Revisiting the role of IL-2 in autoimmunity
Hans Dooms and Abul K. Abbas
Department of Pathology, University of California, San Francisco, CA, USA
IL-2 was discovered as a T-cell growth factor that promoted T-cell-dependent immune
responses; however, more recent studies suggest that the essential role of IL-2 is to
maintain functional Treg and thus control immune responses. These results are leading to
new ideas about the potential of IL-2 as a therapeutic strategy in autoimmune diseases. In
this issue of the European Journal of Immunology, a study further examines the role of IL-2
in immune regulation and shows for the first time that IL-2 complexes can ameliorate
autoantibody-mediated autoimmunity. This commentary examines the current findings
in relation to what we already know about IL-2 complexes.
Key words: Autoimmunity.IL-2.Myasthenia gravis.Treg
See accompanying article by Liu et al.
IL-2 was initially discovered due to its activity in vitro as a growth
factor for T cells , and was first used as a therapeutic approach
in humans to boost immune responses in patients with
disseminated cancer  and advanced HIV disease . These
therapeutic attempts, however, have had limited success. The
generation of mice deficient in IL-2 or components of the IL-2
receptor [4–6] challenged the notion that promoting T-cell
expansion and differentiation into effector cells is the main
function of IL-2 in the immune system. The observation that mice
lacking IL-2 or the IL-2R developed lymphoproliferation and
autoimmune disease suggested a growth-limiting, rather than a
growth-inducing, function of IL-2. Initial attempts to understand
the mechanism underlying the inhibitory role of IL-2 in T-cell
responses led to the observation that IL-2 sensitized activated
T cells for activation-induced cell death . These experiments
were mostly done with in vitro T-cell cultures and evidence that
IL-2-dependent activation-induced cell death indeed suppresses
in vivo T-cell responses remains limited. The finding that normal
lymphocytes could correct the autoimmune disease of mice
deficient in IL-2 signaling [8, 9] suggested that the major action
of IL-2 is not cell intrinsic. The renewed appreciation for the
existence of suppressor or Treg in the mid–90s  led to a new
hypothesis to explain the regulatory function of IL-2. Multiple
lines of evidence support the idea that IL-2 is essential for Treg
survival and/or function: (i) treatment of mice with a blocking
anti-IL-2 antibody depletes Treg and induces autoimmune
disease ; (ii) IL-2-deficient mice show impaired Treg home-
ostasis leading to autoimmunity [12, 13]; and (iii) Treg are the
first cell population responding to IL-2 produced during immune
A complementary approach to gene deletion for studying the
role of IL-2 in vivo is to administer the recombinant cytokine and
examine which cell populations show enhanced functional respon-
ses. This experimental approach, however, has been hampered by
the short in vivo half-life of exogenously delivered cytokines. A
recent study demonstrated that immune complexes consisting of
IL-2 and anti-IL-2 antibodies could significantly potentiate the in
vivo activity of the cytokine perhaps by reducing its clearance .
One particular IL-2-specific antibody (clone JES2A12), complexed
with IL-2, acted specifically on Treg and induced Treg proliferation
in vivo. This technique has now been applied by several investigators
to show that IL-2 administration can prevent type 1 diabetes ,
improve the severity of EAE, and reduce graft rejection by boosting
Treg numbers . In this issue of the European Journal of Immu-
nology, Liu et al.  add to these studies by demonstrating for the
first time that expanding Treg with IL-2 complexes can ameliorate
Correspondence: Professor Abul K. Abbas
& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI 10.1002/eji.201040617Eur. J. Immunol. 2010. 40: 1538–1540 Hans Dooms and Abul K. Abbas
an autoantibody-dependent disease (in this case, myasthenia
gravis). In accordance with the two previous reports [16, 17], IL-2
treatment is more potent in preventing the disease than in reversing
established disease. Using thymectomized mice, the authors show
that IL-2 complexes work by inducing and expanding peripheral
Treg rather than promoting thymic Treg generation, thus confirm-
ing the experiments done by Webster et al. . The most unex-
pected result in the article, however, is that IL-2 treatment does not
decrease disease severity by reducing the levels of autoantibody
formation but by skewing the isotypes generated after immuniza-
tion with acetyl choline receptor (AChR) from IgG2b and IgG3 to
IgG1. This switch from a Th1- to a Th2-dominant response is likely
responsible for the preventive and therapeutic activity of IL-2.
Although the study does not prove that the IL-2-expanded Treg are
responsible for the Th1 to Th2 shift, such an activity of Treg has not
been described and, if causally related, would provide a novel
mechanism by which IL-2 acts as a therapy for autoimmune disease.
It is also feasible that IL-2 acts on the effector cells themselves,
promoting the differentiation of Th2 cells over Th1 cells. In this
respect, this study highlights once more the problem of separating
the distinct functions of IL-2 in complex cell populations.
The idea that Treg have the capacity to specifically suppress
Th1, Th2, or Th17 responses has gained ground in the past year
and fits well with the conclusions of the article . Recently,
elegant studies have demonstrated that Treg respond to cues
from their cytokine environment and develop into highly
specialized suppressors of Th1, Th2, or Th17 responses. These
tailored suppressive functions are induced in Treg by ‘‘mirroring’’
expression of transcription factors specific for the target popula-
tion. Thus, Rudensky and colleagues  showed that Treg
expressing high levels of interferon regulatory factor 4 (IRF4), an
essential transcription factor for Th2 cells, selectively suppress
Th2 responses. Specific ablation of IRF4 in Treg leads to uncon-
trolled Th2 responses with increased numbers of IL-4- and IL-5-
producing CD41T cells, increased serum IgG1 and IgE, tissue
infiltration, and autoimmunity. In a second study , the same
group showed a similar mechanism for the specific suppression of
Th17 responses. It is suggested that IL-6 and TGF-b, cytokines
that induce Th17 differentiation, activate STAT3 in Treg leading
to the acquisition of a Th17-specific suppression program .
Again, the same transcription factor, STAT3, is used by both Th17
cells and Treg to induce or inhibit the Th17 response respectively.
Deleting STAT3 in Treg led to uncontrolled Th17 responses and
fatal intestinal inflammation . Finally, and perhaps most
relevant to the current study , such a linked transcriptional
program was also identified for the suppression of Th1 responses
. In this case, IFN-g induces T-bet, an essential transcription
factor for Th1 generation in Treg, which in turn enables Treg to
attenuate Th1 responses. In this issue, Liu et al.  convincingly
demonstrate diminished IFN-g responses and increased levels of
IL-4 in AChR-immunized mice treated with IL-2 complexes. This
result suggests that IL-2 specifically promotes the Th1 suppres-
sion program in Treg during myasthenia gravis development. It
would be of interest to ask whether Treg isolated from IL-2-
treated mice express higher levels of T-bet. Alternatively, IL-2
may preferentially expand an already existing T-bet-expressing
Treg population during the AChR autoimmune response.
It should be noted that in disease models where skewing Th1 to
Th2 responses is therapeutically beneficial, such as in the myas-
thenia gravis model described by Liu et al. , it cannot be
excluded that IL-2 directly influences the Th1/Th2 balance. The
role of IL-2 in Th1/Th2 differentiation is still not fully understood.
Early reports suggested that IL-2 facilitated the development of Th1
and Th2 cells in vitro, perhaps by ensuring their survival during the
differentiation process. Using IL-2?/?T cells, we showed that
IL-4 and IFN-g production is deficient after antigenic stimulation
in vitro . IL-2?/?mice do not show significant defects in
Th1/Th2 responses, but these results are compounded by the
absence of Treg in this model. Overall, there is stronger molecular
evidence that IL-2 is important for Th2 generation  than for
Th1 cells. This leaves open the possibility that a direct Th2-skewing
effect of IL-2 may also contribute to the protective function of IL-2-
antibody complexes in myasthenia gravis.
Although recent interest in IL-2 for the treatment of auto-
immunity stems from IL-2’s role in the maintenance of Treg, the
activities of this growth factor on effector cells must be taken into
account when evaluating IL-2’s therapeutic potential. Indeed, in a
study using IL-2 to prevent diabetes in the NOD mouse , it was
found that high doses of IL-2 complexes expanded effector cells and
led to accelerated onset of diabetes. To the contrary, low doses of
IL-2 prevented the onset of diabetes by restoring functional Treg in
the pancreas. The detrimental outcome of IL-2 treatment is likely
due to the induction of strong effector and memory responses in
the autoimmune-prone mice. Recent studies have demonstrated a
prominent role for IL-2 in the generation of CD41and CD81
memory T cells [24, 25]. This function is obviously unwanted when
treating autoimmune disease but the current body of evidence
suggests that careful determination of IL-2 complex doses and
timing to specifically target Treg provides a rationale to circumvent
these problems . It may be that lower doses of IL-2 complexes
favor Treg function, whereas higher doses will boost effector/
memory cell formation. The high levels of CD25 on Treg compared
with naı ¨ve and effector cells may explain this differential sensitivity,
allowing Treg to outcompete effector cells for capturing environ-
mental IL-2. It is likely that assays for IL-2 action, such as phospho-
flow analyses , will help us better define IL-2’s targets under
different conditions of exposure. In addition, combination therapy,
such as IL-2 to promote Treg numbers and function and mTOR
inhibitors to block the generation of effector T cells, may prove to
be beneficial in immunological disorders.
IL-2 is one of the first cytokines discovered and it was thought
that IL-2’s function is well understood. Studies in the past 10 years
have led to new insights into the biology of IL-2 and an astonishing
re-evaluation of the dogma. It is especially remarkable that almost
two decades ago this cytokine was being tested for its ability to
boost immune responses and now it is being considered as a
therapy to inhibit immune responses. The development of better
assays to define cytokine actions in vivo and rational strategies to
optimize the actions of cytokines may help to realize the potential
of IL-2 as an immunotherapeutic agent.
Eur. J. Immunol. 2010. 40: 1538–1540
& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Acknowledgements: Supported by NIH grants RO1 AI073656 and
P01 AI35297 (to A. K. A.), and JDRF grant 32-2008-354 (to H. D.).
Conflict of interest: The authors declare no financial or
commercial conflict of interest.
1 Smith, K. A., Interleukin-2: inception, impact, and implications. Science
1988. 240: 1169–1176.
2 Rosenberg, S. A. and Lotze, M. T., Cancer immunotherapy using
interleukin-2 and interleukin-2-activated lymphocytes. Annu. Rev. Immu-
nol. 1986. 4: 681–709.
3 Abrams, D., Levy, Y., Losso, M. H., Babiker, A., Collins, G., Cooper, D. A.,
Darbyshire, J. et al., Interleukin-2 therapy in patients with HIV infection.
N. Engl. J. Med. 2009. 361: 1548–1559.
4 Schorle, H., Holtschke, T., Hunig, T., Schimpl, A. and Horak, I.,
Development and function of T cells in mice rendered interleukin-2
deficient by gene targeting. Nature 1991. 352: 621–624.
5 Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A. and Alt, F. W.,
Interleukin-2 receptor alpha chain regulates the size and content of the
peripheral lymphoid compartment. Immunity 1995. 3: 521–530.
6 Suzuki, H., Kundig, T. M., Furlonger, C., Wakeham, A., Timms, E.,
Matsuyama, T., Schmits, R. et al., Deregulated T cell activation and
autoimmunity in mice lacking interleukin-2 receptor beta. Science 1995.
7 Lenardo, M. J., Interleukin-2 programs mouse alpha beta T lymphocytes
for apoptosis. Nature 1991. 353: 858–861.
8 Wolf, M., Schimpl, A. and Hunig, T., Control of T cell hyperactivation in
IL-2-deficient mice by CD4(1)CD25(-) and CD4(1)CD25(1) T cells:
evidence for two distinct regulatory mechanisms. Eur. J. Immunol. 2001.
9 Malek, T. R., Yu, A., Vincek, V., Scibelli, P. and Kong, L., CD4 regulatory
T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implica-
tions for the nonredundant function of IL-2. Immunity 2002. 17: 167–178.
10 Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. and Toda, M.,
Immunologic self-tolerance maintained by activated T cells expressing
IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of
self-tolerance causes various autoimmune diseases. J. Immunol. 1995. 155:
11 Setoguchi, R., Hori, S., Takahashi, T. and Sakaguchi, S., Homeostatic
maintenance of natural Foxp3(1) CD25(1) CD4(1) regulatory T cells by
interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutra-
lization. J. Exp. Med. 2005. 201: 723–735.
12 Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. and Rudensky, A. Y.,
A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat.
Immunol. 2005. 6: 1142–1151.
13 D’Cruz, L. M. and Klein, L., Development and function of agonist-induced
CD251Foxp31 regulatory T cells in the absence of interleukin 2 signaling.
Nat. Immunol. 2005. 6: 1152–1159.
14 O’Gorman, W. E., Dooms, H., Thorne, S. H., Kuswanto, W. F., Simonds, E.
F., Krutzik, P. O., Nolan, G. P. and Abbas, A. K., The initial phase of an
immune response functions to activate regulatory T cells. J. Immunol.
2009. 183: 332–339.
15 Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. and Sprent, J.,
Selective stimulation of T cell subsets with antibody-cytokine immune
complexes. Science 2006. 311: 1924–1927.
16 Tang, Q., Adams, J. Y., Penaranda, C., Melli, K., Piaggio, E., Sgouroudis, E.,
Piccirillo, C. et al., Central role of defective interleukin-2 production in the
triggering of islet autoimmune destruction. Immunity 2008. 28: 687–697.
17 Webster, K. E., Walters, S., Kohler, R. E., Mrkvan, T., Boyman, O., Surh, C. D.,
Grey, S. T. and Sprent, J., In vivo expansion of T reg cells with IL-2-mAb
complexes: induction of resistance to EAE and long-term acceptance of
islet allografts without immunosuppression. J. Exp. Med. 2009. 206: 751–760.
18 Liu, R., Zhou, Q., La Cava, A., Campagnolo, D. I., Van Kaer, L. and Shi,
F. D., Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes
suppresses experimental myasthenia. Eur. J. Immunol. 2010. 40: 1577–1589.
19 Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J. M., Chu, T. T., Corcoran,
L. et al., Regulatory T-cell suppressor program co-opts transcription factor
IRF4 to control T(H)2 responses. Nature 2009. 458: 351–356.
20 Chaudhry, A., Rudra, D., Treuting, P., Samstein, R. M., Liang, Y., Kas, A.
and Rudensky, A. Y., CD41 regulatory T cells control TH17 responses in a
Stat3-dependent manner. Science 2009. 326: 986–991.
21 Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B.
and Campbell, D. J., The transcription factor T-bet controls regulatory
T cell homeostasis and function during type 1 inflammation. Nat.
Immunol. 2009. 10: 595–602.
22 Dooms, H., Kahn, E., Knoechel, B. and Abbas, A. K., IL-2 induces a
competitive survival advantage in T lymphocytes. J. Immunol. 2004. 172:
23 Cote-Sierra, J., Foucras, G., Guo, L., Chiodetti, L., Young, H. A., Hu-Li, J.,
Zhu, J. and Paul, W. E., Interleukin 2 plays a central role in Th2
differentiation. Proc. Natl. Acad. Sci. USA 2004. 101: 3880–3885.
24 Dooms, H., Wolslegel, K., Lin, P. and Abbas, A. K., Interleukin-2 enhances
CD41 T cell memory by promoting the generation of IL-7R alpha-
expressing cells. J. Exp. Med. 2007. 204: 547–557.
25 Williams, M. A., Tyznik, A. J. and Bevan, M. J., Interleukin-2 signals
during priming are required for secondary expansion of CD81 memory
T cells. Nature 2006. 441: 890–893.
Abbreviation: AChR: acetyl choline receptor
Full correspondence: Professor Abul K. Abbas, Department of Pathology,
University of California San Francisco, 505 Parnassus Avenue, M-590,
San Francisco, CA 94143, USA
Additional correspondence: Dr. Hans Dooms, Department of Pathology,
University of California San Francisco, 513 Parnassus Avenue, HSW-5,
San Francisco, CA 94143-0511, USA
See accompanying article:
Accepted article online: 10/5/2010
Eur. J. Immunol. 2010. 40: 1538–1540Hans Dooms and Abul K. Abbas
& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim