Immunology and Cell Biology (2002) 80, 351357

Research Article

Possible mechanism for the alpha subunit of the interleukin-2 receptor

(CD25) to influence interleukin-2 receptor signal transduction
JONATHAN M ELLERY and PETER J NICHOLLS
Department of Biosciences, University of Kent at Canterbury, Canterbury, UK
Summary The receptors for interleukin 2 (IL-2) and interleukin 15 (IL-15) in T cells share the IL-2R subunit
(CD122) and C subunit but have private subunits. Despite utilizing the same receptor chains known to be
necessary and sufficient to transduce IL-2 signals the two cytokines manifest different cellular effects. It is
commonly held that the subunit of the IL-2R (CD25) is involved solely in the generation of a high affinity receptor
complex. This is questioned by the development of autoimmune diseases in instances where the expression of CD25
is absent. The timely expression of CD25 in the thymus has been linked with clonal deletion. Evidence from
peripheral T cells indicates that survival signals arising from the intermediate affinity IL-2R (lacking CD25) do not
require the activation of Janus kinase 3 (Jak3) but do require the presence of the membrane proximal region of the
C chain. This particular signalling pathway is not observed in the high affinity receptor complex where Jak3 is
activated. Recent data point to CD25 having a surface distribution consistent with it being localized within
membrane microdomains. Here we suggest that in the absence of CD25 expression, IL-2R activation occurs within
the soluble membrane fraction. This membrane environment and the absence of CD25 promotes Jak3 independent
signal transduction and induction of antiapoptotic mechanisms. T cell antigen receptor (TCR) signalling leads to the
induction of CD25 expression, which localizes to membrane microdomains. There is a dynamic pre-association of
CD25 and CD122 leading to the loose association of the heterodimer with membrane microdomains. High affinity
IL-2R signalling in the context of CD25 and the microdomain environment is characterized by Jak3 activation. The
relative levels of high to intermediate affinity receptor signalling determines whether a cell proliferates or undergoes
activation induced cell death dependent upon cell status.
Key words: CD25, interleukin-2, microdomain, signal transduction.

Introduction

Signalling through the intermediate affinity IL-2R

Interleukin-2 (IL-2) and interleukin-15 (IL-15) are cytokines

involved in the development and survival of T, B and natural
killer (NK) cells and, in the generation of immune responses.
The receptors consist of a private alpha subunit and the shared
beta (CD122) and common gamma (C) subunits of the IL-2
receptor (IL-2R).1 Heterodimerization of the cytoplasmic
domains of CD122 and the C subunit are sufficient and
necessary for signal transduction2 and IL-2 and IL-15 activate
similar signalling molecules.3 This explains why IL-15 and
IL-2 share some physiological effects, but does not explain
the different roles that these two cytokines play in the
generation of immune cells and their peripheral responses to
antigens.4 Currently CD25 is thought to act solely to generate
the high affinity IL-2R consisting of the CD25/CD122/C
subunit heterotrimer, but lack of CD25 expression leads to a
decrease in peripheral T cells and the occurrence of autoreactive clones.5,6 Lack of expression of the alpha subunit of
the IL-15 receptor (IL-15R) in mice, prevents the development of CD8+ or NK cells.7

Nave T cells do not express CD25 and consequently only

express the intermediate affinity IL-2R consisting of CD122
and the C subunit. Stimulation of these T cells with IL-2
leads to the induction of a Janus kinase (Jak3) independent
signalling cascade through the lymphocyte specific tyrosine
kinase, p56l ck (lck), to phosphatidylinositol-3 kinase (PI3-K)
and hence to the induction of antiapoptotic mechanisms. 8 This
signalling cascade was shown to be dependent upon the
presence of the membrane proximal domain (PROX) of the C
subunit9 and a possible mechanism for this has been proposed
previously.10 The expression of a carboxyl terminal truncated
C subunit, retaining the PROX domain, in a C subunit null
mouse background restores T cell development through the
expression of bcl-2 but the functions of the mature T cells
were abnormal.11 This would indicate that the C subunit is
essential for T cell development primarily because of its Jak3
independent antiapoptotic signalling cascade.

Correspondence: Dr PJ Nicholls, Department of Biosciences,

University of Kent at Canterbury, Canterbury CT2 7NJ, UK.
Email: p.j.nicholls@ukc.ac.uk
Received 17 December 2001; accepted 21 March 2002.

Ligation of the T cell antigen receptor leads to the

induction of CD25 expression
Engagement of antigen by T cell antigen receptor (TCR) in
the context of major histocompatability complexes presented
on a cell surface leads to the formation of a TCR signalling
synapse involving the clustering of cholesterol-rich microdomains in the plasma membrane.12,13 The quaternary complex

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JM Ellery and PJ Nicholls

Figure 1 The induction of

CD25 expression upon ligation of
the TCR leads to an association of
CD122 molecules with CD25.
The heterodimer becomes localized to microdomains within the
plasma membrane. , plasma
membrane; , CD 25; , microdomain.

formed promotes tyrosine phosphorylation and excludes the

tyrosine phosphatase CD45. Membrane microdomains are
important in preventing inappropriate protein interactions in
resting T cells but promote these interactions when the cells
are activated.14 One of the consequences of TCR signalling is
the induction of CD25,15 IL-15R16 and the up-regulation of
Jak3 expression.

CD25 associates with CD122 altering its cell surface

distribution
It has recently been shown that CD25 colocalizes with HLA
class I and II molecules and with CD48 in a cholesteroldependent manner17 as well as being isolated in detergentresistant membranes.18 These results indicate that when CD25
is expressed, it localizes to microdomains within the plasma
membrane. Structural analysis of the IL-2R complex in cell
lines and using surface plasmon resonance techniques provide
experimental support for the pre association of CD25 and
CD122 as a heterodimer prior to IL-2 binding. 19,20 The interaction of the cytoplasmic domain of CD122 with that of
CD25 leads to an extracellular conformational change, giving
rise to the increased affinity of the heterodimer for IL-2. 21
This raises the possibility that the surface expression pattern
of CD122 is altered when it is a component of the preformed
CD25/CD122 heterodimer (Fig. 1). Fluorescence resonance
energy transfer (FRET) analysis of the proximities of CD25,
CD122 and the C subunit in Kit225 K6 T lymphoma cells,
supports the notion that all three subunits are already loosely
associated and that the addition of IL-2 brings the subunits
together.22 It must be emphasized that the loose association of
the high affinity receptor subunits must be a dynamic one
because of the different fates of the subunits upon endocytosis

due to natural turnover or in response to IL-2 ligation. CD25

is recycled to the plasma membrane whilst CD122 and the C
subunit are predominantly degraded. 23,24 The result is an
excess of CD25 molecules, which will promote the loose
association of CD122 with microdomains. Excess CD25
would also favour the formation and signalling through high
affinity receptors at the expense of signalling through intermediate affinity receptors. The change in membrane localization as well as the change in orientation of the cytoplasmic
domains25 is likely to have profound effects upon receptor
signalling. To date there are no data upon the surface distribution of IL-15R in T cells, but we would predict that it will
not be found to localize to microdomains.

Signalling through the high affinity IL-2R

Signalling through the high affinity IL-2R is associated with
T cell proliferation and up-regulation of cytotoxic cellular
processes. This occurs through a Jak3-dependent mechanism
leading to the activation of a number of different signal
transducers and activators of transcription (STAT) molecules.
The ability of IL-2 to mediate such effects is critically
dependent upon the expression and activation of STAT molecules. Lack of STAT3 or STAT5a expression inhibits the
expression of CD25 in response to either TCR or IL-2
signalling, leading to a failure of IL-2-driven T cell proliferation.26,27 Such observations demonstrate that CD25 plays a
more fundamental role in IL-2R signalling than just the
generation of a high affinity receptor form. It has also been
shown that the immobilization of microdomains by antibodies
against molecules such as Thy1 and CD48 prevents high
affinity IL-2R formation, a reduction in Jak1/3 activation
states and the prevention of T cell proliferation. 28 Janus

CD25 and interleukin-2 signal transduction

kinase1 and Jak3 were found to be still associated with

CD122 and the C subunit, respectively, but their activation
was reduced.
The strength of antigen signalling will have a direct effect
upon the level of CD25 induction. As the level of induction
increases, more of the population of CD122 molecules will
become associated with the nascent CD25 and become associated with microdomains. The consequent effect is a depletion of the number of CD122 present in the soluble fraction of
the plasma membrane and thus a reduction in the levels of
intermediate affinity IL-2Rs. Matk et al. have shown that
high affinity IL-2Rs localize to microdomains and their
disruption by cholesterol depletion impaired STAT activation.29 This at first appears to be at odds with the findings of
Mina and Julius who used Brij58 to isolate the detergentresistant microdomains.30 In both cases CD25 was found to
localize to microdomains. The differences in opinion with
regards the localization of CD122 and the c subunit are a
reflection upon the loose peripheral association that these
molecules have with the detergent-resistant membrane fraction. Different techniques will lead to either a disruption or
strengthening of the association. In the scenario that we
present here, just as intermediate affinity IL-2Rs are incapable of Jak3-dependent signal transduction, high affinity IL2Rs are not capable of generating Jak3-independent antiapoptotic signals. This is not an unrealistic situation, as there
appears to be a clear delineation between signalling molecules that are activated by Jak3 or by lck.31 For T cells to
survive, a threshold level of intermediate affinity IL-2Rs need
to be maintained. Below this threshold, cells become susceptible to activation-induced cell death (AICD) in the absence of
other costimulatory survival signals. Here then is a mechanism which can be used to explain how a T cell will react to a
given antigen.
A very high affinity/avidity interaction with a target cell
will lead to aggregation of microdomains and sequestering of
CD25. The T cell does not proliferate but also does not
undergo apoptosis because CD122 and the C subunit can still
form a functional intermediate IL-2R. This makes sense
because a T cell that interacts too strongly with its target will
not be an efficient agent of the immune system because it
will not be able to repeatedly disengage and re-engage
antigen-bearing cells. T cells demonstrating no interaction
will retain intermediate affinity IL-2Rs and remain viable but
will not proliferate. The remaining T cells which interact with
the target antigen will do so with a spectrum of affinity and
avidity. TCR induction of CD25 will promote the formation
of high affinity IL-2Rs provided that microdomains are not
immobilized within the plasma membrane. The level to which
this occurs will determine the relative levels of high and
intermediate affinity IL-2Rs and thus the amount of proliferative and survival signal generated within a T cell clone. Too
strong an interaction will lead to CD25 sequestering CD122
and the C subunit into high affinity IL-2Rs because the
microdomains remain mobile and also because of a corresponding lack of intermediate affinity IL-2Rs. Thus one of the
first decisions that influences whether a T cell will either
become anergic or proliferative or undergo apopotosis, i.e.
ACID, in response to TCR engagement can be dependent
upon the level of CD25 induction and the extent to which
microdomains aggregate (Fig. 2). Signalling through high

353

affinity IL-2Rs also causes an increase in FasL expression

and a decrease in C subunit expression with a subsequent
knock-on effect upon bcl-2 induction.32 Cells can be rescued
from AICD by other cytokines, which are still able to supply
these signals, such as IL-15.33 It is clear that as T cells downregulate IL-2R expression34 other costimulatory pathways
become more important for long-term activated T cell function.

The role of Jak3 in T cell development

A number of researchers have shown that in mouse knockout
models of Jak3, the phenotype is the same as that for C
subunit knockouts. It is difficult to determine the exact
mechanism that is at work here because of the large number
of cytokines utilizing the C subunit and Jak3 for signal
transduction. The phenotype is essentially manifested as a
severe reduction in mature T cell populations and an inability
to delete auto-reactive clones in the thymus and peripheral
tissues.35 The reduction in lymphoid cells is attributed to the
apoptosis of thymocytes by elevated levels of Bax and
reduced levels of Bcl2 in Jak3-deficient T cells. These cells
can in part be rescued by transduction with a Bcl2 expressing
retrovirus.36 Interleukin-7 is a cytokine that utilizes the C
subunit as a component of its receptor and is known to be
important for T cell development. Mouse models lacking
either IL-7, IL-7R or Jak3 display a near absence of thymic
progenitor cells.37,38 The finding that Jak3 provides survival
signals has been taken as evidence to support the proposal
that Jak3-independent survival signals are not relevant. Interestingly Jak3 null mice did not generate CD25+ CD4+ T
cells.39 The vastly reduced number of thymic progenitor cells
would point to the requirement of Jak3-dependent cytokine
signalling before any effect that CD25 may have in clonal
deletion. Thus Jak3 survival signals may be generated
through cytokine receptors that utilize the c subunit other
than IL-2 at specific times during the developmental process.
In turn the role that CD25 plays will be but one aspect of the
entire process and will be relevant in a particular cell context.

Differences between the biological effects of IL-2 and IL-15

explained
The finding in IL-15 transgenic mice that IL-2-induced AICD
is inhibited highlights the differences in signal transduction
between these two cytokines.32 There are clearly differences
in the way that the high affinity receptors bind their cytokine
ligands. Data indicate that CD25 pre-associates with CD122
and together they capture IL-2 simultaneously before recruiting the C subunit. Interleukin-15R has a very high affinity
for IL-15 independent of CD122. Once IL-15 has been bound
the complex then recruits CD122 and IL-2RC. The binding of
IL-15 by CD122 and the C subunit is different and cannot be
inhibited by IL-2.40 There are also differences in the interaction of the alpha subunits with CD122 and the C subnuit.41
We postulate that the differences in the interaction of the
alpha subunits provide the basis for the alternate signalling
pathways observed. CD25 appears to be essential for Jak3dependent IL-2 signalling but we predict that this is at the
expense of Jak3-independent antiapoptotic signalling. The
high affinity IL-15R on the other hand, generates both types
of signalling cascade. The role that microdomains play is an

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JM Ellery and PJ Nicholls

Figure 2 The role of microdomains in IL-2R signalling. The number of high affinity IL-2Rs formed influence the strength of IL-2 Janus
kinase 3 (Jak3)-dependent signal transduction leading to cellular proliferation. If the consequent reduction in the number of intermediate
affinity IL-2Rs falls below a threshold there will be insufficient Jak3-independent antiapoptotic signal transduction. Over-expression of
CD25 may lead to a critical lack of intermediate affinity receptors exposing the cell to possible activation-induced cell death (AICD).
Sequestering of CD25 by microdomain immobilization will prevent the formation of high affinity IL-2R and a subsequent reduction in
Jak3-dependent cell proliferation.
, CD 122; , plasma membrane; , CD 25; , microdomain.

added dimension in the control of IL-2R signalling and we

predict that such an association is not required for IL-15R
function. The different cellular effects of IL-2 and IL-15 can
be explained by the interaction of their alpha receptor subunits and the localization of CD25 in microdomains.
Interleukin-15R can bind tumour necrosis factor receptorassociated factor 2 (TRAF2) and possibly protect against
certain receptor-mediated apoptotic pathways. Through TRAF2,
IL-15 is able to activate the transcription factor NF-B42

although the consequences of this are not fully understood.

Crucially, because the high affinity IL-15R resides outside of
microdomains it maintains Jak3-independent antiapoptotic
signalling. The stability of the receptor complex and its
orientation are such that Jak1 and Jak3 also become activated
and lead to proliferative signal transduction (Fig. 3). Thus
high-affinity IL-15 signalling provides both proliferative and
protective signals unlike CD25-associated IL-2 signalling
which can be involved in the negative regulation of cell

CD25 and interleukin-2 signal transduction

355

Figure 3 Interleukin-15 signalling occurs outside of microdomains. The ability of IL-15R to bind tumour necrosis factor receptorassociated factor 2 (TRAF2) coupled with activation of Janus kinase 3 (Jak3)-independent antiapoptotic signalling protects against
activation induced cell death (AICD). The orientation of the receptor complex and its stability allows Jak1/Jak3 activation to promote
cell proliferation. , IL-15R; , CD122, , IL-2Rc.

expansion.43 In fact the expression of CD25 appears to be

critical for clonal deletion and avoidance of autoimmune
diseases44 both in the thymus and periphery.45 The pivitol role
that CD25 plays in clonal deletion within the thymus was
confirmed by blockade. T cell antigen receptor stimulation of
thymocytes led to the expression of CD25 and IL-2. The
subsequent AICD in some thymocytes could be prevented by
antibody blockade of CD25.46 In our proposed scenario those
thymocytes that could be rescued still retained intermediate
affinity IL-2Rs. These could provide antiapoptotic signals
when the high affinity receptors were blocked. For example,
over-expression of bcl-2 in transgenic mice can prevent clonal
deletion.47 This is a clear indication that CD25 is involved in
the prevention of antiapoptotic signalling through the IL-2R
and we believe that this is mediated through a change in
receptor compartmentalization and subunit orientation within
the receptor complex.

Conclusion
Although the receptors for IL-2 and IL-15 share CD122 and
the C subunit they have different cellular effects and contrasting roles within the body. In this paper we have put forward a
mechanism to explain how the private alpha subunits of the
receptors mediate these differences. The intermediate affinity

form of the IL-2R (lacking CD25) is located primarily in the

soluble subcompartment of the plasma membrane. Signalling
through this receptor form under normal conditions is mediated by a Jak3-independent mechanism and is antiapoptotic.
Expression of CD25, in response to TCR engagement, leads
to preferential association with CD122 and subsequently
leads to CD122 being loosely associated with microdomains.
The level of CD25 induction determines the proportion of
CD122 that becomes associated with microdomains. In the
context of CD25 and the microdomain environment, the
predominant signalling cascade from the high affinity IL-2R
is Jak3 dependent. Just as the presence of CD25 in the
receptor complex alters the binding of IL-2 by CD122 it is
likely to alter the orientation of the cytoplasmic domain of
CD122 as well. It is this interaction we believe that effectively leads to the loss of the protective Jak3-independent
signalling. Cell proliferation and survival are dependent upon
the relative levels of signalling through high and intermediate
affinity IL-2Rs. A depletion of intermediate affinity IL-2R
will lead to susceptibility to AICD due to a lack of survival
signals. The high affinity IL-15R does not localize to the microdomain. Interleukin-15R binds IL-15 with high affinity and
then binds CD122 and the C subunit in a manner which
prevents IL-2 binding. The resultant signalling comprises
both proliferative and protective elements. Thus the private

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JM Ellery and PJ Nicholls

alpha chains play a pivitol role in controlling the response of

a cell to IL-2 and IL-15. The compartmentalization of CD25
provides an additional level of regulation to IL-2, in response
to the type of stimuli the T cell has encountered.

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