experimental release - spontaneous release)/(total release - spontaneous release) x 100%.
Cytokine release assay
T cells were cultured in 96-well U-bottom plates at 5 x
104 cells/well in the presence of 5 x 104
HLA-A2 transfected Hmy2.C1R cells and peptides in triplicate in 200
µl of serum-free AIM-V medium (Life Technologies, Gaithersburg, MD).
After 48 h, 100 µl of supernatant was taken, and the
concentrations of cytokines were quantitated by ELISA using the
following pairs of cytokine-specific unconjugated/biotinylated Abs:
human IFN-
, TNF-, IL-2 (PharMingen, San Diego, CA), and
macrophage inflammatory protein-1 (R&D Systems, Minneapolis, MN);
the appropriate recombinant cytokines were used as standards. For
cytokine quantification, 96-well flat-bottom Fluoronunc plates (Nunc,
Roskilde, Denmark) were coated overnight at 4°C with the unconjugated
cytokine-specific Ab at 1 µg/ml in bicarbonate buffer (pH 9.6).
Following three washes with PBS/0.05% Tween-20, plates were blocked
with PBS/10% FCS (blocking buffer) for 2 h at room temperature.
The blocking buffer was removed, and samples and cytokine standards,
diluted 1/1 in blocking buffer, were added. Following an overnight
incubation at 4°C, plates were washed three times, and biotinylated
detection Ab was added at 0.5 µg/ml in blocking buffer. After a 2-h
incubation at room temperature, plates were washed three times, and
europium-labeled streptavidin (diluted 1/2000) was added. Following a
1-h incubation at room temperature, plates were washed five times, and
100 µl of Delfia enhancement solution was added to each well.
Fluorescence was quantitated after a 1-h incubation in a fluorometer
(DELFIA 1234, Wallac, Gaithersburg, MD).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The Tax11–19-specific CTL clones were previously generated from two patients with HTLV-I-associated myelopathy (15). A T cell clone (2G4) that had the same TCR sequence as clone A6 was used in this study. This clone was established from the same patient 3 yr after A6 had been isolated, indicating that this expanded clone had persisted in vivo.
The crystal structures demonstrate that the B7 TCR is different from
the A6/2G4 TCR at 16 of the 17 residues that contact the HLA-A2/Tax
peptide. Comparison of these two T cell clones therefore represents an
opportunity to investigate the structural basis of peptide specificity.
Titration of the Tax11–19 peptide in a CTL assay
demonstrates a similar dose-response curve for both clones (Fig. 1
). Clone 2G4 secretes greater quantities
of IFN-, macrophage inflammatory protein-1, and TNF- than
clone B7. The 51Cr release assay was therefore used to
compare the specificities of the two T cell clones; IFN- secretion
was examined for peptides that were of particular interest.
|
). Peptides for which marked differences
were observed between the two T cell clones were titrated using
peptides at concentrations of 0.1–100 nM (Fig. 3 and data not shown). This analysis
demonstrates differences in the specificity of the two T cell clones
for every peptide position examined, except G4. Glycine at position 4
could not be substituted (not even by alanine), and the crystal
structures demonstrate that there is no space for a larger residue in
either MHC/peptide/TCR complex. The panel of single amino acid analogue
peptides was also examined in an secretion assay (peptide
concentration of 200 nM). The motif based on the secretion assay is
very similar to that based on the 51Cr release assay (data
not shown).
|
|
A deep pocket that accommodates the P5 side chain (tyrosine) of
the peptide is a prominent feature of both TCR structures. Apart from
this pocket, the binding surface of both TCRs is relatively flat. The
P5 pocket differs markedly between the two TCRs in terms of both size
and surface properties. Previous analysis had demonstrated that alanine
substitution of Y5 abrogated T cell recognition by clone B7 but not by
clone A6. Analysis of a large panel of Y5 analogue peptides now
demonstrates that the B7 clone is exquisitely specific for aromatic
residues (Y, F) at this position (Figs. 2
and 3). Only the Y5F analogue
shows a dose response similar to that of the wild-type peptide. The Y5W
analogue shows an approximately 100-fold reduction in activity, and
none of the other Y5 analogues is active in the CTL assay (Fig. 3). In
contrast, clone 2G4 is more degenerate at this peptide position, since
10 of 17 analogue peptides show strong CTL activity at a peptide
concentration of 10 nM (Fig. 3).
The absolute requirement for an aromatic side chain by the B7 T cell
clone is explained by the structure of the P5 pocket in which the
aromatic ring of Y5 stacks against Y104ß (CDR3 loop of the TCR
ß-chain; Fig. 4A). The
A6/2G4 TCR has a larger P5 pocket than the B7 TCR, and there is no
interaction of Y5 with an aromatic TCR residue (Fig. 4B).
These data demonstrate that the TCR P5 pocket can be very specific or
quite degenerate depending on the sequences of the CDR3 loops that
determine its shape and surface properties.
|
The T cell clones differ in the fine specificity for all the other
peptide side chains (L1, V7, and Y8) that are directly contacted by TCR
residues in the crystal structures. At a functional level, clone 2G4
demonstrates a greater degree of specificity for peptide position 8,
while clone B7 is more specific for position 1 (Fig. 2).
In the A6/2G4 crystal structure, the hydroxyl group of Y8 makes a
hydrogen bond to TCR residue E30ß (CDR1 loop of the ß-chain). The
aromatic ring of Y8 is also contacted by L98ß (CDR3 loop) in the
A6/2G4 structure. The hydrogen bond between Y8 and E30ß is
important, since removal of the hydroxyl (Y to F substitution)
greatly reduces the activity of the peptide for clone 2G4. This is
evident both with the single amino acid analogue (Fig. 2) as well as
with peptides in which multiple TCR contact residues have been
substituted (Fig. 5). In such a
multisubstituted peptide, the Y to F substitution reduces the activity
>200-fold (TM10 vs TM11 peptide, respectively). In contrast, there is
no hydrogen bond between the hydroxyl of Y8 and the CDR1 loop of ß in
the B7 structure, and the aromatic ring of Y8 is only contacted by a
small TCR residue (G98ß, CDR3 loop). As a result, many different Y8
substitutions are tolerated by clone B7 (Fig. 2).
|
),
confirming that such a substitution is tolerated by clone 2G4. Since
there is not enough room for a lysine at position 7 in the crystal
structure, the two glycine residues that interact with this peptide
side chain (G100ß and G101ß) may allow for a certain degree of
flexibility of the TCR loop that interacts with this peptide residue.
|
) interacts
with the L1 side chain. The B7 clone shows a preference for aliphatic
side chains, phenylalanine and threonine at this position. In contrast,
the majority of analogues sensitize target cells for lysis by clone 2G4
(Fig. 2). Due to the interaction with M28, less space is available
in the B7 structure, which may account for the differences among the
two T cell clones for position 1 of Tax11–19. Peptide side chains that are not directly contacted by TCR residues contribute to specificity
For MHC class I-bound peptides, the conformation of the peptide
backbone and the position of side chains are strongly dependent on the
peptide sequence. Comparison of the structures of five peptide-HLA-A2
complexes demonstrated dramatic differences in the conformation of the
peptide backbone and the positions of side chains among these peptides
(20). Two Tax peptide residues, F3 and P6, which are not directly
contacted by TCR residues in the crystal structure, contribute to the
specificity of the CTL clones. F3 binds in a pocket (the D pocket)
nestled between the aromatic rings of Tyr99 and
Tyr159 of HLA-A2. Nevertheless, there are major differences
in the specificity of clones 2G4 and B7 for F3 analogue peptides. For
clone B7, there is a strong preference for aromatic residues (F, Y, W)
and histidine at this position. In contrast, clone 2G4 tolerates many
substitutions of F3. Several of these analogue peptides (for example, K
or Q at position 3) represent drastic changes, yet have an activity
similar to that of the wild-type peptide in the CTL assay (Fig. 2 and
data not shown).
The P6 side chain is also not directly contacted by TCR residues in the
crystal structures. All substitutions of the native proline greatly
reduce or abolish CTL activity by clone 2G4. In contrast, several
analogue peptides (A, V, I, T) show strong CTL activity with clone B7
(Fig. 2). Substitution of F3 and P6 may affect the conformation of the
peptide backbone as well as the positions of neighboring side chains,
such as Y5 and V7, which directly interact with TCR residues.
TCR recognition of peptides in which multiple TCR contact residues have been substituted
We next wished to determine whether these CTL clones could also recognize peptides in which the TCR contact surface has been substantially changed. In a previous study we identified microbial peptides that activate MHC class II-restricted T cell clones specific for myelin basic protein. In these peptides major TCR contact residues were conserved, while structurally related amino acids were allowed at MHC anchor positions (6). In the experiments involving the Tax peptide, TCR contact residues were changed, while the two HLA-A2 anchor residues (L2 and V9) were conserved. G4 was also conserved, since no other amino acid is tolerated at this position.
Based on the amino acid preferences of the two T cell clones, two
peptides were synthesized that activate only clone 2G4 (peptide TM10)
or clone B7 (TM28; Fig. 5). These peptides are selective for either
clone due to the amino acid at position 7 (K vs H in TM10 and TM28,
respectively). The single amino acid analogue V7K induces lysis only by
clone 2G4, while V7H induces lysis only by clone B7 (Fig. 2). The TM10
peptide differs from Tax11–19 at five positions (L1T, F3W,
Y5W, P6V, V7K), resulting in a TCR contact surface that is distinct
from the Tax peptide (L-FGYPVY- vs T-WGWVKY-). The TM28 peptide differs
from both TM10 and Tax11–19 at every peptide position,
except for G4 and the HLA-A2 anchor residues (L2 and V9).
Further substitutions were made in the TM10 peptide to determine the
degree of sequence identity with Tax11–19 required for TCR
recognition (Fig. 6). In the TM6 peptide, both HLA-A2 anchor residues
have been substituted (L2I, V9L), resulting in a peptide that has
two-amino acid identity with the Tax peptide (at G4 and Y8). Compared
with TM10, an approximately 10-fold higher peptide concentration is
required in the CTL assay to compensate for the suboptimal HLA-A2
anchor residues. Substitution of Y8 (to F, K, or W) greatly reduces the
activity of the TM10 peptide, again demonstrating the importance of the
hydrogen bond between Y8 and E30ß (CDR1 loop of ß). HLA-A2 has been
refolded with the TM10 peptide and was found to gel-shift with soluble
A6/2G4 TCR, confirming binding of this TCR to the HLA-A2/TM10 peptide
complex. Also, crystals have been obtained of the HLA-A2/TM10
peptide/A6 TCR complex (data not shown). These data indicate that amino
acid identity with Tax11–19 is required at a minimum of
two positions due to the importance of the Y8 side chain for
recognition by the 2G4 T cell clone and the lack of space in the
complex for a larger residue at position 4.
Natural peptide sequences that induce CTL activity
The recognition motif of 2G4 and B7 was used to search the GenPept
protein database for human and microbial peptides. Fifteen peptides
were synthesized and tested in CTL and IFN- secretion assays (Tables
I and II).
At a peptide concentration of 10 µM, eight of these peptides
sensitized target cells for lysis by clone 2G4; three of these peptides
also showed activity with clone B7. These peptides represent partial
agonists, since they induce CTL activity but little or no production of
IFN-.
Interestingly, two human peptides (TM9, TM23) that induce CTL activity by both clones are derived from the paraneoplastic encephalomyelitis Ags HuD and HuR (21, 22). Tax peptide-stimulated PBL bulk cultures from the two patients from whom 2G4 and B7 had been derived also lysed target cells pulsed with the HuD peptide (TM9, peptide concentration of 1–10 µM; data not shown). The requirement for a relatively high peptide concentration is probably due to the presence of glycine at position 2, which is a poor anchor residue for HLA-A2 binding. HuD is expressed predominantly in neuronal tissue (21, 23), and the sequence lies within a region that is immunodominant for autoantibodies from patients with paraneoplastic encephalomyelitis (24).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Both T cell clones use the same Vß-Jß segments (Vß12.3-Jß2.7)
but different V-J segments (V2.3-J24 for clone 2G4 and
V17.2-J54 for clone B7) (15). Since the TCR ß-chain appears to
be relatively conserved, it is surprising that 16 of the 17 residues of
the B7 TCR that interact with the MHC/peptide complex are not conserved
in the A6/2G4 TCR (11). This is due to the fact that the majority of
TCR ß-chain residues that contact the HLA-A2/peptide complex are
encoded by the N-D-N segment, which is distinct between the two TCRs
and located between the conserved Vß and Jß segments. The conserved
TCR Jß residues do not directly interact with the HLA-A2/peptide
surface. The interaction of the TCR Vß domains with the
HLA-A2/peptide complex is also distinct because the Vß domain of the
B7 TCR is tipped closer to the MHC molecule than is the Vß domain of
the A6 TCR. This allows contacts between the CDR2 loop of B7 and
HLA-A2 that are not present in the ternary complex of the A6 TCR.
The CDR1 loop of TCR ß-chain contacts the peptide only in the A6/2G4
structure (hydrogen bond between Y8 and E30ß). The hydrogen bond
between Y8 of the peptide and E30ß (CDR1 loop) on the lateral face of
the TCR is important for recognition by clone 2G4, since removal of the
Y8 hydroxyl group (Y to F substitution) results in a major loss of
activity. The fact that this interaction is not seen in the B7
structure explains why a large number of Y8 analogue peptides are
active at low peptide concentrations (Fig. 2).
Based on the recognition motif of the two
Tax11–19-specific T cell clones, peptides were synthesized
in which the TCR contact surface is distinct from
Tax11–19. Two peptides were synthesized that activate only
clone 2G4 (peptide TM10) or clone B7 (peptide TM28). The TM10 peptide
differs from the Tax peptide at five positions that contribute to the
specificity of TCR recognition. The TM28 peptide differs from the
sequence of both TM10 and Tax11–19 at six positions. These
results demonstrate that both TCRs can recognize peptide surfaces that
are distinct from Tax11–19. The T cell
recognition motif was also used to search for natural peptides that
activate these CTL clones. The peptides that were identified induce CTL
activity at a relatively high peptide concentration but little or no
IFN- production, indicating that they are partial agonists.
Additional human peptides that activate Tax peptide-specific T cells
remain to be identified, since only a relatively small fraction of the
human genes that are expressed in the central nervous system have been
sequenced.
A large number of studies have demonstrated that the same TCR can
cross-react with a number of distinct MHC/peptide complexes (1, 2, 3, 4, 5, 6, 7, 8, 9).
Peptides distinct in their sequence from the nominal Ag have been
identified for human T cell clones as well as murine T cell hybridomas
(5, 6, 7, 8). Also, transgenic mice that express a single MHC class II
molecule with a covalently linked peptide were found to have a diverse
repertoire, indicating that a single MHC/peptide complex is sufficient
for the maturation of these T cells (2). The structural basis of TCR
cross-reactivity with different MHC/peptide complexes has been examined
for the murine 2C TCR that has been cocrystallized with a low affinity
self-peptide (dEV8) bound to H-2Kb (12, 25, 26, 27). Comparison of the
structures of the bound and unbound TCR demonstrated large
conformational changes in three of the TCR CDR loops. Also, the
interface between peptide and TCR exhibited extremely poor shape
complementarity. Alanine scanning mutagenesis of this TCR indicated
that the most significant contribution for the binding energy was
provided by the CDR1 and CDR2 loops of TCR and -ß. These results
provide a structural basis for the ability of the 2C TCR to bind
distinct MHC/peptide complexes.
HTLV-I-associated myelopathy is characterized by spinal cord atrophy with perivascular demyelination and axonal degeneration. Patients with HTLV-I-associated myelopathy have very high levels of circulating CD8+ HTLV-I-specific CTL. The frequency of HTLV-I-specific T cells is >40-fold higher in patients than in asymptomatic carriers, and the majority of HLA-A2-restricted T cells are specific for the Tax protein (28, 29, 30). It is therefore possible that Tax peptide-specific T cells mediate the disease. These CTL could contribute to the disease process by lysis of infected cells in the central nervous system and/or by lysis of cells that present cross-reactive self-peptide(s). Since these T cell clones have already greatly expanded in vivo (15), relatively small quantities of a self-peptide or relatively low affinity peptides may be sufficient to induce CTL lysis of particular target cells. Triggering of Tax peptide-specific CTL by cross-reactive self-peptides may contribute to the pathogenesis of HTLV-I-associated myelopathy.
|
|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Kai W. Wucherpfennig, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. E-mail address:
Received for publication November 3, 1998. Accepted for publication February 8, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
ß T cell receptor structure at 2.5 Å and its orientation in the TCR-MHC complex. Science 274:209.ß T cell receptor: mapping the energy of antigen recognition. Immunity 8:413.[Medline]
This article has been cited by other articles:
|
|
 |
|
  Y. N. Naumov, E. N. Naumova, M. B. Yassai, K. Kota, R. M. Welsh, and L. K. Selin Multiple Glycines in TCR {alpha}-Chains Determine Clonally Diverse Nature of Human T Cell Memory to Influenza A Virus J. Immunol., November 15, 2008; 181(10): 7407 - 7419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Purbhoo, D. H. Sutton, J. E. Brewer, R. E. Mullings, M. E. Hill, T. M. Mahon, J. Karbach, E. Jager, B. J. Cameron, N. Lissin, et al. Quantifying and Imaging NY-ESO-1/LAGE-1-Derived Epitopes on Tumor Cells Using High Affinity T Cell Receptors. J. Immunol., June 15, 2006; 176(12): 7308 - 7316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Laugel, J. M. Boulter, N. Lissin, A. Vuidepot, Y. Li, E. Gostick, L. E. Crotty, D. C. Douek, J. Hemelaar, D. A. Price, et al. Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition J. Biol. Chem., January 21, 2005; 280(3): 1882 - 1892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Lee, G. Stewart-Jones, T. Dong, K. Harlos, K. Di Gleria, L. Dorrell, D. C. Douek, P. A. van der Merwe, E. Y. Jones, and A. J. McMichael T Cell Cross-Reactivity and Conformational Changes during TCR Engagement J. Exp. Med., December 6, 2004; 200(11): 1455 - 1466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Baxter, S. J. Gagnon, R. L. Davis-Harrison, J. C. Beck, A.-K. Binz, R. V. Turner, W. E. Biddison, and B. M. Baker Strategic Mutations in the Class I Major Histocompatibility Complex HLA-A2 Independently Affect Both Peptide Binding and T Cell Receptor Recognition J. Biol. Chem., July 9, 2004; 279(28): 29175 - 29184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. M. Bangham The immune control and cell-to-cell spread of human T-lymphotropic virus type 1 J. Gen. Virol., December 1, 2003; 84(12): 3177 - 3189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. E. Biddison, R. V. Turner, S. J. Gagnon, A. Lev, C. J. Cohen, and Y. Reiter Tax and M1 Peptide/HLA-A2-Specific Fabs and T Cell Receptors Recognize Nonidentical Structural Features on Peptide/HLA-A2 Complexes J. Immunol., September 15, 2003; 171(6): 3064 - 3074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tzagarakis-Foster, R. Geleziunas, A. Lomri, J. An, and D. C. Leitman Estradiol Represses Human T-cell Leukemia Virus Type 1 Tax Activation of Tumor Necrosis Factor-alpha Gene Transcription J. Biol. Chem., November 15, 2002; 277(47): 44772 - 44777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Castilleja, D. Carter, C. L. Efferson, N. E. Ward, K. Kawano, B. Fisk, A. P. Kudelka, D. M. Gershenson, J. L. Murray, C. A. O'Brian, et al. Induction of Tumor-Reactive CTL by C-Side Chain Variants of the CTL Epitope HER-2/neu Protooncogene (369-377) Selected by Molecular Modeling of the Peptide: HLA-A2 Complex J. Immunol., October 1, 2002; 169(7): 3545 - 3554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hernandez, F. Garcia-Pons, Y. C. Lone, H. Firat, J. D. Schmidt, P. Langlade-Demoyen, and M. Zanetti Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells PNAS, September 17, 2002; 99(19): 12275 - 12280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wang, R. Turner, B. M. Baker, and W. E. Biddison MHC Allele-Specific Molecular Features Determine Peptide/HLA-A2 Conformations That Are Recognized by HLA-A2-Restricted T Cell Receptors J. Immunol., September 15, 2002; 169(6): 3146 - 3154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Bourcier, D.-G. Lim, Y.-H. Ding, K. J. Smith, K. Wucherpfennig, and D. A. Hafler Conserved CDR3 Regions in T-Cell Receptor (TCR) CD8+ T Cells That Recognize the Tax11-19/HLA-A*0201 Complex in a Subject Infected with Human T-Cell Leukemia Virus Type 1: Relationship of T-Cell Fine Specificity and Major Histocompatibility Complex/Peptide/TCR Crystal Structure J. Virol., October 15, 2001; 75(20): 9836 - 9843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Karanikas, D. Colau, J.-F. Baurain, R. Chiari, J. Thonnard, I. Gutierrez-Roelens, C. Goffinet, E. V. Schaftingen, P. Weynants, T. Boon, et al. High Frequency of Cytolytic T Lymphocytes Directed against a Tumor-specific Mutated Antigen Detectable with HLA Tetramers in the Blood of a Lung Carcinoma Patient with Long Survival Cancer Res., May 1, 2001; 61(9): 3718 - 3724. [Abstract] [Full Text]
|
|
|
|
|
|
B. M. Baker, R. V. Turner, S. J. Gagnon, D. C. Wiley, and W. E. Biddison Identification of a Crucial Energetic Footprint on the {alpha}1 Helix of Human Histocompatibility Leukocyte Antigen (Hla)-A2 That Provides Functional Interactions for Recognition by Tax Peptide/Hla-A2-Specific T Cell Receptors J. Exp. Med., March 5, 2001; 193(5): 551 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kraj, R. Pacholczyk, and L. Ignatowicz {{alpha}}{{beta}}TCRs Differ in the Degree of Their Specificity for the Positively Selecting MHC/Peptide Ligand J. Immunol., February 15, 2001; 166(4): 2251 - 2259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Garcia-Peydro, A. Paradela, J. P. Albar, and J. A. L. d. Castro Antagonism of Direct Alloreactivity of an HLA-B27-Specific CTL Clone by Altered Peptide Ligands of Its Natural Epitope J. Immunol., November 15, 2000; 165(10): 5680 - 5685. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Trop, J. Charron, C. Arguin, and P. Hugo Thymic Selection Generates T Cells Expressing Self-Reactive TCRs in the Absence of CD45 J. Immunol., September 15, 2000; 165(6): 3073 - 3079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Wienhold, G. Malcherek, C. Jung, S. Stevanovic, G. Jung, H. Schild, and A. Melms An example of immunodominance: engagement of synonymous TCR by invariant CDR3{beta} Int. Immunol., June 1, 2000; 12(6): 747 - 756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.M. BAKER, Y.-H. DING, D.N. GARBOCZI, W.E. BIDDISON, and D.C. WILEY Structural, Biochemical, and Biophysical Studies of HLA-A2/Altered Peptide Ligands Binding to Viral-peptide-specific Human T-cell Receptors Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 235 - 242. [Abstract] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
