SHOR T R EVIEW
www.The-R DS.org 81 DOI 10.1900/R DS.2009.6.81
The Review of
The Role of the CXCL10/CXCR3 System
in Type 1 Diabetes
Akira Shimada1, Yoichi Oikawa1, Yoshifumi Yamada1,
Yoshiaki Okubo1 and Shosaku Narumi2
1 Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Ja-
kyo 113, Japan. Address correspondence to: Akira Shimada, e-mail: email@example.com
Manuscript submitted July 27, 2009; resubmitted August 3, 2009; accepted August 7, 2009
Despite intervention with insulin, type 1 diabetes gradually
deteriorates the patients’ quality of life. The disease is char-
acterized by an immune-mediated destruction of pancreatic
beta-cells. Its etiology, however, remains controversial.
Some studies argue that glutamic acid decarboxylase (GAD)
antigen and GAD-reactive T cells are critical players in the
development of diabetes by affecting the Th cell balance. A
T-helper 1 (Th1)-dominant immune response is considered
to be important in beta-cell failure in both human and animal
2 Department of Molecular Preventive Medicine, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, To-
models of type 1 diabetes. The Th1-type chemokine,
CXCL10, and its receptor, CXCR3, are involved not only in
the immune response, but also in the suppression of beta-
cell proliferation. Thus, understanding the CXCL10/CXCR3
system may be important for finding a cure. In this short re-
view, we discuss the role of the CXCL10/CXCR3 system in
type 1 diabetes and propose relevant treatment options.
Keywords: type 1 diabetes · GAD · T cell · CD4 · CD8
· T helper cell · Th1 · beta-cell proliferation · NOD ·
insulitis · CD45RB · IL-10 · IL-18 · IGRP
ype 1 diabetes is an autoimmune disease
characterized by the destruction of pancre-
atic beta-cells. It especially affects the young
and the chronic complications reduce their quality
of life. To date, there has been no cure for the dis-
ease. Even with treatment by islet transplanta-
tion, survival of the transplanted islets is less
than 5 years in most cases . There is pressing
need for a better understanding of the disease
pathogenesis and a new treatment strategy based
on immune intervention.
The T-helper (Th) cell system is critical for a
healthy immune system that balances reactive
and suppressive cell compartments. It has been
argued that an imbalance in the Th cell system,
caused by a predominance of the Th1 response, fa-
vors the development of autoimmune diabetes .
CXCL10 is an interferon-gamma
chemokine and reacts with its receptor, CXCR3,
on Th1 cells . Elevated levels of CXCL10 were
detected in new onset type 1 diabetes patients and
correlated with levels of GAD-reactive CD4 T cells
. In addition, CXCL10 is produced by beta-cells,
and suppresses beta-cell proliferation . There-
fore, we believe that the CXCL10/CXCR3 system
plays a decisive role in the pathogenesis of type 1
diabetes. In this short review article, we take a
closer look at the CXCL10/CXCR3 system, and
discuss its relevance in the disease process and in
potential therapy approaches.
The Review ofDIABETIC STUDIES
Vol 6 No 2 2009
82 The R eview of Diabetic Studies
Vol. 6 ⋅ No. 2 ⋅ 2009
Shimada, Oikawa, et al.
R ev Diabet Stud (2009) 6:81-84 Copyright © by the SBDR
T he role of the T h1 response in beta-
cell failure in the NOD mouse
In the non-obese diabetic (NOD) mouse model,
insulitis, with lymphocytic infiltration into the is-
lets, is observed from 5-6 weeks of age. However,
this infiltration does not result in rapid onset of
diabetes. It takes 3-4 months for the NOD mouse
to become diabetic. Therefore, a regulatory
mechanism must be at work in this model, at least
until the onset of diabetes.
During the early phase of the disease, autore-
active lymphocytes react with insulin, which is
why insulin is considered to be a primary autoan-
tigen in type 1 diabetes . Reactivity against in-
sulin results in insulitis, but the occurrence of in-
sulitis does not necessarily mean the onset of dia-
betes. Diabetes onset may be regulated by a dif-
ferent mechanism. One of the possible mecha-
nisms is a change in the function of regulatory
CD4 T cells, (CD45RB
ease course. In the “regulatory phase”, glutamic
acid decarboxylase (GAD)-reactive CD45RB
cells produce IL-10, which suppresses the onset of
diabetes . This GAD-reactive IL-10 response by
response by the same cell type during the disease
course. However, it has been reported that the
function of CD45RB
low CD4 cells) during the dis-
low CD4 cells balances the polyclonal Th1
low CD4 T cells can change from
protective to pathogenic in NOD mice [8-10].
When the Th1 response by CD45RB
overcomes the GAD-reactive IL-10 response, then
diabetes onset can occur .
In fact, artificial induction of GAD-reactive T
cells in an adoptive transfer system results in the
induction of a GAD-reactive IL-10 response and
diabetes suppression . This finding supports
the view that GAD-reactive responses can be regu-
latory. On the other hand, the induction of a Th1
response by IL-18 production results in an accel-
erated diabetes onset . Therefore, the autoim-
mune Th1 response plays an important role in
pancreatic beta-cell failure in type 1 diabetes.
However, it is assumed that islet-specific glucose 6
phosphatase catalytic subunit-related protein
(IGRP)-reactive CD8 T cells are the “actual kill-
ers” of beta-cells . Increased proportions of
CD8 T cells in islet lesions have been observed in
both animal diabetes models and humans [14, 15].
Therefore, we hypothesize that Th1 cells cooperate
with CD8 T cells to destroy beta-cells (Figure 1).
low CD4 cells
T h1 type chemokine CXCL 10 in hu-
man type 1 diabetes
A Th1 type chemokine, CXCL10 (also known as
IP-10), reacts with its receptor, CXCR3, which is
mainly expressed on Th1 cells. These CXCR3-
positive cells migrate towards re-
gions of high CXCL10 concentration.
Therefore, it has been suggested that
CXCL10 could be an important
chemokine in type 1 diabetes. A
J apanese study  reported that
serum CXCL10 levels in type 1 dia-
betes patients, including those ex-
periencing a slow onset disease ,
were significantly higher than that
measured in type 2 diabetics and
healthy controls. This observation
was confirmed in a study with Cau-
casian patients , indicating that
this is a consistent phenomenon in
type 1 diabetes irrespective of race.
Another interesting observation
was that CXCL10 levels correlated
with the number of islet antigen-
specific CD4 T cells in type 1 diabet-
ics [17, 19, 20]. This suggested that
the level of CXCL10 may indicate
anti-beta-cell immunity in type 1
diabetes. Also, the serum CXCL10
levels were negatively correlated
Figure 1. Hypothetical illustration of beta-cell destruction. The Th1
cell plays an important role in beta-cell destruction, although CD8 T
cells are the actual killers. APC: antigen-presenting cell. IFNγ: interfe-
ron gamma. IL: interleukin. TNFα: tumor necrose factor alpha. NO:
The CX CL10/CX CR 3 System in Diabetes
with disease duration and age of disease
onset in type 1 diabetes, suggesting that
the CXCL10 level may reflect “disease ac-
tivity”. Thus, serum CXCL10 appears to
be a useful marker in type 1 diabetes, and
its level may be used to define disease
The R eview of Diabetic Studies
Vol. 6 ⋅ No. 2 ⋅ 2009
www.The-R DS.org R ev Diabet Stud (2009) 6:81-84
R ole of the CXCL 10/CXCR 3 sys-
tem in type 1 diabetes
As mentioned above, serum CXCL10
levels in type 1 diabetics are higher than
those in healthy controls, but what does
this mean in terms of pathogenesis? In the
NOD model of type 1 diabetes, serum
CXCL10 levels seem to correlate with high
levels of CXCR3 (and high CXCL10) in
pancreatic lymph nodes, where T cells are
educated . Moreover,
analysis of serum CXCL10 levels during
the disease course indicated that the
CXCL10 level seems to predict the onset
of diabetes. Taken
CXCL10 levels reflect an accumulation of
CXCR3-positive T cells in pancreatic
lymph nodes , a phenomenon that occurs just
before the onset of diabetes.
These data provoke the following question:
could the disease course be altered favorably, if
the CXCL10/CXCR3 system were blocked by neu-
tralizing CXCL10 antibodies? We tested this hy-
pothesis and found that administration of CXCL10
monoclonal antibodies to a cyclophosphamide-
induced NOD diabetes model resulted in a decel-
eration of diabetes onset . Moreover, induction
of anti-CXCL10 antibodies by a gene transfer sys-
tem in young NOD mice even resulted in disease
suppression . These results indicate that
blocking the CXCL10/CXCR3 system can be an ef-
fective intervention strategy to suppress diabetes
onset both in the malignant phase , i.e. the ac-
tive disease phase, and in the benign phase, i.e.
the less active phase.
Interestingly, when both CXCL10 and CXCR3
were blocked, no difference in immunological re-
sponses, i.e. in cytokine profile, was found. In-
stead, a difference in pancreatic beta-cell prolif-
eration was discovered. This means that beta-cells
were significantly increased by a blockade of the
CXCL10/CXCR3 system. It is of note that these
interventions were performed before, rather than
after, diabetes onset. We do not know, whether or
not this approach is similar effective when applied
in the hyperglycemic state.
There is evidence that the effect relates to the
beta-cell regeneration capacity. It has recently
been shown that an interaction between CXCL10
and Toll-like receptor 4 (TLR4) can result in sup-
pression of beta-cell proliferation . As CXCL10
and CXCR3 are co-expressed in pancreatic beta-
cells , and CXCL10 expression increases as in-
sulitis progresses , we believe that, beside its
role in the immune response, the CXCL10/CXCR3
system is also critical for the suppression of pan-
creatic beta-cell proliferation (Figure 2).
It is commonly assumed that both immune
regulation and beta-cell regeneration are required
to cure type 1 diabetes . Some studies have
suggested that the CXCL10/CXCR3 chemokine
system plays a critical role in the autoimmune
process and in beta-cell destruction in type 1 dia-
betes. Blocking the CXCL10 chemokine in new on-
set diabetes seems to be a possible approach for
treatment. In combination with another regula-
tory intervention strategy, such as GAD autoanti-
gen sensitization, this approach could contribute
to a curative treatment for type 1 diabetes. We en-
visage that further
CXCL10/CXCR3 system will enable to develop a
new and effective therapy.
research into the
Figure 2. Suppression of beta-cell proliferation by the
CXCL10/CXCR3 system. The destruction of beta-cells by effector
cells results in CXCL10 production in beta-cells. CXCL10 binds
to CXCR3 on beta-cells, and suppresses beta-cell proliferation in
an autocrine manner. Blocking this cycle by CXCL10 neutrali-
zing antibody results in beta-cell proliferation.
84 The R eview of Diabetic Studies
Vol. 6 ⋅ No. 2 ⋅ 2009
Shimada, Oikawa, et al.
R ev Diabet Stud (2009) 6:81-84 Copyright © by the SBDR
Conflict of interest statement: Dr. Akira Shimada
(M.D., Ph.D.) has research grants from Eli Lilly. All
1. Shapiro AM, Ricordi C, Hering BJ, Auchincloss H,
Lindblad R, Robertson RP, Secchi A, Brendel MD,
Berney T , Brennan DC, et al. International trial of the
Edmonton protocol for islet transplantation. N Engl J Med
2. Sia C. Imbalance in Th cell polarization and its relevance in
type 1 diabetes mellitus. R ev Diabet Stud 2005. 2(4):182-
3. Rotondi M, Lazzeri E, Romagnani P, Serio M. R ole
for interferon-gamma inducible chemokines in endocrine
autoimmunity: an expanding field. J Endocrinol Invest 2003.
4. Shigihara T , Oikawa Y , Kanazawa Y , Okubo Y , Na-
rumi S, Saruta T , Shimada A. Significance of serum
CX CL10/IP-10 level in type 1 diabetes. J Autoimmun 2006.
5. Morimoto J, Y oneyama H, Shimada A, Shigihara T ,
Y amada S, Oikawa Y , Matsushima K, Saruta T , Na-
rumi S. CX C chemokine ligand 10 neutralization suppresses
the occurrence of diabetes in nonobese diabetic mice through
enhanced beta cell proliferation without affecting insulitis. J
Immunol 2004. 173(11):7017-7024.
6. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu
E, Miao D, Y u L, Wegmann DR, Hutton JC, Elliott
JF, Eisenbarth GS. Prime role for an insulin epitope in the
development of type 1 diabetes in NOD mice. Nature 2005.
7. Funae O, Shimada A, T okui M, T akei I, Saruta T .
Balance of GAD65-specific IL-10 production and polyclonal
Th1-type response in type 1 diabetes. Autoimmunity 2001.
8. Shimada A, Rohane P, Fathman CG, Charlton B.
Pathogenic and protective roles of CD45R B(low) CD4+
cells correlate with cytokine profiles in the spontaneously
autoimmune diabetic mouse. Diabetes 1996. 45(1):71-78.
9. Shimada A, Charlton B, T aylor-Edwards C, Fathman
CG. Beta-cell destruction may be a late consequence of the
autoimmune process in nonobese diabetic mice. Diabetes
10. Shimada A, Charlton B, Rohane P, T aylor-Edwards
C, Fathman CG. Immune regulation in type 1 diabetes. J
Autoimmun 1996. 9(2):263-269.
11. Kanazawa Y , Shimada A, Oikawa Y , Okubo Y , T ada
A, Imai T , Miyazaki J, Itoh H. Induction of anti-whole
GAD65 reactivity in vivo results in disease suppression in
type 1 diabetes. J Autoimmun 2009. 32(2):104-109.
12. Oikawa Y , Shimada A, Kasuga A, Morimoto J, Osaki
T , T ahara H, Miyazaki T , T ashiro F, Y amato E, Mi-
yazaki J, Saruta T . Systemic administration of IL-18 pro-
motes diabetes development in young nonobese diabetic
mice. J Immunol 2003. 171(11):5865-5875.
13. Han B, Serra P, Amrani A, Y amanouchi J, Maree AF,
other authors declare that they have no conflict of inter-
Edelstein-Keshet L, Santamaria P. Prevention of diabetes
by manipulation of anti-IGR P autoimmunity: high efficiency
of a low-affinity peptide. Nat Med 2005. 11(6):645-652.
14. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Mor-
gan NG. Analysis of islet inflammation in human type 1 dia-
betes. Clin Exp Immunol 2009. 155(2):173-181.
15. Coppieters KT , von Herrath MG. Histopathology of type
1 diabetes: Old Paradigms and New Insights. R ev Diabet
Stud 2009. This issue.
16. Suzuki R, Shimada A, Maruyama T , Funae O, Mori-
moto J, Kodama K, Oikawa Y , Kasuga A, Matsubara
K, Saruta T , Narumi S. T-cell function in anti-
GAD65(+)diabetes with residual beta-cell function. J Auto-
immun 2003. 20(1):83-90.
17. Shimada A, Morimoto J, Kodama K, Suzuki R, Oi-
kawa Y , Funae O, Kasuga A, Saruta T , Narumi S.
Elevated serum IP-10 levels observed in type 1 diabetes. Dia-
betes Care 2001. 24(3):510-515.
18. Nicoletti F, Conget I, Di Mauro M, Di Marco R,
Mazzarino MC, Bendtzen K, Messina A, Gomis R.
Serum concentrations of the interferon-gamma-inducible
chemokine IP-10/CX CL10 are augmented in both newly di-
agnosed type I diabetes mellitus patients and subjects at risk of
developing the disease. Diabetologia 2002. 45(8):1107-1110.
19. Shimada A, Kodama K, Morimoto J, Oikawa Y , Irie
J, Nakagawa Y , Matsubara K, Maruyama T , Saruta T .
Detection of GAD-reactive CD4+ cells in so-called “type
1B” diabetes. Ann N Y Acad Sci 2003. 1005:378-386.
20. Itoh A, Shimada A, Kodama K, Morimoto J, Suzuki
R, Oikawa Y , Irie J, Nakagawa Y , Shigihara T , Kana-
zawa Y , Okubo Y , Motohashi Y , Maruyama T , Saruta
T . GAD-reactive T cells were mainly detected in autoim-
mune-related type 1 diabetic patients with HLA DR 9. Ann
N Y Acad Sci 2004. 1037:33-40.
21. Shigihara T , Shimada A, Oikawa Y , Y oneyama H,
Kanazawa Y , Okubo Y , Matsushima K, Y amato E,
Miyazaki J, Kasuga A, Saruta T , Narumi S. CX CL10
DNA vaccination prevents spontaneous diabetes through en-
hanced beta cell proliferation in NOD mice. J Immunol
22. Y amada S, Irie J, Shimada A, Kodama K, Morimoto
J, Suzuki R, Oikawa Y , Saruta T . Assessment of beta cell
mass and oxidative peritoneal exudate cells in murine type 1
diabetes using adoptive transfer system. Autoimmunity 2003.
23. Schulthess FT , Paroni F, Sauter NS, Shu L, Ribaux P,
Haataja L, Strieter RM, Oberholzer J, King CC,
Maedler K. CX CL10 impairs beta cell function and viability
in diabetes through TLR 4 signaling. Cell Metab 2009.
24. Okubo Y , Shimada A, Kanazawa Y , Shigihara T , Oi-
kawa Y , Imai T , Miyazaki J, Itoh H. Hyperplastic islets
observed in “reversed” NOD mice treated without hemato-
poietic cells. Diabetes R es Clin Pract 2008. 79(1):18-23.