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on One Cell Can Present IL-2 to IL-2Rß/
c on Another Cell to Augment IL-2 Signaling
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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augments IL-2 signaling. Although this is generally
believed to occur only when the three known components of IL-2R are
associated within a single cell membrane, we demonstrate here an
intercellular interaction. Cocultivation of cells individually
expressing chimerae incorporating the extracellular domain of IL-2R
alone with cells expressing chimerae of IL-2Rß alone permitted IL-2
dose-dependent oligomerization of the chimerae. Likewise, native
IL-2R-bearing cells augmented the IL-2 proliferative response of ex
vivo large granular lymphocytic leukemia cells expressing
IL-2Rß/
c but lacking IL-2R. In both cases, the
response was inhibitable by an Ab to IL-2R. Intercellular
augmentation of cytokine effects, acting in trans, has
important implications for biology and medicine. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,
IL-2Rß, and IL-2R (or c) (1, 2, 3, 4, 5). These receptor
proteins are encoded by distinct and structurally unrelated genes
(6, 7, 8, 9, 10). The IL-2Rß chain is expressed constitutively in CD8
cytotoxic T cells but not in CD4 Th cells and is further induced upon T
cell activation (1, 4). The c is expressed
constitutively in lymphoid cells (1, 4, 11). In contrast, IL-2R is
expressed only upon activation (1, 2, 4). The IL-2Rß and
c together bind IL-2 with intermediate affinity
(10-9 M) (1, 2). IL-2Rß and c, but not
IL-2R, belong to the hematopoietin receptor superfamily of cytokine
receptors characterized by four conserved cysteines and the membrane
proximal sequence WSXWS (1, 2). Heterodimerization of the intracellular
regions of IL-2Rß and c is sufficient to effect IL-2
signal transduction (12, 13). These receptors serve as intracellular
docking sites, respectively, for Jak1 and Jak3 tyrosine kinases (14, 15), which become juxtaposed and phosphorylated upon
IL-2Rß/c receptor heterodimerization, leading
subsequently to the activation of STAT proteins 3 and 5 and ultimately
to transcriptional regulation (16, 17). IL-2R has a molecular mass
of 55 kDa and contains only 13 cytosolic amino acids (2). While there
is no evidence that the IL-2R subunit can independently generate
intracellular signals (2, 5), it appears that the formation of the
high-affinity IL-2R (10-11 M) is dependent on the
expression of IL-2R.
Here, we present the results of experiments that suggest a novel role
for IL-2R in supporting high-affinity interactions of IL-2 in
trans between cells that express one or two receptor
subunits. We observed this phenomenon initially in experiments
utilizing cells transfected with individual chimeric IL-2R molecules
and then extended the observations to studies of the proliferation of
nontransfected leukemic large granular lymphocytic
(LGL)2 cells and T
cells bearing native IL-2R components.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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YT and YTU14 were gifts of Y. Tagaya (National Cancer
Institute, National Institutes of Health (NIH), Bethesda, MD). YT1 was
a gift of W. Leonard (NIH). TF1ß was a gift of P.
Sondel (University of Wisconsin) and required IL-2 or
granulocyte-macrophage CSF for growth. CEM, HUT102, and MJ were
obtained from American Type Culture Collection (Manassas, VA). Jurkat T
Ag (Jurkat transfected with SV40 T Ag) cell line was a gift of G.
Crabtree (Stanford University, Stanford, CA). Kit225 K6 and
Kit225 IG3 are sublines of Kit225 as described (18). K6Trans is a
subline of Kit225 K6 expressing an intra-antibody to IL-2R on a
tetracycline-inhibitable promoter (19). ATAC4 was a gift of R.
Kreitman (NIH). L3 was a gift of B. Azzarone (Institut
National de la Santé et de la Recherche Médicale, Hospital
Paul Brousse, Villejuif, France). MT1 was obtained from M. Tsudo
(Kyoto-Katsura Hospital, Japan). Cells were cultured in complete medium
(RPMI 1460 with 10% FCS plus Pen-Strep and glutamine).
Plasmids and plasmid construction
Leader sequence, extracellular and transmembrane domains of
IL-2R components, and TCR
cytoplasmic domain with stop codon were
amplified by PCR (Perkin-Elmer, Norwalk, CT) using Pfu
polymerase (Stratagene, La Jolla, CA) with a Kozak consensus
sequence preceding the start site and Spe1 and
XbaI sites at 5' and 3' ends, respectively. TCR cDNA was
a gift of A. Weissman (NIH). Other cDNAs were obtained by
RT-PCR. Chimeras of each IL-2R linked to TCR were constructed by
sequential ligation in the pEFneo (gift of Y. Tagaya) expression
vector. pNF-AT-SX plasmid was a gift of G. R. Crabtree.
Oligomerization assay
Jurkat T Ag cells (107) were electroporated at 280
mV and 975 µFD (Bio-Rad GenePulser, Bio-Rad, Richmond, CA)
with 4 µg of the chimeric plasmid(s) along with a reporter plasmid
pNF-AT-SX as described (20). After 24 h, the cells were washed and
subsets of cells (
105) were plated in 96-well plates,
unmixed or mixed, and incubated at 37°C for an additional 16 h
in the presence of IL-2 (Hoffmann-LaRoche, Nutley, NJ) at
10-fold dilutions in 200 µl Xvivo10 (BioWhittaker, Walkersville,
MD) with glutamine. After stimulation, 90 µl (X2) of
heat-treated supernatants (68°C, 1 h) were assayed for secreted
alkaline phosphatase (SEAP) activity by addition of an equal volume of
1 mM 4-methylumbelliferyl phosphate (Sigma, St. Louis, MO) in 2
M diethanolamine buffer (pH 10) and incubation at 37°C for several
hours. Fluorescence was determined in duplicate with a Wallac Victor
Multilabel Counter (Wallac, Gaithersburg, MD) and/or Titertek
FloroskanII (Labsystems, Franklin, MA) at 355 nm excitation and
460 nm emission.
LGL purification
LGL expressing IL-2Rß/c, but not IL-2R, were
obtained from peripheral blood of a patient with T-LGL leukemia. LGL
were purified with lymphocyte separation medium (LSM) (ICN
Biochemicals, Costa Mesa, CA), and some LSM-purified cells were
further purified by negative selection of CD4-, CD14-, and
CD19-expressing cells using Ab-coated beads (Miltenyi Biotech,
Sunnyvale, CA) and magnetic separation (MACS). The purified LGL
expressed CD8, CD16, CD57, CD122, and C, but not CD4 or
CD25 (fluorochrome-conjugated Abs from Becton Dickinson, Cockeysville,
MD) by flow cytometry (FACSort). The mixed population of
irradiated IL-2R-bearing Kit225-IG3 and T-LGL cells showing
augmented proliferation were stained simultaneously with
fluoresceinated anti-CD57 and phycoerythrin-labeled anti-CD25
after 96 h of cocultivation.
Proliferation assay
Purified LGLs (105) were added to irradiated cell
lines Kit225 IG3 or YTU14 (1.25–2.5 x 105 cells;
1000 rad, Gammacell 1000, 137Cs source, Nordion, Ontario,
Canada) in Xvivo20 (BioWhittaker) in 96-well plates and
stimulated with various concentrations of IL-2. Anti-Tac
(anti-IL-2R) mAb was added at 10 µg/ml. Cells were pulsed with
[3H]thymidine (Amersham, Arlington Heights, IL) on
the third day of culture and harvested 16 h later (Tomtec 96-well
harvester; Wallac, Turku, Finland). ß emission was counted
(1205 Betaplate liquid scintillation counter; Wallac).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/TCR chimera on one cell
interacts intercellularly with IL-2Rß/TCR chimera on another cell
We wished to define the interactions among the three IL-2R
subunits involved in the transduction of the IL-2 signal. To this end,
DNA constructs of each of the three IL-2R subunits were generated in
which the portions of the genes encoding the extracellular and
transmembrane domains of each IL-2R subunit were linked individually to
the cytoplasmic domain of the TCR chain (20, 21, 22, 23). These transiently
transfected constructs, designated "," "ß," and
"," enabled study of the oligomerization of the subunits
alone and in combination with each other both in the presence and
absence of IL-2. To measure TCR chain oligomerization, the Jurkat T
Ag cells (Jurkat cells stably transfected with the SV40 T Ag) were
cotransfected with the pNF-AT-SX reporter plasmid, which directs
synthesis of SEAP under the control of a NF-AT-responsive promoter
element (20). SEAP was quantitated by its ability to convert a
fluorescent substrate. Using this system, the oligomerization response
of TCR-signaling chimeras was comparable to that seen with
anti-CD3 Ab cross-linking in the Jurkat T Ag cell line. Flow
cytometric (FACS) analysis confirmed the cell surface expression of
transfected and ß chimeras (data not shown), while
expression was not detectable by FACS but was inferred as noted below.
As shown in Fig. 1
, ß, when
transiently transfected either alone or together with , gave no
oligomerization response even in the presence of IL-2, suggesting that
the interaction of ß and involves dimerization only. Using
an identical signaling and reporter system, Spencer et al. showed that
dimerization of the cytoplasmic domain was not sufficient for the
generation of reporter SEAP; rather oligomerization was required (20).
The construct alone also showed no alteration of its
oligomerization signal following IL-2 addition, although its baseline
signal is greater than that observed with the other two subunits. We
believe that this higher baseline represents spontaneous
cytokine-independent IL-2R oligomerization. When the and
ß (±) constructs were transfected into the same group of
cells, this spontaneous IL-2-independent IL-2R oligomerization was
reduced; however, IL-2 dose-dependent oligomerization was observed
(Fig. 1).
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alone and ß (±)-expressing cell
populations that individually showed no IL-2 response were cocultured,
IL-2 dose-dependent oligomerization was also observed, suggesting an
intercellular interaction of IL-2-bridged receptor subunits in
trans between and ß (±) receptor
components that were expressed on different cells. The addition of IL-2
at picomolar levels led to an oligomerization response of
transfectant cells cocultured with ß plus cotransfected
cells. A 10-fold higher dose was necessary for oligomerization in the
absence of , suggesting the presence of transfected in the
high-affinity interaction (Fig. 1
). The lower oligomerization response
of the receptors in cis rather than the situation where they
are expressed on separate cells appears to be due to a dampening effect
of ß on spontaneous oligomerization when both are expressed
in the same cell.
The IL-2 induced oligomerization response, both occurring when
and ß were cotransfected in a single cell population and when
and ß were individually transfected into different cell
populations and then mixed, was largely inhibited by the addition of
the anti-Tac Ab that blocks the binding of IL-2 to IL-2R (Fig. 2). The monomeric anti-Tac Fab
promoted greater inhibition. The intact Ab, while blocking the binding
of IL-2 to IL-2R, may also promote weak oligomerization of the
IL-2R construct by virtue of its dimeric structure. While the
anti-Tac Ab blocks IL-2-induced hetero-oligomerization of
and ß, it does not inhibit the spontaneous homoassociation of
subunits, an association which does not involve the interaction
of IL-2 with its receptor. A murine isotype control Ab, UPC10, did not
block the oligomerization response (not shown).
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and ß transfectants
contributed to the intercellular oligomerization signal. The total
amplitude and dose-related difference in amplitude of signal indicate
that both and ß contribute to the response and that their
responses to IL-2 over their respective baseline values are similar
(Fig. 3). The ß chimera-bearing
cells also exhibited IL-2 dose-dependent oligomerization associated
with intercellular interaction when mixed with Jurkat T Ag cells
transfected with a wild-type IL-2R construct (Fig. 4). The chimera also interacted
intercellularly with expressed wild-type IL-2Rß construct (not
shown).
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and IL-2Rß chimera interact
intercellularly with their naturally expressed counter-receptors on
human cells
In the presence of IL-2, an intercellular signal was also observed
when the ß-transfected cells were cocultured with
IL-2R-expressing cell lines such as Kit225 K6 (Figs. 4 and 5B), ATAC4, L3, MT1, HUT-102,
MJ, and Kit225 IG3 (Table I), but not
when cells were cocultured with these cell lines. In a parallel
observation, the chimera exhibited IL-2 dose-dependent
oligomerization when this transfectant was mixed with cell lines such
as YT, YT1, YTU14, and TF1ß, which express IL-2Rß and
c but little or no IL-2R (Table II), while the ß chimera exhibited
no response to coculture with these cell lines in the presence of IL-2.
In control studies, the transfected or ß expressing cells
did not respond by oligomerization following IL-2 addition when
cocultured with cell lines such as CEM and Jurkat T Ag, which do not
express IL-2R or IL-2Rß (Table II).
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in the intercellular interaction was
also confirmed in experiments that utilized a subline of the T cell
leukemia cell line Kit225 K6 (K6Trans) that contained an intra-antibody
to IL-2R. When this anti-IL-2R Ab was activated, it reduced
the expression of native IL-2R (19). Using this system, the
IL-2-induced oligomerization signal of comixed Jurkat T Ag cells
expressing ß was present when IL-2R was expressed on K6Trans
(Fig. 6A), but not when
IL-2R expression was inhibited following expression of the
intra-antibody (Fig. 6B). (In K6Trans cells, the expression
of IL-2R was confirmed by FACS; data not shown.)
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bridged
by IL-2 to chimeric IL-2Rß, or from the chimeric to the native
receptors, expressed on different cells was observed.
An irradiated T cell line bearing IL-2R amplifies the IL-2
proliferative signal of IL-2Rß/c-bearing leukemic LGL
cells
In the studies described above, at least one of the
receptor-paired cells examined expressed a chimeric receptor and
reporter construct. We have extended these observations to naturally
occurring cells expressing IL-2R subunits to determine whether cellular
transactivation by IL-2 can occur under more physiologic conditions. A
critical cellular element of these studies was an ex vivo leukemic T
cell-type LGL cell population (24) that expresses native IL-2Rß and
c but not IL-2R. These T-LGL leukemic cells responded
to intermediate doses of IL-2 by proliferation. In accord with the
bridging action of IL-2 described above, the leukemic cells responded
to previously substimulatory concentrations of IL-2 when cocultured
with irradiated nonproliferating Kit225 IG3 cells that expressed large
amounts of IL-2R (Fig. 7). This
amplification of IL-2 responsiveness at subnanomolar concentrations of
IL-2 by the IL-2R negative, IL-2Rß/c expressing
leukemic cells when cocultured with irradiated Kit225 cells was largely
abolished by the addition of an anti-IL-2R Ab, anti-Tac,
which blocks IL-2 binding to IL-2R. Although most of the experiments
were performed with LGLs that were approximately 90% pure (i.e., CD8
expressing) after Ficoll separation, the same results were obtained
using Ficoll-purified LGLs further depleted of CD4-, CD14-, and
CD19-expressing cells by MACS separation with magnetic beads bearing
these Abs to yield a purity of 97%.
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expression was not induced on the IL-2Rß/c
expressing T-LGL leukemic cells when they were cultured with IL-2 alone
or when cocultured with both IL-2 and irradiated Kit225 cells. In
particular, following this coculture the CD57-expressing T-LGL leukemic
cells did not express IL-2R (Fig. 8).
In another control study, no augmentation of IL-2-induced proliferation
was observed when we substituted irradiated IL-2R-nonexpressing
YTU14 cells for the IL-2R-expressing Kit225 IG3 cells (Fig. 9). In additional studies, we
demonstrated that this IL-2-mediated proliferative effect required
cell-to-cell contact and was not the result of the production of a
soluble mediator by the Kit225 cells (Fig. 10). In this experiment, the two cell
populations (T-LGL and Kit225 IG3) were separated by a membrane (Costar
Transwell, Cambridge, MA) of 0.4-µm pore size. No augmented
proliferation following IL-2 addition was observed in the wells in
which a membrane separated the two cell populations.
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chain on irradiated Kit225 interacts with
IL-2 molecules that in turn bind to IL-2Rß/c chains on
the cocultured T-LGL. This interaction leads to the oligomerization of
the latter cells’ IL-2Rß/c-receptor subunits, which
in turn is associated with augmented proliferation. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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on
one cell with IL-2Rß/c expressed on another cell.
Furthermore, IL-2R on one cell appears to present the IL-2 molecule
to IL-2R-/IL-2Rß+
/c+ receptor-bearing cells in an interaction
that yields a high-affinity IL-2 response and thus an amplification of
the proliferative signal of IL-2. This phenomenon may have important in
vivo physiologic relevance in terms of dissemination of a program of T
cell activation in which Ag-activated T cells augment the proliferation
and differentiation of bystander cytotoxic T cells as well as NK cells
that constitutively express IL-2Rß/c but not IL-2R.
Resting granulocytes (25, 26, 27, 28) and monocytes (29, 30) also bear
IL-2Rß/c but not IL-2R, which raises the
possibility that activated IL-2R-bearing cells might amplify a
program of adherence, cytokine production, or receptor up-regulation in
phagocytes at low concentrations of IL-2 that would not otherwise
produce such effects. This amplification mechanism may also be involved
in the vascular leak syndrome associated with IL-2 administration and
neutrophil adhesion (31). In addition, such interactions of activated T
cells or other IL-2R-bearing cells, whether normal or malignant,
might mediate effects specific to the IL-2R system in diverse cells
(32, 33) by this mechanism relatively unconstrained by HLA or TCR
recognition. Thus, intercellular activation in the IL-2 cytokine system
might have far-reaching implications in cancer and autoimmune disease.
The present observations with IL-2 and its receptor may be relevant to
other heterodimeric or heterotrimeric cytokine systems. For example,
IL-15R is known to form a high-affinity signaling complex with
IL-2Rß/c (34, 35, 36). Thus, it is conceivable that
IL-15R may similarly present IL-15 in an intercellular fashion to
the IL-2Rß/c receptor expressed on neighboring cells.
These observations may prompt a search for more ""-type
components of cytokine receptor systems that serve critical
amplification and bridging functions in addition to or in lieu of
intracellular receptor-signaling functions.
In our chimeric system, the quality of the interaction between IL-2R
and IL-2Rß extracellular domains is notably different in one respect
when the single cell, cotransfectant model is compared with the
intercellular model. That difference relates to the fact that
spontaneous IL-2-independent oligomerization is noted as a high
baseline signal when ß is present on a neighboring cell, but is
interfered with when ß is present on the same cell. We have also
found that spontaneous oligomerization of appears to require the
juxtamembrane region of the IL-2R molecule (D.M.E. and T.A.W.,
unpublished observations), while it is known that IL-2 binds close to
the N-terminus of IL-2R (37). These findings support the idea that
the presumed antiparallel orientation of IL-2R to IL-2Rß in the
intercellular interaction prevents interference by IL-2Rß with the
spontaneous oligomerization of IL-2R as occurs in the parallel
orientation. Perhaps juxtamembrane motifs of receptors and their
associated molecules may control whether such receptors will act
intercellularly or merely contiguously within a single membrane.
Receptor aggregation is a common theme in immune system function.
The primary example of receptor clustering is the TCR (38), but the
phenomenon of aggregation-mediated cell activation probably encompasses
many other important immune system proteins (39) such as that observed
with CD4 and CD8 with their MHC class II and I counterparts,
respectively; CD28 or CTLA-4 with the B7.1 and B7.2 (CD80, CD86)
family, as well as CD40, Fas (40), CD30, and their ligands. These
receptor-counter-receptor pairs are examples of molecules transmitting
information from one cell to another. In the case of the TCR and MHC, a
third molecule, peptide Ag, participates in the interaction and
determines specificity. We suggest here that the IL-2R complex also
sends signals by clustering. The analogy with the TCR is even more
striking in that we have shown that IL-2R on one cell can present
IL-2 in trans to IL-2Rß/c expressed on
another cell to augment IL-2 signaling. In the case of IL-2R, the IL-2
molecule itself acts as a peptide linking the two cells by its
receptors, thereby determining the specificity of the interaction
between activated cells expressing oligomerized IL-2R and other
often quiescent cells (T lymphocytes, NK cells, granulocytes, and
monocytes) expressing IL-2Rß/c.
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Footnotes |
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2 Abbreviations used in this paper: LGL, large granular lymphocytic; NF-AT, NF of activated T cells; SEAP, secreted alkaline phosphatase.
Received for publication March 13, 1998. Accepted for publication July 9, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß chain cDNAs. Science 244:551. chain of the human IL-2 receptor. Science 257:379. chain expression on resting and activated lymphoid cells. J. Exp. Med. 180:241. chains mediate the signal for T-cell proliferation. Nature 369:333.[Medline]
-chain cytoplasmic domains is required for signalling. Nature 369:330.[Medline]
chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu. Rev. Immunol. 14:179.[Medline]
subunit alters the function of the IL-2Rß subunit to enhance IL-2 binding and signaling by mechanisms that do not require binding of IL-2 to IL-2R subunit. Proc. Natl. Acad. Sci. USA 89:2165. subunit of the
receptor. Proc. Natl. Acad. Sci. USA 92, 3137.
chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 64:891.[Medline]
family proteins. Proc. Natl. Acad. Sci. USA 88:8905. chain. Cell 68:889.[Medline]
production from human neutrophils by IL-2 via IL-2-Rß. J. Immunol. 150:1979.[Abstract]
chain on human neutrophils. Blood 84:3870.c chain of the interleukin 2 receptor. Proc. Natl. Acad. Sci. USA 92:8353. chain of the IL-2 receptor. EMBO J. 14:3654.[Medline]
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