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*
Institut National de la Santé et de la Recherche Médicale, Unité 345, Institut Necker, Paris, France; and
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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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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- and ß-chains, precursor T lymphocytes each express a unique
receptor (TCR) that regulates mature Ag-induced effector function.
Because of the unpredictable diversity in their binding specificity,
the differentiation and survival of precursor T cells include a test of
the recognition properties of these somatically generated receptors
against the internal antigenic environment (1, 2, 3, 4). A key
aspect of this process involves the death of developing thymocytes with
TCR whose interactions with self Ags (short peptides bound to MHC
molecules) might result in full activation of the mature T cell bearing
that TCR (5, 6). This creates an apparent paradox: how the
same set of self peptide-associated MHC molecules can deliver both
death-inducing signals that yield a repertoire depleted of potentially
harmful self-reactive T cells and positive signals ensuring survival
but not overt activation of other T cells also recognizing these
ligands (7). One hypothesis proposed to explain how this distinction between cell fates arises comes from the demonstration that full activation of mature T cells requires cosignals delivered by a variety of receptor/counter-receptor interactions, especially those involving CD28 on the T cell and CD80/86 (B7.1, B7.2) on the APC. This model postulates that thymocytes simultaneously signaled through the TCR and by this costimulatory pathway are induced to undergo apoptosis and that epithelial thymic stromal cells differ from the hemopoietic cells typically involved in activation of mature T cells in lacking expression of these key costimulatory molecules (8, 9, 10, 11, 12, 13, 14, 15). Thus, only thymocytes with TCR recognizing peptide:MHC complexes uniquely expressed on the costimulatory-deficient stromal cells (16) would survive the selection process, preventing maturation of cells recognizing self ligands on activated, costimulatory hemopoietic presenting cells in the peripheral immune system.
The experiments examining this model have involved single ligand concentrations, one stage of T cell maturation, or failed to compare thymocyte differentiation vs death in the same experiments (8, 11). Differences in these parameters among experimental models may account for the discrepant results and also obscure the real role of these interactions in thymocyte development. In addition, this proposal implies that no peptides shared between epithelial cells and hemopoietic cells can be involved in positive selection, a conclusion for which no support currently exists and that is at odds with recent data from this laboratory on the ability of dendritic cells to support late stages of positive selection in reaggregate organ cultures (17).2
To re-examine the role of cosignaling during thymocyte development in a quantitative manner, we have used an in vitro model system in which thymocytes and mature T cells can be exposed to self-peptide:MHC molecule ligands or to graded concentrations of foreign Ag:MHC molecule ligands, each in the presence or the absence of various cosignaling molecules on MHC class II-expressing transfected L cells. While it has its own limitations, this in vitro approach allows direct analysis of the response of pure populations of thymocytes at discrete developmental stages to a homogenous accessory cell population. In vivo or organ culture models cannot provide such quantitative information, enforce such a limitation of the cell types involved in signal delivery or receipt, or restrict the surface molecule display as completely. The latter is an important point, as many studies using mice, whole organs, or isolated stromal cells are confounded by the operation of redundant pathways that obscure the capacity of the deleted or blocked molecule to perform a given function, while not being absolutely required for that function.
Our results using this model system suggest a key role for ICAM-1 in allowing immature double-positive (DP)3 thymocytes interacting with cortical epithelial cells to achieve a level of intracellular signaling suitable for initiation of positive selection without activation of a death program. This window of opportunity provided by ICAM-1 is lost as the thymocytes mature. B7:CD28 interactions, in contrast, work especially efficiently with maturing thymocytes to augment signaling that can lead to cell death, helping to enforce negative selection upon TCR engagement of even a low density of high affinity/high quality ligands on hemopoietic cells in the thymic medulla. Together with prior evidence for maturation-related changes in the nature of signal generation by the TCR complex itself (18, 19, 20), the present findings of differential, developmentally controlled modification of the outcome of this TCR signaling by integrin and CD28 cosignaling pathways provide additional insight into how the decision to mature or die is made by thymocytes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The H-2b AND TCR transgenic (21) RAG-2-/- (22) mice were generated by breeding and were maintained in a National Institute of Allergy and Infectious Diseases Research Animal Facility. They were provided by Dr. B. J. Fowlkes.
Cells
DAP.3 (23) is an MHC class II-negative fibroblast
cell line derived from H-2k mice. DCEKhi7 and
P13.9 L cells are daughter cell lines of DAP.3 stably transfected with
cDNA expression constructs encoding I-Ek or
I-Ek, B7.1, and ICAM-1, respectively
(24) (Table I
). FT7.1C6 and P12 are
daughter cell lines of DAP.3 transfected with cDNA expression
constructs encoding I-Ab or
I-Ab, B7.1, and ICAM-1 respectively. EKAM1.5 is a
cell line derived from DCEKhi7 L cells by transfection with pßA-ICAM
(25), a cDNA construct encoding the costimulatory molecule
ICAM.1. EKAM2.5 L cells were obtained from the same transfection but do
not express ICAM.1 and therefore are phenotypically identical with
their parental cell line DCEKhi7 (18).
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Abs were purchased from PharMingen (San Diego, CA). For inhibition of cell surface molecule function during cell culture, purified anti-B7.1 (16-10A1), anti-B7.2 (GL1), and/or purified anti-ICAM.1 (3E2) were used. These Abs were stored in a no azide/low endotoxin buffer. For flow cytometry, the following Ab combination was used: PE-anti-CD4 (RM4-5), FITC-anti-CD8 (53-6-7), and biotinylated anti-CD69 (H1-2F3) revealed by Tricolor-streptavidin (Caltag, South San Francisco, CA). Surface staining was performed as previously described (26).
In vitro culture assay
Thymi or pooled mesenteric lymph nodes and spleens were homogenized on a nylon cell strainer (Falcon, Franklin Lakes, NJ) in complete RPMI 1640 medium with 10% heat-inactivated FCS. Thymocytes (1 x 106) or 0.5 x 106 peripheral T cells and 1 x 106 or 0.5 x 106 fibroblasts of the indicated cell line, respectively, were centrifuged and then incubated in 6-ml polypropylene, round-bottom tubes with caps (Falcon) at 37°C in an atmosphere containing 5% CO2. Where indicated, peptides were added at 5 x 10-5 µM to 50 µM. The following peptides were used for these experiments. PCC88–104 is KAERADLIYLKQATAK; P99 and Q99 peptides are synthetic peptides in which the lysine in position 99 is changed to proline or glutamine, respectively. All peptides were synthesized and purified by the National Institute of Allergy and Infectious Diseases Peptide Synthesis Facility, National Institutes of Health (Bethesda, MD). For Ab-mediated inhibition studies, fibroblasts were preincubated for 4 h at 4°C with the indicated Ab. After 18–21 h of culture, thymocyte cell death, IL-2 production by peripheral T cells, and CD69 expression on thymic DP cells or on thymic and peripheral CD4+ cells were determined.
IL-2 production
Pooled peripheral mesenteric lymph node and spleen cells were cultured with peptide and APCs overnight in 2.5 ml of complete medium. Supernatants were assayed in triplicate for the presence of IL-2 by ELISA, using jES6-1A12 mAb (PharMingen, San Diego, CA) as a capture reagent. Bound cytokine was detected with biotinylated jES6-5H4 mAb. To detect the binding of biotinylated Abs, alkaline phosphatase-conjugated avidin (Sigma, St. Louis, MO) was followed by p-nitrophenyl phosphate (Sigma). The reaction product was measured at 405 nm.
In vitro cell death assay
After overnight culture, thymocytes were harvested, and cell
death was measured as previously described (27, 28, 29). These
previous studies have shown that this method accurately assesses cell
loss resulting from T cell apoptosis. Briefly, all recovered cells were
stained for CD4, CD8, and CD69; washed; then resuspended in identical
volumes. Data were acquired for 60 s at a constant flow rate using
a FACScan equipped with CellQuest software (Becton Dickinson, Mountain
View, CA). Total viable cells were enumerated using a restricted gate
defined by forward/side scatter parameters and verified by the absence
of propidium iodide incorporation. The numbers of viable DP thymocytes
were quantified by setting a gate on the basis of CD4/CD8 fluorescence
intensity (as shown in Fig. 1A). The results were
converted to percentage of maximal cell death as explained below. No
increase in cell death was observed among peripheral
CD4+ cells during culture at any peptide
concentration.
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Because reactivity against some fibroblast cell lines was observed without adding any source of peptide, the various measured parameters were expressed as percentages of maximal response after subtraction of the response obtained with the same APCs not exposed to peptide: this protocol allowed us to measure specific reactivities against the added peptide (PCC 88–104) by subtracting the "natural" reactivity against the APCs. Because a significant percentage of DP thymocytes died during culture due to peptide exposure and because CD69 expression on DP thymocytes was routinely measured by flow cytometry only on viable cells, we have corrected for this by assuming that all DP cells induced to die by peptide exposure also expressed CD69. Specifically, the percentages of CD69+ DP thymocytes obtained by cytometry analysis were modified as follows: % of CD69 induced on DP cells = (% of viable DP cells x % of CD69 measured by cytometry) + (% of dead DP cells).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To achieve a quantitative understanding at discrete developmental stages of the contributions of Ag-specific and unspecific signaling to T cell differentiation or death, we employed an in vitro cell-cell interaction system in which cell death, the expression of relevant marker genes for differentiation, or other outcomes of TCR-dependent signaling can be measured and in which the TCR ligands and cosignaling molecules available to the thymocyte can be carefully controlled. CD69 expression, which occurs on all thymocytes undergoing Ag-induced positive as well as negative selection (26, 30, 31, 32), was analyzed as an indicator of TCR signaling for differentiation, in parallel with induction of cell death. The thymocytes were from RAG-2-/- AND TCR transgenic H-2b/b mice (21, 33), in which selection of mature CD4+ T cells bearing this TCR occurs, but which do not express the I-Ek MHC class II molecule able to present the cognate foreign Ag ligand for this TCR (pigeon cytochrome c, residues 88–104). All T-lineage cells from these mice express a single defined TCR.
Neither fibroblasts (DAP.3) lacking the I-Ek MHC
class II molecule that is involved in foreign Ag recognition by this
TCR nor I-Ek+ but ICAM-1-,
B7.1low fibroblasts (EKAM2.5) induced CD69
expression upon overnight coculture with AND thymocytes (Fig. 1
A). Strikingly, without any exogenous source of peptide, a
significant number of thymic DP and CD4+ mature
thymocytes expressed CD69 after overnight culture with
I-Ek+, ICAM-1+ (EKAM1.5) or
I-Ek+, ICAM-1+,
B7.1+ (P13.9) fibroblasts. These responses were
not due solely to interactions with ICAM-1 and/or B7.1, because
ICAM-1+, B7.1+,
I-Ab+ fibroblasts (P12) did not induce any CD69
up-regulation (data not shown). These results suggest that the
I-Ek+ fibroblasts express a ligand capable of
engaging the AND transgenic TCR, but that this TCR-ligand pair only
produces a signal able to induce a visible functional response in the
presence of ICAM-1 and/or B7.1. This ability of
I-Ek+, ICAM-1+ fibroblasts
to induce CD69 up-regulation is consistent with the capacity of
I-Ek bound to self-peptides to negatively select
many AND TCR transgenic thymocytes (34).
Interestingly, the roles of ICAM-1 and B7.1 in this CD69
response appear to be different at distinct stages of T cell
development. DP cells respond to coculture with ICAM-1-expressing
I-Ek+ fibroblasts (EKAM1.5), and this response is
not markedly affected by the coexpression of B7.1 (Fig. 1A). In contrast, B7.1 overexpression considerably increases
thymic (as well as peripheral) SP CD4+ T cell
responses, which are marginal using I-Ek+ cells
with only ICAM-1 but not B7.1 expressed at high levels. These results
help explain why various analyses that do not discriminate among the
effects of blocking these cosignaling pathways at different stages on T
cell development yield different interpretations.
Differing roles of ICAM-1 and B7.1 costimulation in DP vs mature thymocyte responses to foreign agonist ligand
ICAM-1 expression is high on both cortical epithelial cells and
dendritic cells (35), whereas CD80/86 expression is
largely confined to the latter in the thymus (36). Because
these two cell populations have been proposed to function almost
exclusively in positive and negative selection, respectively, it was
clearly of interest to examine more quantitatively ICAM-1 and B7.1
contributions to DP cell activation and death. This was done using
different fibroblast cell lines (Table I) in the presence of different
concentrations of PCC88–104, the full agonist
peptide recognized by the AND transgenic TCR. Some investigators have
claimed that low concentrations of such agonists can be effective in
positive selection (37, 38, 39), whereas others could not
obtain such agonist-driven maturation, but observed only induction of
apoptosis when using thymic organ cultures (40, 41, 42). CD4
and CD8 coreceptor down-regulation was examined (Fig. 1B).
The results obtained by measuring coreceptor loss were identical with
those obtained studying the induction of CD69 expression, in agreement
with earlier findings (26, 43, 44, 45, 46). Thus, as a measure of
TCR signaling potentially adequate for induction of differentiation, we
examined CD69 levels, whose up-regulation is known to correlate with
initiation of thymocyte selection (26, 30, 31, 32), and
compared these to the extent of induced cell death under various
stimulation conditions.
In the absence of ICAM-1 expression, all tested concentrations of
ligand induced CD69 expression on and death of the same fraction of DP
thymocytes, that is, no thymocyte was induced to differentiate without
also being signaled to die (Fig. 2A). These data are
superficially consistent with results indicating that potent agonists
cannot induce positive selection without overriding induction of
apoptotic cell death (42). Surprisingly, however, in the
presence of ICAM-1 the induction of a given amount of cell death
required the same or only slightly lower Ag concentrations, whereas the
induction of a given number of high CD69-expressing cells occurred at
significantly lower Ag concentrations, with a 5- to 10-fold
concentration window opening up within which many cells could be
induced to high CD69 expression without accompanying cell death (Fig. 2B). For example, at a concentration of 0.05 µM
PCC88–104, 20.5, 27.6, and 24.3% of DP
thymocytes were induced to die using EKAM 2.5-, EKAM 1.5-, and
P13.9-presenting cells, respectively. However, 22.3, 75.1, and 74.2%
of the remaining viable cells were induced to express CD69 under the
same condi- tions. Because reactivity to some fibroblast lines
was observed without adding any PCC peptide (Fig. 1A), the
results shown in the figure have taken account of this and also of
variations in the absolute levels of induced differentiation and death
among different experiments by expressing the data as a percentage of
the maximal response after subtraction of the values obtained with the
same APCs not exposed to peptide (Fig. 2A). Results similar
to those seen using APC with varying expression of ICAM-1 were obtained
using Ab inhibition to interfere with ICAM-1 binding to its integrin
receptor(s) (Fig. 3). Thus, ICAM-1 does
not appear to substantially protect thymocytes against death induced by
TCR signaling per se as previously concluded (11), but
instead, it seems to selectively synergize with TCR signaling for
thymocyte activation, permitting ligands in a specific concentration
range to induce biologic responses associated with positive selection
without apoptotic loss (37, 38).
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A and 3). Using
assays for death only or analysis at only one ligand concentration,
however, this effect would appear as a selective increase in cell loss,
as these previous studies have reported. It is also important to note that inhibition of B7.1 expression did not totally abrogate DP thymocyte CD69 responses or induction of death, whereas IL-2 production by peripheral CD4SP cells was reduced to nearly undetectable levels. These results suggest that B7/CD28 interaction is not required to induce immature thymocyte cell death (and therefore negative selection), and also that the signaling required for death in the thymus is not equivalent to the signaling cascade allowing IL-2 production at the peripheral level.
ICAM-1 and B7.1 show the same functionalities using variant ligands with partial agonist properties for mature AND T cells
The preceding data were obtained using a potent agonist ligand for
the TCR. Although recent data (18, 47) indicate that
variant peptides that create partial agonist or antagonist ligands for
mature T cells act as weak agonists for DP, it was of interest to
determine whether the roles of ICAM-1 and B7.1 revealed above were also
true when these less potent ligands were employed as stimuli. Fig. 4 shows that although using these weak
ligands results in a striking shift in the overall dose response to a
requirement for higher peptide concentrations for equivalent responses,
the effects of ICAM-1 and B7.1 on the relationship between CD69
induction and cell death is similar for the P99 and Q99 variant
peptides and the full agonist PCC peptide. Thus, ligands that may more
closely simulate those involved in thymic positive selection do not
reveal a different role for these counter-receptors from that seen
using a strong ligand expected to mediate negative selection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although many of these conclusions are based on analysis of CD69, CD4, and CD8 expression using an in vitro model and transfected cells for presentation, we have been able to show recently that the CD69+CD4lowCD8low thymocytes, generated either under the conditions described here with fibroblasts (unpublished observations) or using CD45-negative, nontransformed thymic stromal cells or dendritic cells (17) (see Footnote 2), show enhanced differentiation into functional CD4+ T cells in reaggregate thymic organ culture. Such findings clearly indicate that thymocytes induced in vitro under our conditions to acquire the CD69+CD4lowCD8low phenotype have initiated intracellular changes involved in positive selection, supporting the physiological relevance of the above conclusions concerning the roles of cosignals and TCR ligands in the selection process.
It is more difficult to provide such confirmatory data using either animals or organ cultures for our in vitro analysis of cell death, and questions have been raised about the validity of such in vitro models of negative selection. Thymic selection is not grossly disturbed in mice with targeted deletions in ICAM-1 (51, 52) (our unpublished observations). Only specific exons were targeted in these animals, however, and the resulting mice are thus not null (53). In addition, these animals still express alternative LFA-1 ligands such as ICAM-2. Thymic development has not been carefully studied in LFA-1 (54) or in CD43 (55) targeted mice. Functional redundancy in these pathways can complicate attempts to see the contribution of a single pathway when others are still active. Thus, the in vivo studies do not contradict our observations and might be considered less informative about what a molecule is capable of as opposed to what it is absolutely necessary for. Furthermore, our results are in agreement with the recent data reported by Dautigny et al. (56). Indeed, they found that although endogenous superantigen-driven thymic negative selection could occur at different steps during DP/SP cell transition, this event was never observed among CD69+CD4lowCD8low thymocytes, i.e., within the first subset to be generated upon TCR-mediated activation of immature DP cells. Numerous other reports have also reported that thymocytes can initiate selection and then be induced to undergo cell death at a later stage of development (57, 58, 59).
All these data suggest that strong agonist ligands can initiate thymic positive selection, and we have recently been able to directly demonstrate the generation of Ag-responsive mature T cells using TCR transgenic thymocytes and full agonist ligand to start the differentiation process (see Footnote 2). Thus, further mechanisms must exist that operate later in development to insure deletion of potentially autoreactive clones. Negative selection could result from dramatic changes in the thymic environment (a change possibly involving thymocyte migration from the thymic cortex to the thymic medulla) and/or changes in the perception of self ligands by thymocytes. We and others have recently shown that the signaling properties of TCR change during thymocyte maturation (18, 19, 20). Weak agonists for DP thymocytes lose potency during development, whereas sensitivity to strong agonists is maintained. These changes together with the lower expression of ICAM.1 on bone-marrow derived medullary stromal cells compared with epithelial cortical cells (35) are precisely those required for deletion of potentially autoreactive clones seeing potent self-ligands and for generation of a mature T cell pool possessing a wide margin of safety against activation by self ligands. This conclusion is consistent with and amplifies the findings of Page on the role of accessory molecules in thymocyte selection in fetal thymic organ culture (60), while agreeing with quantitative data on late negative selection by hemopoietic cells in the thymus (61). It also suggests that overt autoreactivity among peripheral T cells might be observed in animals with limited B7 expression on thymic presenting cells but intact cosignaling by presenting cells in lymphoid organs.
Some previous attempts to explain how mature T cells can receive an essential differentiation-promoting signal through the TCR upon self recognition without this leading to effector function, yet remain highly responsive to full activation upon recognition of a slight variant in ligand structure (foreign peptide:MHC molecule complexes), have treated the developmental process leading to this state in a largely one-dimensional way. Signaling by self-ligand recognition was presumed to occur at a specific stage of thymocyte development and to have a particular quantity or quality that defined its ability to promote differentiation vs death. Our results indicate that a one-time, one-place model for decision-making in the thymus is untenable, and that therefore a more multidimensional view is required to explain ligand-dependent thymic development and the properties of the mature T cell repertoire.
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Acknowledgments |
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Footnotes |
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2 K. Yasutomo, B. Lucas, and R. N. Germain. Submitted for publication.
3 Abbreviations used in this paper: DP, double positive; RAG, recombinase-activating gene; PCC, pigeon cytochrome c; SP, single positive.
Received for publication March 24, 2000. Accepted for publication June 5, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is required for TCR-induced T cell activation. Immunity 12:151.[Medline]
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