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Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
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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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In contrast to APCs, modulation of naive CD4 response by altering the nature of the peptide Ag has received little attention. Many studies have established that single amino acid substitutions, largely at TCR contact residues, can alter responses of long-term T cell clones (16, 17, 18). A range of activities has been described from studies of clones, such as antagonism and anergy induction due to differential signal transduction, and cytokine production in the absence of proliferation (19, 20, 21, 22, 23, 24, 25, 26). It is not clear, however, whether the parameters of activation and responses observed in these studies equally apply to the naive cell. In addition, the majority of studies on peptide ligands to date have not taken into account the characteristics of the APC and the contribution of costimulatory accessory molecules to the overall response.
In the present study, we have used naive CD4 T cells specific for
pigeon cytochrome c
(PCC)3 and moth cytochrome
c (MCC), obtained from Vß3/V
11 TCR transgenic mice, to
analyze aspects of a response that result when peptides possessing
various amino acid substitutions are presented on both weakly and
highly costimulatory APC. Several analogues of cytochrome c
were selected based on similar binding to class II MHC but that had
differential stimulatory capacities, suggesting that they represent
peptides that have both lower and higher affinity for the TCR than the
native peptides. Our results show that the nature of the peptide can
dramatically alter the ability of an APC to initiate early events of
naive CD4 activation, such as induction of the surface Ags CD69 and
IL-2R, and can result in differential IL-2 secretion that dictates the
extent of the proliferative phase of naive responses. In particular,
weakly agonistic peptides can reduce the stimulatory capacity of an APC
expressing accessory molecules to that of an APC lacking accessory
molecules. Highly agonistic peptides can partially compensate for the
lack of such molecules on an APC. These studies demonstrate that the
nature of the APC and the nature of the peptide ligand are both
important mediators of naive T cell activation, and optimization of
both is critical for determining the extent of the primary T cell
response through support of long-lasting IL-2 production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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AND TCR transgenic mice expressing the Vß3/V11 TCR were
bred on a B10.BR background (H2k) as previously
described (5, 10).
Altered peptide ligands (APLs)
Peptides of MCC or PCC were synthesized in the peptide facility
at La Jolla Institute for Allergy and Immunology. Each peptide was
selected based on similar binding to purified IEk as
shown in Table I
, with single amino acid
substitutions as indicated. Binding assays were as previously described
(27) using a competition assay with radioiodinated PCC. Values
represent concentrations of unlabeled peptides required to inhibit 50%
of the binding of the iodinated peptide.
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CD4+ T cells were purified from spleen and
lymph nodes of TCR transgenic mice as before (5, 10) by nylon wool
depletion, followed by complement treatment with Abs to CD8 (3.155),
heat-stable Ag (J11D), class II MHC (M5/114 and CA-4.A12), macrophages
(M1/70), and dendritic cells (33D1), cross-linked with mouse
anti-rat 
(MAR 18.5). Any residual APC and any in vivo-activated
T cells were removed by isolating high density cells spun through a
Percoll gradient (45, 53, 62, and 80%). The resultant cells were
resting (low forward scatter, CD69-, CD95-,
CD71-, CD40L-, CD25-) and >95%
CD4+. More than 95% of these cells possessed a phenotype
associated with naive CD4 cells (CD45RB+,
CD62L+, CD44low) along with expression of the
Vß3/V11 TCR (5, 10). In most experiments, T cells were further
purified by positive selection with anti-CD62L (Mel 14) using
magnetic beads (Miltenyi Biotech, Sunnyvale, CA) as in previous
studies (5).
Ag-presenting cells
Fibroblast cells transfected with IEk (originally generated by Dr. R. Germain, National Institutes of Health, Bethesda, MD) were used as APC. Two fibroblast lines were used as before (9, 10) that expressed, or lacked, B7-1 and ICAM-1 (DCEK.ICAM, referred to as ICAM+B7+; DCEK-/-, referred to as ICAM-B7-). These cells do not express vascular cell adhesion molecule-1, very late Ag-4, B7-2, Ox-40L, 4-1BBL, LFA-1, heat-stable Ag, or CD48 by FACS analysis. APC populations were treated with mitomycin c (75–100 µg/ml; Sigma, St. Louis, MO) for 30 min at 37°C before use.
Cell cultures
Cells were cultured in RPMI 1640 (Irvine Scientific, Santa Ana, CA) with penicillin, streptomycin, glutamine, 2-ME, sodium pyruvate, and 7% FCS (HyClone, Logan, UT, and Irvine Scientific). Cultures were generally set up in 0.2-ml vol in 96-well plates (Costar, Cambridge, MA) in triplicate. Naive CD4 cells were plated at a concentration of 2.5 x 105/ml with half as many APC. APLs of MCC or PCC were added into culture at varying concentrations, or APC were prepulsed with the indicated concentrations at 2 x 106/ml for 2 h at 37°C.
Fluorescence analysis
CD25 expression was assessed using FITC-labeled anti-CD25 (rat IgM; PharMingen, San Diego, CA) and CD69 with FITC-labeled anti-CD69 (hamster IgG; PharMingen). Controls were FITC-labeled purified rat IgM or hamster IgG (Caltag, Burlingame, CA). CD4+ T cells were identified using phycoerythrin-conjugated anti-CD4 (PharMingen). FACS analyses were performed on a FACScan flow cytometer (Becton Dickinson, Mountain View, CA) with Cellquest software. Data were gated for viable CD4+ T cells and are plotted as the number of cells positive for each marker at 22 h.
Proliferation
Cell division was assessed by addition of 1 µCi of tritiated thymidine (ICN Pharmaceuticals, Costa Mesa, CA) to 0.2-ml cultures for approximately 12 h at the end of culture. Response was assessed at different times depending on the experiment, either between 36 to 48 h, 60 to 72 h, or 84 to 96 h.
Cytokine secretion
Triplicate supernatants were recovered 20 to 24 h and 35 to 40 h after T cell stimulation and pooled to assess cytokine content. IL-2 production was determined as before (5, 9) by titrating pooled replicate supernatants onto NK.3 cells, in duplicate, in the presence of anti-IL-4 (purified from the 11B11 cell line; American Type Culture Collection, Rockville, MD). Standard curves were constructed with purified IL-2 (supernatant from the X63.Ag.IL-2 cell line).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Peptides of MCC and PCC were screened for reactivity with
naive CD4 cells expressing the Vß3/V11 TCR and isolated from AND
transgenic mice. Initial screening was conducted with presentation on a
highly stimulatory fibroblast APC expressing IEk along with
B7-1 and ICAM-1, as used in previous studies (9, 10). Several peptides
were selected to give a range of activities compared with the native
peptides from nonstimulatory to heteroclitic (agonists that are more
stimulatory than the native peptide). Because each peptide displayed
similar binding to IEk (Table I
), reactivities are most
likely attributable to varying affinities of interaction between the
TCR and the peptide/MHC complex.
Figure 1 shows proliferation and IL-2
secretion of naive CD4 cells assessed at times previously found to give
maximal responses to the native peptides. Generally, substitutions at
the dominant (positions 99 and 102) and subdominant (position 97) TCR
contact residues result in peptides that produce altered T cell
responses (28), and largely these have been utilized in the studies
here. However, substitutions at adjacent residues can also produce APLs
of differential activity, e.g., an L to A substitution at position 98
results in a heteroclitic peptide that induces proliferation and IL-2
secretion from naive T cells at lower doses than the native peptide
(Fig. 1, left hand graphs). In addition,
different amino acid substitutions at the same position can result in
tremendous variations in activity. Thus, T to S at position 102 results
in a better agonist peptide than MCC, whereas T to L produces a peptide
that can antagonize responses induced by the native peptide (P. R.
Rogers, unpublished observations using B7+ICAM+
fibroblasts as APC) and does not induce proliferation or IL-2 secretion
from naive cells even with optimal costimulation (Fig. 1).
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were conducted with
B7+ICAM+ fibroblast APCs that we have
previously shown are equivalent in stimulatory capacity to dendritic
cells (10). These APCs therefore potentially provide optimal accessory
molecule help as relates to provision of both adhesion to maximize the
ability to form conjugates and costimulation to promote late events of
T cell response. Even with such APC, naive T cell responses were
dramatically different depending on the peptide. Heteroclitic peptides
(L98A and T102S) induced similar maximum levels of proliferation to the
native peptide, but responses were induced with approximately 10- to
50-fold less Ag. Similar results were apparent assessing IL-2
production, which is largely responsible for the extent of naive T cell
proliferation (our unpublished observations), although these peptides
induced higher total levels of IL-2 in most experiments as well as
shifting the dose-response curves. In contrast, weak agonist peptides
displayed two activities with the highly costimulatory APC. Some
peptides such as K99E were also capable of promoting responses of
similar magnitude to the native and heteroclitic peptides but only when
present at doses 10- to 100-fold above those with the native peptide.
In contrast, other peptides such as Y97K and K99A only initiated naive
CD4 responses at concentrations in excess of 1000-fold more than those
required with the native peptide, and the responses obtained were far
lower in magnitude than that with the MCC regardless of the
concentration. This was evident for both IL-2 secretion taken at
24 h and proliferation from 60 to 72 h, suggesting that the
extent of IL-2 produced was critical for the overall response and could
be governed by the nature of the peptide. APLs modulate the ability of highly costimulatory APC to promote naive T cell activation
The data presented in Figure 1 suggested that APLs affected the
extent of IL-2 production from naive CD4 cells and that this dictated
the later proliferative response, but did not address whether the
peptides varied in capacity to promote early phases of naive T cell
activation. We therefore assessed expression of the activation Ags CD69
and IL-2R (CD25), which during the initial stages of naive T cell
response are not dependent on costimulatory signaling or the extent of
IL-2 produced (our unpublished observations). This analysis represents
a reliable method for determining the number of T cells that are
activated in culture. Several different phenomena were observed
depending on the peptide analyzed (Fig. 2). The antagonist peptide, T102L, was
virtually incapable of promoting T cell activation at any dose tested
correlating with its inability to promote IL-2 and proliferation. In
contrast, the very weak agonist, K99A, which only induced IL-2 and
proliferation at minimal levels, was capable of activating virtually
all of the T cells present in culture at doses of 10 to 100 µM, which
was 10,000-fold more than that required for a similar response with the
native Ag (0.001 µM). The other weak agonists, Y97K and K99E, which
induced greater proliferative and IL-2 responses than K99A but also
varied in stimulatory capacity with respect to each other, were
identical in their ability to promote naive activation as assessed by
CD69 and IL-2R expression. The threshold of response occurred between
0.01 and 0.1 µM. Heteroclitic peptides (T102S, Fig. 2, and L98A not
shown) were equivalent to the native peptide in their capacity to
promote early activation, the majority of cells expressing CD69 and
IL-2R at doses of 0.0001 to 0.001 µM. Interestingly, significant IL-2
production and proliferation were only observed at Ag doses that
resulted in the majority of T cells in culture being activated (compare
dose responses of Figs. 1 and 2), but early activation of naive T cells
was not strictly correlated with the later phases such as the extent of
IL-2 produced. Thus, weak agonist peptides varied from the native
peptide in the ability to promote all aspects of naive CD4 activation
at low Ag doses, but at higher doses were largely defective in the
ability to induce IL-2 production and promote later responses such as T
cell proliferation. In contrast, heteroclitic peptides functioned
primarily by promoting enhanced IL-2 when present at low doses.
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Because the majority of T cells were activated with weak agonist
peptides at higher Ag concentrations and some IL-2 was produced
depending on the nature of the peptides, we investigated whether this
would affect the kinetics of proliferation compared with the native
peptide. Figure 3 shows proliferation
over time, induced by APLs presented on highly costimulatory APC
(B7+ICAM+ fibroblasts). As seen in
previous studies (5, 9) and shown in Figure 1, optimal proliferation of
naive T cells in response to native MCC was between 3 and 4 days after
activation. Differing kinetics were seen with weak agonists. K99E,
which was the most stimulatory of the weak agonists, maintained
proliferation at levels similar to MCC over the 3 days studied, with
the dose required for similar response being relatively constant at
approximately 10- to 50-fold more. Y97K, which could not induce
equivalent IL-2 secretion regardless of concentration, also induced
equivalent proliferative responses at days 2 and 3, but could not
maintain a strong response past this time. High doses of K99A, able to
promote only minimal IL-2 secretion, induced similar levels of
proliferation to the native peptide at day 2 (36–48 h) but were
incapable of sustaining the response beyond this time point. Thus,
peptides of presumed low affinity, when expressed on highly stimulatory
APC, were capable of promoting naive CD4 activation as assessed by
early induction of CD69/IL-2R (Fig. 2) and early proliferation (Fig. 3)
but were lacking in ability to induce the high levels of IL-2 required
for sustaining T cell expansion.
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We have previously shown that the extent of proliferation and IL-2
secretion from naive CD4 cells in response to native PCC is determined
by the expression of accessory molecules on the APC, and that an APC
lacking one or more of these molecules induces minimal proliferation
and little IL-2 (9). To investigate the role of accessory molecule help
in response to APLs, we examined naive CD4 activation (IL-2R induction)
by APCs that lack B7 and ICAM but are still able to present Ag (Fig. 4). Expression of IL-2R was assessed
at 21 h, with similar results obtained at 15- and 42-h time
points. Identical results were obtained when analyzing CD69 expression
(data not shown). Similar to ICAM+B7+
cells, the APC lacking those accessory molecules were capable of
activating the majority of T cells in culture with native MCC; however,
about 100-fold more peptide was required. The heteroclitic peptide,
T102S, when compared with native Ag, did not further enhance the
ability of ICAM-B7- APC to promote early T
cell activation as assessed by IL-2R expression. However, weak agonist
peptides presented by these APC became much less effective than when
presented by APC with accessory molecules. Thus, K99A that induced all
T cells to become activated when present at high concentrations with B7
and ICAM help was at least 100-fold less efficient in the absence of B7
and ICAM and capable of promoting activation of only a small fraction
of T cells at the maximum dose tested (50 µM). A similar lower
effectiveness was seen with other weak agonist peptides (K99E, Y97K)
when presented in the absence of B7 and ICAM. Significantly, a peptide
such as K99A presented on an APC expressing accessory molecules was
less effective in promoting early phase T cell activation than MCC or
T102S presented on an accessory molecule-deficient APC. Conversely, the
so-called weak agonists K99E and Y97K could be equally as effective
when presented with accessory molecule help as T102S and MCC presented
without accessory molecules. Thus, naive T cell activation is both a
function of the nature of the peptide and the nature of the APC, and
the distinction between strong vs weak agonist is directly related to
the presence of accessory molecules on the APC.
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The heteroclitic peptide, T102S, was next assessed for its ability
to promote later phases of naive activation with and without help from
B7 and ICAM. Naive CD4 cells were stimulated with peptide-pulsed
ICAM-B7- APC, and proliferation and IL-2
secretion were assessed over time compared with that elicited with
ICAM+B7+ APC (Fig. 5). In the absence of B7 and ICAM, IL-2
production at 20 h was similar regardless of whether T102S or the
native peptide was used, with naive cells producing only minimal
quantities even at a high Ag dose. This low level of IL-2 induced only
minimal proliferation at day 2, which again was similar regardless of
peptide. With accessory molecule help at this early time, T102S did not
enhance proliferation compared with MCC even though T102S promoted
higher levels of IL-2 at lower doses. In contrast, late phase
proliferation was enhanced with the heteroclitic peptide, regardless of
the APC, and this correlated with significant differences in IL-2
production at 37 h. Although T102S presented on the accessory
molecule-deficient APC enhanced IL-2 secretion somewhat, and
proliferation to a large extent, responses were still less than those
of the native peptide presented in the presence of B7 and ICAM.
Therefore, heteroclitic peptides can partially overcome the need for
multiple accessory molecules on APC and can result in enhanced naive
responses at late times, but cannot totally compensate for the
costimulatory signals and adhesion provided by these molecules.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our previous studies on Ag presentation to naive CD4 cells using native
PCC demonstrated that the later phase response was highly
dependent on expression of accessory molecules by the APC. Much lower
levels of both proliferation and IL-2 secretion were produced if only
one accessory molecule was expressed (e.g., B7 or ICAM alone) and very
little response was seen in the absence of B7 or ICAM (9). Data in
Figure 4 assessing CD69/IL-2R expression extend these observations and
show, in striking contrast to IL-2 and proliferation, that equivalent
early phenotypic changes of activation are induced regardless of
whether the APCs possess several of the major accessory molecules
(e.g., B7, ICAM, 4-1BBL, Ox-40L, or heat-stable Ag). However, this only
applies to situations in which sufficient quantities of native peptide
are presented. At low peptide concentrations that are otherwise not
sufficient for induction of a discernible response, the presence of
accessory molecules is required for an APC to activate T cells. How
these molecules function in this regard is not clear. Both adhesion and
costimulatory functions have been described for many such molecules,
including B7 and ICAM. Therefore, it is feasible that when peptide/MHC
complexes are rare, an increased stability of the T cell-APC
interaction may result in the presence of accessory molecules that is
not achieved in their absence. In this case, the overall effect may be
translated into a higher level of TCR signaling over time.
Alternatively, cosignaling may purely compensate for the lack of TCR
signaling. Recent observations from Valitutti et al. (29) and Viola and
Lanzavecchia (30) suggested that a threshold number of TCRs needed to
be engaged to produce a response in a T cell, and that this number was
diminished approximately fivefold (from 8000 to 1500) if the
interacting APC expressed B7. Thus, in our studies, it is possible that
additional signals generated through both CD28 and LFA-1 may compensate
for low level TCR signaling with limiting Ag, and produce a level of
total signals that is equivalent to the level induced with higher doses
of Ag presented without CD28 and LFA-1 engagement. The enhanced
responses at low dose Ag were apparent regardless of the peptide
ligand, with APC expressing multiple accessory molecules inducing CD25
and CD69 expression at 10- to 100-fold lower concentrations (Fig. 4).
Accessory molecules had a profound bearing on T cell activation by weak
agonist peptides. APC with B7 and ICAM were able to efficiently induce
early events of naive activation with all peptides tested as long as
sufficient concentrations could be achieved (Fig. 2). The only
exceptions were peptides that could actively antagonize responses of
the native peptides (e.g., T102L). In contrast, peptides that were very
weak agonists on B7+ICAM+ APC were either
unable to activate naive cells on B7-ICAM-
APC (as assessed by CD69/IL-2R expression), at least with the maximal
amounts used here (e.g., K99A at 50 µM; Fig. 4), or only resulted in
activation if at least 100-fold more peptide was available (e.g., K99E,
Y97K; Fig. 4). The stimulatory capacity of the peptides is likely to be
a function of the affinity of interaction between the peptide/MHC
complex and the TCR, as each peptide was chosen for similar binding to
MHC. Based on studies with soluble antagonist peptide/MHC complexes
binding to immobilized TCR, it has recently been proposed that the
affinity of each complex is largely due to the rate of dissociation
from the individual TCRs (31, 32). Therefore, it could be argued that
accessory molecule-coreceptor engagement may compensate for the
intrinsic fast dissociation rate of the weak agonist ligands and allow
T cell activation. Thus, peptides such as K99A may have an off-rate
that is too high, if presented in the context of minimal accessory
help, to induce sufficient signals for the T cell to express surface
activation markers such as IL-2R. The off-rate may not be altered
unless cosignaling induces conformational changes in the TCR; however,
the ability to associate may be increased due to enhanced T cell-APC
avidity, which ultimately could result in greater densities of TCR/MHC
complexes and overall increased TCR signaling. Another question is
additionally raised, and that is whether expression of costimulatory
accessory molecules has a bearing on the ability of a peptide to
antagonize T cell activation. Antagonist peptides appear to function by
competing with agonist/MHC complexes for binding to TCRs (20) and
inducing incomplete intracellular signaling (22, 23, 26), the latter
potentially being related to the high dissociation rates discussed
above. In line with this concept, two recent studies showed that weak
agonist peptides can become antagonists if CD4 is unable to bind MHC
(33, 34), again suggesting that the overall avidity of TCR-MHC
interaction and length of engagement is crucial for determining the
outcome. Although CD4 is known as an accessory molecule, because of
binding to MHC, it is not classically viewed as costimulatory although
signaling through the molecule can obviously occur. Therefore, whether
lack of engagement of conventional costimulatory accessory molecules
such as B7 and ICAM can turn a weak agonist peptide such as K99A into
an antagonist peptide is unclear. If B7 and ICAM are primarily
important for delivering cosignals, this phenomenon may not be seen,
whereas if they are equally important for stabilizing MHC/TCR
engagement, antagonism may occur. These and other questions are
currently being pursued.
As well as focussing on early phases of naive T cell activation, the
studies presented here also highlight the stringent requirements of
these cells for making large quantities of IL-2 and proliferating, and
show that T cell activation per se can be largely dissociated from the
production of IL-2. Thus, weak agonist peptides such as K99A and Y97K
promoted efficient T cell activation at a high dose when presented on
B7+ICAM+ APC (as assessed by CD69/IL-2R
expression; Fig. 2), but were unable to induce IL-2 at the same levels
as those seen with the native MCC peptide (Fig. 1). Using intracellular
staining to detect IL-2-secreting cells, we also found a correlation
between peptide dose and the number of IL-2-secreting cells (data not
shown). A total of 100 (K99E) to 1000 (K99A) times more peptide was
required to obtain an equivalent number of IL-2-secreting cells
compared with agonist (MCC) peptide. Therefore, even in the presence of
multiple accessory molecules and potentially high levels of
costimulation, the ultimate outcome of Ag presentation was still
dependent on the extent of TCR ligation. Similar conclusions were
reached in our earlier studies of naive T cell activation using
anti-CD3 to vary the magnitude of TCR signals (9), showing that
IL-2 secretion is critically controlled by the balance between TCR
signaling and cosignaling. This was also exemplified in the studies
with the heteroclitic peptide, T102S. This peptide could partially
compensate for the lack of B7 and ICAM on the APCs and produced an
enhanced response compared with the weak proliferation and IL-2
secretion observed with native MCC, but could not promote responses of
similar magnitude to those induced in the presence of B7 and ICAM
(Fig. 5).
The final evidence that demonstrated that IL-2 production was the main
facet of naive T cell activation that distinguished strong from weak
agonists were the kinetic studies of proliferation (Figs. 3 and 5).
High doses of weak agonists (K99A, Y97K) promoted similar levels of
proliferation to native MCC at earlier times (day 2, and days 2 and 3,
respectively), but were unable to sustain these responses, a phenomenon
that directly correlated with the differences in the extent of IL-2
production observed. Similarly, the heteroclitic peptide (T102S) did
not possess a greater ability to initiate early activation of the T
cells compared with the native peptide (Figs. 2 and 4), regardless of
APC, but did promote higher levels of IL-2 that resulted in greater
proliferation at late times. We also obtained a similar pattern of
responses using activated B cells rather than the fibroblast
transfectants. Weak agonists such as K99A induced higher proliferative
responses on day 2 vs day 3, whereas agonist or heteroclitic peptides
induced higher proliferation on day 3. These studies therefore suggest
that the magnitude of IL-2 induction is critical for determining the
overall extent of naive responses. Such a conclusion is supported by a
recent study of APLs and cloned T cells that suggested that the major
difference between peptides that vary in their capacity to induce
anergy is the ability to promote IL-2 secretion rather than early
intracellular signaling events (35).
In summary, the data in this report demonstrate that the ultimate
outcome of naive T cell interaction with an APC is a function of both
the affinity of interaction between peptide/MHC and the TCR, and the
engagement of accessory molecules by T cell coreceptors. The data also
indirectly support the contention that there is a hierarchy of steps
during T cell activation that is governed by the overall level of
signaling achieved, with early phases of naive response having less
stringent requirements than later phases. Such a phenomenon was
recently observed with a T cell clone using various altered peptides of
MCC, with the conclusion that events such as 
-chain phosphorylation
required a shorter duration of TCR ligation than Ca flux, which in turn
was more easily triggered than proliferation (36). Although our studies
cannot discriminate between a requirement for enhanced TCR ligation
over time and the provision of costimulatory signals, they do highlight
the fact that accessory molecule-coreceptor engagement plays a critical
role in determining the stimulatory capacity of a peptide.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael Croft, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121. E-mail address:
3 Abbreviations used in this paper: PCC, pigeon cytochrome c; MCC, moth cytochrome c; APL, altered peptide ligand.
Received for publication September 29, 1997. Accepted for publication December 11, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T. Sasada, H. Yang, and E. L. Reinherz CD2 Facilitates Differentiation of CD4 Th Cells Without Affecting Th1/Th2 Polarization J. Immunol., February 1, 2002; 168(3): 1113 - 1122. [Abstract] [Full Text] [PDF]
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J. A. Gebe, E. J. Novak, W. W. Kwok, A. G. Farr, G. T. Nepom, and J. H. Buckner T Cell Selection and Differential Activation on Structurally Related HLA-DR4 Ligands J. Immunol., September 15, 2001; 167(6): 3250 - 3256. [Abstract] [Full Text] [PDF]
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D. M. Jelley-Gibbs, N. M. Lepak, M. Yen, and S. L. Swain Two Distinct Stages in the Transition from Naive CD4 T Cells to Effectors, Early Antigen-Dependent and Late Cytokine-Driven Expansion and Differentiation J. Immunol., November 1, 2000; 165(9): 5017 - 5026. [Abstract] [Full Text] [PDF]
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C. D. Chung, V. P. Patel, M. Moran, L. A. Lewis, and M. C. Miceli Galectin-1 Induces Partial TCR {zeta}-Chain Phosphorylation and Antagonizes Processive TCR Signal Transduction J. Immunol., October 1, 2000; 165(7): 3722 - 3729. [Abstract] [Full Text] [PDF]
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 J. Huang, D. Tilly, A. Altman, K. Sugie, and H. M. Grey Inaugural Article: T-cell receptor antagonists induce Vav phosphorylation by selective activation of Fyn kinase PNAS, September 26, 2000; 97(20): 10923 - 10929. [Abstract] [Full Text] [PDF]
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 T. A. Colella, T. N.J. Bullock, L. B. Russell, D. W. Mullins, W. W. Overwijk, C. J. Luckey, R. A. Pierce, N. P. Restifo, and V. H. Engelhard Self-Tolerance to the Murine Homologue of a Tyrosinase-Derived Melanoma Antigen: Implications for Tumor Immunotherapy J. Exp. Med., April 3, 2000; 191(7): 1221 - 1232. [Abstract] [Full Text] [PDF]
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P. R. Rogers and M. Croft CD28, Ox-40, LFA-1, and CD4 Modulation of Th1/Th2 Differentiation Is Directly Dependent on the Dose of Antigen J. Immunol., March 15, 2000; 164(6): 2955 - 2963. [Abstract] [Full Text] [PDF]
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P. R. Rogers, C. Dubey, and S. L. Swain Qualitative Changes Accompany Memory T Cell Generation: Faster, More Effective Responses at Lower Doses of Antigen J. Immunol., March 1, 2000; 164(5): 2338 - 2346. [Abstract] [Full Text] [PDF]
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J. Zivny, M. DeFronzo, W. Jarry, J. Jameson, J. Cruz, F. A. Ennis, and A. L. Rothman Partial Agonist Effect Influences the CTL Response to a Heterologous Dengue Virus Serotype J. Immunol., September 1, 1999; 163(5): 2754 - 2760. [Abstract] [Full Text] [PDF]
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P. R. Rogers and M. Croft Peptide Dose, Affinity, and Time of Differentiation Can Contribute to the Th1/Th2 Cytokine Balance J. Immunol., August 1, 1999; 163(3): 1205 - 1213. [Abstract] [Full Text] [PDF]
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N. G. Saito, H.-C. Chang, and Y. Paterson Recognition of an MHC Class I-Restricted Antigenic Peptide Can Be Modulated by para-Substitution of Its Buried Tyrosine Residues in a TCR-Specific Manner J. Immunol., May 15, 1999; 162(10): 5998 - 6008. [Abstract] [Full Text] [PDF]
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 L. Rivoltini, P. Squarcina, D. J. Loftus, C. Castelli, P. Tarsini, A. Mazzocchi, F. Rini, V. Viggiano, F. Belli, and G. Parmiani A Superagonist Variant of Peptide MART1/Melan A27-35 Elicits Anti-Melanoma CD8+ T Cells with Enhanced Functional Characteristics: Implication for More Effective Immunotherapy Cancer Res., January 1, 1999; 59(2): 301 - 306. [Abstract] [Full Text] [PDF]
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I. Gramaglia, A. D. Weinberg, M. Lemon, and M. Croft Ox-40 Ligand: A Potent Costimulatory Molecule for Sustaining Primary CD4 T Cell Responses J. Immunol., December 15, 1998; 161(12): 6510 - 6517. [Abstract] [Full Text] [PDF]
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P. R. Rogers, G. Huston, and S. L. Swain High Antigen Density and IL-2 Are Required for Generation of CD4 Effectors Secreting Th1 Rather Than Th0 Cytokines J. Immunol., October 15, 1998; 161(8): 3844 - 3852. [Abstract] [Full Text] [PDF]
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R. Wang, Y. Wang-Zhu, and H. Grey Interactions between double positive thymocytes and high affinity ligands presented by cortical epithelial cells generate double negative thymocytes with T cell regulatory activity PNAS, February 19, 2002; 99(4): 2181 - 2186. [Abstract] [Full Text] [PDF]
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M. Gerloni, S. Xiong, S. Mukerjee, S. P. Schoenberger, M. Croft, and M. Zanetti From the Cover: Functional cooperation between T helper cell determinants PNAS, November 21, 2000; 97(24): 13269 - 13274. [Abstract] [Full Text] [PDF]
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