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*
Department of Immunology, Division of Medicine, and
Transplantation Biology Group, Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, London, United Kingdom
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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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First, it remains unclear whether the requirement for CD28-mediated costimulation can be partly or completely bypassed by the display of high Ag density by physiological APCs. Many studies have involved nonphysiological stimuli where TCR with an unusually high affinity (7), anti-CD3 mAbs (8), or MHC-peptide complexes (9) were used to provide signal 1, or tumor cell lines (7) have been used as APCs. For example, purified T cells from CD28-deficient mice were able to respond to immobilized anti-CD3 mAb if 10-fold more mAb was provided (8), and high doses of peptide presented by CD80/CD86-negative RMA-S.Ld transfectants, or immobilized MHC class I-peptide complexes, induced proliferation by purified 2C TCR-transgenic (Tg)4 CD8+ T cells (7, 9). While in vitro studies have demonstrated an important role for B7 costimulation (10), in vivo studies have indicated that antiviral responses can be within the normal range. For example, anti-lymphocytic choriomeningitis virus CTL responses are effective in CD28 and IL-2 knockout mice (11, 12), indicating that CD8+ T cells may not be completely costimulation-dependent.
Second, although CD80 and CD86 both bind to CD28 and CD152, it is not clear whether these molecules mediate distinct functions (13, 14). Some reports have suggested that CD86 is the primary costimulatory molecule for initiating a T cell response and providing cognate help for B cells, while CD80 plays a more important role in antitumor responses (15). Furthermore, in vivo blocking studies using mAb specific for CD80 or CD86 have been interpreted as indicating that these two molecules have distinct roles in amplifying or regulating autoimmune responses in disease models, such as experimental autoimmune encephalomyelitis (16) and diabetes (17).
Third, the existence of two receptors (CD28 and CD152) for B7 molecules adds further complexity to the issue of costimulation. It is clear from in vitro (18, 19) and in vivo studies using anti-CTLA4 mAb that CD152 delivers a negative signal in the context of T cell activation. For example, in vivo, blockade of CTLA4 led to the exacerbation experimental autoimmune encephalomyelitis (20), the enhancement of an antitumor response (21), and the augmentation of a T cell response in an adoptive transfer model (22). The data from CTLA4 knockout mice provide further strong evidence that CTLA4 has an inhibitory function (23, 24). Two recent reports also suggested that CTLA4 engagement may be required for the induction of peripheral T cell tolerance (25, 26).
In this study, using thymic or peripheral T cells as costimulation-deficient APCs, we investigated the costimulation requirements of naive TCR-Tg CD8+ T cells. The independent effects of CD80 and CD86, and the consequences of costimulation-deficient Ag presentation on the subsequent reactivity of mature and immature CD8+ T cells, were also examined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C6 TCRhigh Tg mice, specific for the H-Y
Ag-derived peptide TENSGKDI presented by H2-Kk,
were generated using a CD2 cassette (27) encoding the 
8
and 
11 TCR chains from the H-Y-specific CD8+ T
cell clone C6 (28). The C6 TCRlow
strain was on a CBA/Ca; C58 (H-2k) background and
has been described previously (29), while the C6
TCRhigh strain was on a CBA/Ca; C57BL/6
(H-2k) background. CBA/Ca mice were purchased
from Olac Harlen (Bicester, U.K.) and used at 6–8 wk of age.
Peptide, Abs, Fab fragments, and fusion proteins
The Smcy gene product-derived H-Y peptide (TENSGKDI) (30) was used as cognate Ag for the C6 TCR. The mAbs (in the form of hybridoma culture supernatant) used for T cell purification were: anti-H2-Ak (10.2.16, TIB-93; American Type Culture Collection (ATCC), Manassas, VA), anti-H2-Ek (14-4-4S, HB-32; ATCC), anti-H2-Ek (Y-17, HB-179; ATCC), anti-H2-Ek (17-3-3S, HB-6; ATCC), anti-H2-Ek,d/Ab,d (M5/114, HIB-120; ATCC), anti-CD4 (GK1.5, TIB-207; ATCC and YTS 191), anti-CD8 (53.6.7 and YTS 169), and anti-CD44/Ly-24/Pgp-1 (I42.5) (the references of YTS191, 53.6.7, YTS169, and I42.5 have been described previously (31)). The purified mAbs and fusion proteins used in T cell proliferation assays included: anti-CD3 (145-2C11, CRL-1975; ATCC), anti-CD80/B7-1 (16-10A1), anti-CD86/B7-2 (GL1), anti-CD28 (37.51), anti-CD152/CTLA4 (UC11-4F10-11), murine CTLA4-Ig (mCTLA4-Ig), and mCD28-Ig (the references of these mAbs and fusion proteins have been described previously (32)). Purified rat IgG, hamster IgG, and human IgG1 (PharMingen, San Diego, CA) were used as negative controls. All Abs and fusion proteins were purified from culture supernatant or normal serum using protein G-Sepharose (Pharmacia, Uppsala, Sweden). Fab fragments of anti-CD80, anti-CD86, anti-CD28, anti-CD152, rat-IgG, or hamster IgG were generated using the ImmunoPure Fab Preparation Kit (Pierce, Rockford, IL) according to the manufacturer’s instructions.
Preparation of APCs and peptide pulsing
Both CD4+ thymocytes and peripheral (both CD4+ and CD8+) T cells were used as nonprofessional APCs in the present study. To purify CD4+ thymocytes, total thymocytes from CBA/Ca mice were treated with a mixture of anti-H2-Ak/-Ek (10.2.16, 14.4.4S, Y17, M5/114, and 17.3.3S) and anti-CD8 mAbs (YTS169 and 53.6.7) and then with sheep anti-mouse/rat IgG Dynabeads (Dynal A.S, Oslo, Norway). To purify peripheral T cells, spleen and pooled lymph node (both subcutaneous and mesenteric) cells from the same donors were initally passed over nylon wool columns, according to a standard protocol. The nonadherent populations, i.e., enriched T cells, were treated with a mixture of anti-H2-Ak/-Ek (and anti-CD8 to purify a CD4+ T cell population) mAbs and then with sheep anti-mouse/rat IgG Dynabeads. To obtain naive T cells, the purified T cells were further treated with anti-CD44 mAb (I42.5) followed by sheep anti-rat IgG Dynabeads. The resulting T cell purity was routinely >95% by flow cytometric analysis. The nylon wool-adherent populations, including B cells, macrophages, and dendritic cells, were eluted by flushing the columns with cold medium, and used as professional APCs without further purification. Peptide pulsing was conducted by incubating CD4+ thymocytes, peripheral T cells, or adherent cells with different concentrations of peptide at a cell density of 5 x 106/ml overnight. Con A- or LPS-blasts were prepared by stimulating spleen cells from CBA/Ca females with 5 µg/ml Con A or 20 µg/ml of LPS (both from Sigma, St. Louis, MO) for 2 days. For these cells, peptide pulsing was limited to 4 h. In all cases, cells were washed three times after pulsing to remove free peptide. All APCs received g-irradiation (30 Gy) before they were added into plates.
Preparation of responders
Both CD8+ thymocytes and peripheral CD8+ T cells from TCR Tg mice were used as responders. Purification of these populations was as for the CD4+ cells above, except that anti-CD4 (GK1.5 and YTS191) was substituted for anti-CD8 mAb (53.6.7 and YTS169).
Activation of CD8+ T cells using immobilized anti-CD3 and anti-CD28
Round-bottom 96-well plates were coated with purified anti-CD3 (145-2C11; ATCC) (0.1 µg/ml) alone, or together with hamster IgG (10 µg/ml), anti-CD80 (10 µg/ml), anti-CD28 (10 µg/ml), anti-CTLA4 (10 µg/ml), anti-CD28 (10 µg/ml) plus anti-CTLA4 (10, 20, or 40 µg/ml) in 100-µl vol for 2 h at 37°C, then washed extensively and 100 µl of complete medium added. C6 TCRhigh-Tg CD8+ T cells were added at 5 x 104/well in 100 µl of complete medium, and all cultures were incubated at 37°C for 3 days.
T cell proliferation assays
RPMI 1640 medium supplemented with 10% FCS (Globepharm, Esher, U.K.), 2 µM glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, and 50 mM 2-ME was used as complete culture medium in all T cell proliferation assays. T cells were routinely cultured in round-bottom 96-well plates (Costar, Cambridge, MA) in a volume of 0.2 ml for 3 days. A total of 1 µCi of [3H]thymidine (ICN, Costa Mesa, CA) was added into each well 2 days later, and T cells were harvested onto glass fiber filters by an LKB 96-well harvester (Wallac Oy, Turku, Finland) after an additional 24 h. [3H]thymidine uptake was measured by an LKB Betaplate counter (Wallac Oy). The results are expressed as mean cpm for triplicate cultures. SEs were routinely <10%.
Measurement of cytokines
Cell-free culture supernatants harvested from T cell cultures at
the different time points were immediately frozen at -70°C. IL-2 and
IFN-
content of the supernatants was measured using ELISA kits,
according to the the manufacturer’s instructions (Endogen, Cambridge,
MA). To calculate cytokine concentrations, Thermomak Microplate Reader
and SoftMaxPro 1.2 Software (Molecular Devices, Sunnyvale, CA)
were used.
Flow cytometric analysis
FITC- or PE-conjugated anti-CD4, -CD8,
-H2-Ak, -H2-Ab, -CD25,
-CD24, -CD54, -CD80, -CD86, -CD44, -CD45RB, -CD69, -CD62L, -TCR V11
mAbs and their isotype-matched controls were purchased from PharMingen
and were used for direct immunofluoresence staining. FITC-conjugated
goat anti-human IgG (Fc specificity), supplied by Binding Site
(Birmingham, U.K.), were used as second layer Abs for indirect
immunofluoresence staining. Percent of TCR remaining was calculated by:
[mean fluorescence intensity (MFI) of V11 measured after
activation]/[MFI of V11 measured before activation] x 100%. All
flow cytometric analysis was conducted on a Becton Dickinson (Franklin
Lakes, NJ) FACScaliber running CellQuest software.
Induction of unresponsiveness/anergy in vitro
Peripheral or thymic naive TCR Tg CD8+ T cells (1 x 106/well) were incubated with peptide-pulsed CD4+ thymocytes, peptide-pulsed naive CD4+ T cells, or peptide-pulsed splenic adherent cells (5 x 106/well) overnight in 24-well plates (Costar). The next day, APCs were removed using anti-CD4 or anti-class II mAbs followed by Dynabeads, and T cells were allowed to rest for 3 days. After resting, T cells (1–4 x 104/well) were restimulated with peptide-pulsed splenocytes (5 x 105/well) in round-bottom 96-well plates (Costar) for 3 days.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A new line of TCR-Tg mice (C6 TCRhigh)
expressing a high level of the H-2Kk-restricted
TCR V8V11 specific for an H-Y peptide has recently been
developed. Double staining of thymocytes from female Tg mice from this
line with anti-CD4-FITC and anti-CD8-PE revealed strong
positive selection to single positive CD8 thymocytes (Fig. 1
A). This phenotype is
reflected in the periphery where CD8+ T cells
predominate (
60% CD8+/4%
CD4+ in lymph nodes; and 20%
CD8+/4% CD4+ in spleen)
(Fig. 1B). Naive TCR-Tg CD8+ T cells
purified from thymus or peripheral lymphoid tissues were TCR
V11-positive (Fig. 1, C–F) and were used as responders.
Unlike the thymic C6 TCRhigh phenotype, very few
single positive CD8 thymocytes are produced in C6
TCRlow Tg females (data not shown), reflecting
inefficient positive selection in this strain as previously reported
(29). However, in C6 TCRlow mice,
CD8+ T cells appear in the periphery and
represent the major T cell subset. As shown in Fig. 1G,
purified peripheral CD8+ T cells from C6
TCRlow mice express less surface V11 in
comparison to the C6 TCRhigh strain. The
CD8-CD4-TCR+
population, as described in 2C TCR-Tg mice (7), was not
present in the peripheral lymphoid tissues of either C6 TCR-Tg
strain.
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, H, K,
and L). Although some of the purified T cells expressed a
low level of CD86, no surface expression of CD80, CD54 (ICAM-1), CD24
(HSA), CD69, or CD25 was detected (Fig. 1, I and
J, and data not shown). Interestingly,
CD80-CD86+ naive T cells
showed significant binding to both mCD28-Ig and mCTLA4-Ig (Fig. 1, M–O), suggesting that CD86 expressed on T cells binds CD28
and is therefore functionally competent. The greater proportion of
cells detected with recombinant ligand in comparison with anti-CD86
Ab may reflect the relative affinities of the two reagents. Purified
responder C6 TCR-Tg CD8+ T cells expressed an
identical phenotype and were additionally
CD62Lhigh (data not shown), confirming their
naive phenotype. The minimal proliferation induced in naive CD8+ T cells by T-APC could be enhanced by soluble anti-CD28 mAb or exogenous IL-2
To determine the requirement for costimulation of naive
CD8+ T cell activation, naive T cells were used
as APC for naive TCR-Tg CD8+ T cells. Splenic
adherent cells, LPS-and Con A-activated blasts, which express both B7
isoforms, were used as control APC populations. As expected, optimal
proliferation by naive C6 TCR CD8+ T cells was
induced by the three types of professional APC at low concentrations of
peptide. The TCRlow T cells required 10-fold
higher concentrations of peptide to induce maximal proliferation.
Conversely, proliferation induced by naive T cell APC at these
concentrations of peptide was not above background (Fig. 2A). Measurable proliferation
was induced when naive T cells presented high concentrations of peptide
(1000 nM) to naive C6 TCRhigh
CD8+ T cells (Fig. 2B). However, an
3 log higher peptide concentration was required to induce the level
of proliferation seen in response to the other APC populations. Similar
conclusions can be drawn from the levels of IL-2 and IFN- that were
secreted in response to peptide Ag presented by naive T cell vs
specialized APC (Fig. 2, C and D).
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E),
suggesting that the inability of T-APC to induce naive T cell
proliferation was not due to insufficient TCR engagement.
To investigate whether a lack of costimulation provided by the T cell
APC was responsible for these results, naive C6
TCRhigh CD8+ T cells were
stimulated with peptide-pulsed T-APCs in the absence or presence of
either soluble anti-CD28 mAb or exogenous IL-2. Both anti-CD28
and IL-2 greatly amplified proliferation, IL-2, and IFN- production
by naive T cells (Fig. 2F, and data not shown). These
findings provide further evidence of adequate peptide display by the
T-APC, and suggest that inadquate B7-mediated costimulation accounts
for the incompetence of the T cells as APC.
It was of interest to compare the behavior of mature
CD8+ thymocytes with peripheral T cells, as the
thymocytes represent a more Ag naive population and may be more fully
costimulation-dependent. When C6 TCRhigh-Tg
CD8+ mature thymocytes were used as responder
cells, no proliferation was induced by T-APC, even at very high peptide
concentrations (Fig. 2G), unless anti-CD28 or IL-2 were
added to the cultures (Fig. 2H, and data not shown).
Although the other three types of peptide-pulsed APCs can induce
proliferation in CD8+ thymocytes, at least 4-fold
more responder cells and 10-fold higher peptide concentrations were
required to reach a level of proliferation equivalent to that of
peripheral T cells. These data suggest that the activation of
CD8+ thymocytes is more costimulation-dependent,
and that the maturation stage of a T cell also influences the
requirement for costimulation.
mCTLA4-Ig, mCD28-Ig, or anti-CD28-Fab dramatically inhibit proliferation and cytokine production in TCRhigh-Tg CD8+ T cells
To further clarify the importance of CD28-mediated costimulation
during CD8+ T cell activation, naive C6
TCRhigh CD8+ T cells were
stimulated with peptide-pulsed APCs in the absence or presence of
mCTLA-4Ig, mCD28-Ig, or anti-CD28-Fab fragments. mCTLA4-Ig
abolished and mCD28-Ig subtantially reduced T cell proliferation, while
both treatments abolished IFN- production when naive T cells were
used as APCs (Fig. 3, A and
B). When adherent cells were employed as APCs, mCTLA4-Ig
inhibited T cell proliferation by >90%, while mCD28-Ig and
anti-CD28-Fab inhibited by >50% (Fig. 3C). mCTLA4-Ig
inhibited IL-2 and IFN- production to background levels (Fig. 3, D and E). The incomplete block to proliferation
is likely to reflect an incomplete costimulation blockade in the
presence of professional APCs expressing high surface densities of B7
molecules. In all assays, the inhibitory effect of mCTLA4-Ig was
greater than that of mCD28-Ig. These results demonstrate that the low
level of proliferation induced by T-APC at very high peptide
concentrations was due to the low levels of CD86 expressed by the naive
T cells, and that CD28-mediated costimulation is critically important
in the activation of naive CD8+ T cells.
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To address the possibility that the two B7 isoforms have distinct
functional effects in regulating the activation of naive
CD8+ T cells, specific mAbs were added to
cultures containing TCR-Tg T cells and either T cells or specialized
APC pulsed with peptide. As shown in all four panels of Fig. 4, anti-CD86 mAb inhibited
proliferation and cytokine release. In marked contrast, the
anti-CD80 mAb led to an increase of up to 6-fold in these
parameters. This finding was of particular note in the cultures
containing T-APC, which expressed no CD80 and low levels of CD86, at
the start of the cultures, in that it implies that CD80 expression was
induced during the culture and inhibited the costimulation provided by
CD86. Analysis of CD80 expression on the responder C6 T cell population
indeed demonstrated CD80 was strongly induced (Fig. 4G).
Control, species-matched, Ig preparations had no inhibitory
effects.
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E). Second,
when C6 TCRhigh Tg CD8+ T
cells were stimulated with immobilized anti-CD3 and anti-CD28,
the effect of coimmobilized anti-CTLA4 was inhibitory and
titratable (Fig. 4F). It is likely that the contrasting
effects of the anti-CTLA4 in these experiments reflects blockade of
the inhibitory CD80/CTLA4 interaction in the former experiment and
direct delivery of a negative signal under cross-linking conditions in
the latter experiment. Ag presentation by naive CD8+ T cells induces unresponsiveness in TCRhigh-Tg thymocytes, but not in peripheral T cells
It is well established from many experimental systems that
activated T cells from both mouse and man are rendered unresponsive
following costimulation-deficient Ag presentation (2).
Whether a similar outcome is seen in naive T cells remains unclear. The
consequences of ineffective Ag presentation by T-APC to peripheral T
cells, and to thymocytes, were examined in a three-step culture system.
CD8+ T cells were incubated with peptide-pulsed
CD4+ thymocytes, peripheral
CD4+ T cells, or adherent cells. After overnight
incubation, APCs were removed by anti-CD4 or anti-class II mAbs
together with Dynabeads, and T cells were rested for 3 days before
antigenic rechallenge. As shown in Fig. 5, A–C, peripheral T cells
remained responsive to peptide-pulsed spleen cells following all
primary culture conditions. As T-APC were found to express a limited
amount of costimulatory activity that was blockable by CTLA4-Ig (Fig. 3A), this experiment was repeated in the presence of
CTLA4-Ig with an identical outcome (data not shown). These data
demonstrate that naive CD8+ T cells are not
rendered anergic following signal 1 in the absence of costimulation. In
sharp contrast, proliferation by the purified
CD8+ thymocytes was completely abolished
following culture with T-APC in the absence of anti-CD28 mAb (Fig. 5D). This unresponsiveness reflected anergy rather than
apoptosis, since IL-2 restores the proliferation in the rechallange
culture (Fig. 5E).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production in naive
CD8+ T cells stimulated by T-APC were greatly
up-regulated by costimulation provided by anti-CD28 mAb. Potential responder T cell ignorance of the interaction with the T cell APCs was ruled out by the observation that peptide-pulsed T- and B-APC caused comparable TCR down-regulation on Tg T cells during coculture, and thus transduce equivalent intensities of signal 1. Consistent with our results, two recent studies using either costimulation-deficient Drosophila cells as APCs (33) or MHC-peptide complexes immobilized on plastic (34) have demonstrated that TCR down-regulation depends solely on the interaction between TCR and MHC-peptide complexes and does not require a costimulatory signal. These findings confirm the critical importance of costimulation for activating naive CD8+ T cells (10), and do not support the notion that costimulation becomes redundant in the context of supraoptimal TCR occupancy (7). Strikingly, >80% of the TCR can be removed from the cell surface of reponsive T cells during Ag presentation by T cell APC, which, in the presence of CD28 blockade, does not trigger cell activation. It remains possible that heterogeneity exists in TCR mediated "signal 1" and that TCR down-regulation does not indicate receipt of full TCR-mediated signals. The efficiency of TCR cross-linking and/or structural modulation involved in signal transduction may be dependent on APC type and be particular to given TCR/MHC/peptide combinations. Interestingly, 2C TCR-Tg CD8+ T cells were found to be costimulation-independent at high Ag density when RMA-S cells were used as APC (7), but costimulation-dependent when Drosophila cells presented peptide (35). Whether these distinct outcomes are due to RMA-S cells possessing limited costimulatory activity (36) or an aspect(s) of the alloreactive 2C receptor that has an unusually high affinity for peptide/MHC is unclear.
The second conclusion from this study is that naive
CD8+ T cell proliferation is up-regulated by
CD86-CD28, and down-regulated by CD80-CD152 interactions. Both
proliferation and cytokine production were greatly suppressed by
anti-CD86 mAb. Several studies have suggested that CD86 is the
primary costimulatory molecule for T cell activation (15).
For example, the maximal up-regulation of CTLA4 expression on naive T
cells requires costimulation that is primarily provided by CD28-CD86
interaction (37). CD86-mediated costimulation can
up-regulate IL-12R expression in murine Th1 clones, memory, and naive
CD4+ T cells (38). CD86 has been
shown to be the primary costimulatory molecule responsible for
initiating T cell responses and providing cognate help for B cells in
vivo (15). A possible explanation for the effect of
anti-CD80 mAb is that it inhibited interaction of CD80 with CTLA4;
indeed, CD80 is strongly induced on the responder T cells during the
culture period (Fig. 4G). Further anti-CTLA4 had an
inhibitory or enhancing influence on the proliferation of
TCRhigh C6 CD8+ T cells
when they were used in immobilized or soluble form (Fig. 4, E and F), respectively. Thus, CTLA4 behaves as a
negative regulator for T cell activation, consistent with most
published data in this field (18, 19). The inhibitory
effects of CD80:CTLA4 interactions may be particularly pronounced when
the level of B7-mediated costimulation is limiting, as applied when
T-APCs were used in these experiments.
The third conclusion from this study is that thymic and peripheral naive CD8+ T cells display a differential sensitivity to the induction of nonresponsiveness. Consistent with others (39), our results suggest that naive CD8+ T cells were not anergized in the absence of costimulation. It is interesting that, in contrast to peripheral T cells, mature CD8+ thymocytes were rendered unresponsive following interaction with peptide-pulsed T-APCs. One possibility is that mature CD8+ thymocytes are functionally similar to recent thymic emigrants. A late checkpoint in T cell development may allow for a tolerogenic signaling event should a T cell encounter Ag on a nonprofessional APC shortly after leaving the thymic medulla. Should newly emerged T cells not encounter Ag on nonprofessional APCs within this period, they may complete differentiation to a phenotype that is unaffected by Ag encounter on nonprofessional APCs. Functionally, a late checkpoint would promote tolerance to peripheral Ags and help prevent autoimmunity following T cell activation to a cross-reactive exogenous Ag expressed on a professional APC. The distinct behavior of thymocytes in comparison to peripheral T cells implies that the cellular integration of cell surface signaling events in these cell types is distinct.
In conclusion, these results demonstrate the importance of costimulation for naive CD8+ T cell activation, suggest that CD80 and CD86 can have opposing effects, and indicate differences in the senstivity of immature vs mature CD8+ T cells to the induction of nonresponsiveness following costimulation-deficient Ag presentation. The most striking observation regarding the roles of B7 isoform in CD8+ T cell activation was the amplification caused by anti-CD80 mAbs. This suggests that although both CD80 and CD86 can ligate CD28, in the activation of CD8+ T cells, CD80 may have a dominant negative role.
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Acknowledgments |
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Footnotes |
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2 J-G.C. and S.V. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Julian Dyson, Transplantation Biology Group, Medical Research Council Clinical Sciences Centre, Du Cane Road, London W12 ONN, U.K. E-mail address:
4 Abbreviations used in this paper: Tg, transgenic; MFI, mean fluorescence intensity; B/M/DC, B cells, macrophages and dendritic cells-enriched adherent cells; T-APC, T cells as APC.
Received for publication January 14, 1999. Accepted for publication May 24, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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N. V. Serbina, V. Lazarevic, and J. L. Flynn CD4+ T Cells Are Required for the Development of Cytotoxic CD8+ T Cells During Mycobacterium tuberculosis Infection J. Immunol., December 15, 2001; 167(12): 6991 - 7000. [Abstract] [Full Text] [PDF]
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H.-W. Mittrucker, M. Kursar, A. Kohler, R. Hurwitz, and S. H. E. Kaufmann Role of CD28 for the Generation and Expansion of Antigen-Specific CD8+ T Lymphocytes During Infection with Listeria monocytogenes J. Immunol., November 15, 2001; 167(10): 5620 - 5627. [Abstract] [Full Text] [PDF]
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F. Boisgerault, Y. Liu, N. Anosova, E. Ehrlich, M. R. Dana, and G. Benichou Role of CD4+ and CD8+ T Cells in Allorecognition: Lessons from Corneal Transplantation J. Immunol., August 15, 2001; 167(4): 1891 - 1899. [Abstract] [Full Text] [PDF]
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F. M. Marelli-Berg, D. Scott, I. Bartok, E. Peek, J. Dyson, and R. I. Lechler Activated Murine Endothelial Cells Have Reduced Immunogenicity for CD8+ T Cells: A Mechanism of Immunoregulation? J. Immunol., October 15, 2000; 165(8): 4182 - 4189. [Abstract] [Full Text] [PDF]
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J.-G. Chai, S. Vendetti, E. Amofah, J. Dyson, and R. Lechler CD152 Ligation by CD80 on T Cells Is Required for the Induction of Unresponsiveness by Costimulation-Deficient Antigen Presentation J. Immunol., September 15, 2000; 165(6): 3037 - 3042. [Abstract] [Full Text] [PDF]
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