SECTION X: IL-17 DIFFERENTIATION

The IL-17 Differentiation Pathway and Its Role

in Transplant Outcome
Jonathan S. Serody,1,2 Geoffrey R. Hill3,4

The limitations of allogeneic transplantation are graft-versus-host disease (both acute and chronic), infection,
and relapse. Acute GVHD has traditionally been thought of as a Th1-mediated disease with inflammatory
cytokines (eg, inteferon [IFN]-g and tumor necrosis factor [TNF]) and cellular cytolysis mediating apoptotic
target tissue damage in skin, gut, and liver. Chronic GVHD has not fit neatly into either Th1 or Th2 (eg, IL-4,
IL-13) paradigms. Increasingly, the Th17 pathway of differentiation has been shown to play important roles in
acute and chronic GVHD (aGVHD, cGVHD), particularly in relation to skin and lung disease. Here we discuss
the IL-17 pathway of T cell differentiation and the accumulating evidence suggesting it represents an impor-
tant new target for the control of deleterious alloimmune responses.
Biol Blood Marrow Transplant 18: S56-S61 (2012) Ó 2012 American Society for Blood and Marrow Transplantation

KEY WORDS: Bone marrow transplantation, Graft-versus-host disease, Cytokines

INTRODUCTION the A and C subunits, and appears ubiquitously

There have been a number of inconsistencies in the
traditional Th1/Th2 paradigm, many of which have
been explained by the description of regulatory
T cell and Th17 differentiation pathways. Interleukin
(IL)-17 can be produced by most cells (including non-
immune cells such as epithelia [1]), although its gener-
ation by CD41 T cells is the most widely studied. The
IL-17 family includes 6 members from A to F, the main
isoforms studied being IL-17A and IL-17F [2]. IL-17
usually refers to IL-17A, which is the most potent
form, and together with IL-17A/F heterotrimers
reflects the major biologically active cytokine
(reviewed in Shen and Geffen [3]). More recently,
IL-25 (IL-17E) has been shown to play important
roles in promoting Th2 responses in allergic and par-
asitic diseases where it is produced by CD4 T cells and
epithelial cells (reviewed in Paul and Zhu [4]). IL-17A
function is mediated via the IL-17R, which comprises
From the 1Department of Medicine; 2Microbiology and Immunol-
ogy, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina; 3The Bone Marrow Transplantation Labora-
tory, Queensland Institute of Medical Research, Brisbane,
Australia; and 4Department of Bone Marrow Transplantation,
The Royal Brisbane and Women’s Hospital, Brisbane, Australia.
Financial disclosure: See Acknowledgments on page S60.
Correspondence and reprint requests: Geoffrey R. Hill, MD, Bone
Marrow Transplantation Laboratory, Queensland Institute of
Medical Research, 300 Herston Road, Herston, QLD, 4006,
Australia (e-mail: Geoff.Hill@qimr.edu.au).
Ó 2012 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
doi:10.1016/j.bbmt.2011.10.001
expressed on both hematopoietic and nonhemato-
poietic tissues [5].
Generation of Th17 cells is dependent on the
transcription factors RORgt, RORa, IRF4, and
STAT3. Th17 cells generate pro-inflammatory cyto-
kines such as IL-17A, IL-17F, IL-21, IL-22, tumor ne-
crosis factor (TNF), granulocyte macrophage-colony
stimulating factor (GM-CSF), and the chemokines
CXCL1, CXCL2, and CXCL8. Th17 cells express
CCR6 and CCL20 and are particularly recruited to
sites of inflammation via this chemokine receptor.
IL-17A acts predominantly as a chemo attractant to
different cell types via the induction of cytokines
(eg, GM-CSF, granulocyte-colony stimulating factor
[G-CSF], and chemokines [2]. As outlined in
Figure 1, transforming growth factor (TGF)-b1 is cen-
tral to Th17 differentiation from naive T cells, usually
in combination with IL-6. Both TGF-b1 and IL-6 can
be produced by almost any cell type, but myeloid
hematopoietic cells (eg, monocytes, macrophages)
have an enhanced potential during inflammatory
states. Th17 differentiation can also occur indepen-
dently of IL-6, if TGF-b is present in combination
with high concentrations of IL-21 (from natural killer
or natural killer T cells). Stabilization and mainte-
nance of the Th17 phenotype subsequently requires
IL-23 (produced predominantly by antigen presenting
cells), with support from TNF and IL-1b, while
expansion is dependent on IL-21 (produced predomi-
nantly by activated T cells, natural killer cells, and
natural killer T cells).
The RORgt transcription factor is central to Th17
differentiation, in a similar fashion to T-bet for Th1

S56
Biol Blood Marrow Transplant 18:S56-S61, 2012
Figure 1. Schematic of the cytokine-dependent control of Th17 differentiation. Adapted from Bettelli et al [53].
and GATA-3 for Th2 differentiation. Interestingly,
TGF-b in the absence of IL-6 or high concentrations
of IL-21 instead drives regulatory T cell differentia-
tion, where Foxp3 is the critical transcription factor.
Both Th1 and Th2 cells inhibit Th17 differentiation,
via IFN-g and IL-4, respectively [1]. Th-17 cells pro-
mote pathogenic immune-mediated organ damage in
conditions targeting brain (multiple sclerosis), arthritis
(rheumatoid arthritis), colitis (inflammatory bowel
disease), allergic skin (psoriasis), and lung (transplant
rejection; reviewed in Steinman [1]). However, it is
now clear that Th-17 cells may have pathogenic or reg-
ulatory effects, depending on the coproduction of pro-
inflammatory (TNF and IFN-g) or anti-inflammatory
(IL-10 and IL-22) cytokines [6,7]. Whether protective
or pathogenic Th-17 cells are generated may be depen-
dent on the presence or absence of continued IL-6
signaling during phenotype stabilization by IL-23 [6].
IL-17 and Acute Graft-versus-Host Disease
(aGVHD)
It has been established for over 40 years that T cells
are critically required for the generation of the inflam-
matory response termed aGVHD [8-10]. Interestingly,
although a critical role for T cells in the pathology of
aGVHD is clear, which of the specific subsets of
T cells is critical for the pathology that mediates
aGVHD is less clear. Th1 cytokines can be found in
lesional tissue from patients with aGVHD, which has
led investigators to surmise that aGVHD is a Th1-
mediated process [11,12]. However, neither IFN-g
nor the transcription factor T-bet is required to
generate GVHD in animal models [13-15]. This has
suggested that other T cell lineages could potentially
mediate aGVHD.
Can Th17 cells mediate pathology associated with
aGVHD? The answer to this query is certainly yes.
IL-17 in BMT S57
Our group used a novel approach to generate a highly
homogenous population of donor Th17 cells ex vivo.
When we infused these T cells into lethally irradiated
haploidentical, minor or major histocompatibility com-
plex mismatched recipient mice, we found substantial
pathology in GVHD target organs [16]. The
pathology was particularly striking in the skin and lung
and much greater than that found using naive T cells.
However, all GVHD target organs were affected by
Th17 cells with gastrointestinal (GI) tract and liver
pathology being similar to that induced by naive T cells.
Are Th17 cells involved in the pathology associ-
ated with aGVHD? This question has been somewhat
harder to discern. In general, investigators have
attempted to address this by using genetic approaches
or pharmacologic inhibitors of cytokines critical for
the generation, expansion, or effector function of
Th17 cells, or blocking the activity of transcription
factors important for Th17 generation in preclinical
models. These approaches have yielded conflicting
information, which in some instances may relate to
the myriad of activities of proteins important for the
generation of Th17 cells. For instance, 2 different
groups evaluated the role of IL-17A in the pathology
of aGVHD with 1 showing a modest decrease in
aGVHD when donor T cells could not generate
IL-17A, whereas the second group showed increased
pathology in recipient mice given donor T cells unable
to generate IL-17A [17,18]. Interestingly, these
discordant data were generated using the same
models and strain of mice. Subsequently, a report
confirmed a modest pathogenic contribution of
IL-17A to aGVHD in multiple major histocompabil-
ity complexes matched and minor mismatched models
of bone marrow transplantation (BMT) that was most
dominant in the skin [19]. Multiple different groups
have shown that the absence of IL-21 or the IL-21
S58 J. S. Serody and G. R. Hill
receptor inhibits aGVHD (and graft-versus-
leukemia), although the mechanisms for this differed
and included an increase in inducible regulatory
T cells, an increase in natural regulatory T cells, or di-
minished effector T cell function in lymphoid tissue
draining the GI tract [19-23]. Clearly, targeting
TNF diminishes aGVHD, although the contribution
that Th17 cells make to the generation of this
cytokine is not clear [24].
A second approach to evaluate the function of Th17
cells is to block transcription factors critical to their
generation such as RORgt, RORa, and/or IRF-4.
Our group and another have evaluated whether
T cells require the expression of RORC (generates 2 iso-
forms including RORgt). The initial data indicated
that the absence of RORC in a model of GVHD medi-
ated solely by CD41 T cells did not impact on the
incidence or severity of aGVHD [25]. This group did
find that the absence of both TBOX21 (T-bet) and
RORC diminished aGVHD. Our group confirmed
these data but also found that, in models in which
both CD41 T cells and CD81 T cells are critical to
the induction of GVHD pathology, the absence of
RORC in CD41 T cells greatly diminished aGVHD.
This was associated with diminished generation of
IL-17A and TNF in serum and GVHD target organs
(Fulton and Serody, submitted).
Similarly, a number of studies have investigated
the function of the cytokines that generate Th17 cells,
particularly IL-6 and IL-23, in the pathogenesis of
aGVHD. Here, the data are more straightforward,
although the roles that Th17 cells play in these data
are not as clear. The absence of IL-6 in donor T cells
and the inhibition of IL-6R with antibody neutraliza-
tion significantly diminished aGVHD without overtly
effecting GVL [26,27]. This was associated with
diminished generation of Th1 and Th17 cells in
GVHD target organs and the spleen with enhanced
regulatory T cell generation in 1 study [26]. The sec-
ond study, while confirming the potent protective
effect of IL-6 inhibition, found this to be independent
of effects on T cell differentiation [27]. Similarly, using
genetic or pharmacologic approaches, blocking the
function of IL-23 was found to diminish aGVHD
without affecting the antitumor property of donor
T cells critical for the success of allogeneic transplan-
tation [28-30]. This was associated in 1 study with
diminished IFN-g generation in the GI tract of
recipient animals and in another study with
diminished IL-17A. At this time, a role for IL-22 in
the pathogenesis of aGVHD is not clear, although
our group has evidence that this cytokine may be
critically important to the pathology induced by donor
T cells (Ott and Serody, unpublished).
Are Th17 cells critical for pathology found in
patients with aGVHD? Again, this straightforward
question has been somewhat difficult to determine.
Biol Blood Marrow Transplant 18:S56-S61, 2012
A previous study found that the frequency of Th17
cells in the peripheral blood was increased in patients
with aGVHD compared with healthy donors or allo-
graft recipients without GVHD [31]. This correlated
with increased levels of IL-17 in the plasma, but only
in patients with active GVHD, compared with recipi-
ents without GVHD or healthy donors. Interestingly,
they found that patients with active GVHD had a de-
creased percentage of Foxp3-expressing regulatory
T cells, and that in a very small subset of patients the
decrease in this population correlated with increases
in the frequency of Th17 cells. They evaluated for
the presence of T cells in the skin from 6 patients
and found that all of the CD31 T cells were generating
IL-17 and IFN-g, which was similar to the cytokine
expression from T cells isolated from the liver.
Although it is hard to draw firm conclusions from
anecdotal longitudinal assessments, this group used
IL-17 ELISPOT assays to demonstrate that increases
in this cell population correlated with the occurrence
of aGVHD.
However, 2 other groups have not been able to
correlate a specific role for Th17 cells in skin or GI
tract GVHD [32,33]. For both of these evaluations,
the presence of IL-17A was evaluated with the first
group using ex vivo stimulated T cells and the second
using immunohistochemistry. Neither demonstrated
the presence of T cells expressing IL-17A from the
skin. Additionally, the presence of IL-17A in the GI
tract was evaluated and also not found. However, it
should be noted that there are major limitations in
the ability to draw any conclusions in relation to cause
and effect from these clinical studies. For instance, 1 of
these studies found that increased numbers of regula-
tory T cells in tissue correlated with GVHD [33]. Fur-
thermore, it is not clear that alloreactive Th17 cells
will maintain this phenotype in culture over 3 weeks
in the absence of polarizing cytokines, which were
not added in 1 study [32].
A second approach to evaluating the role of the
Th17 axis has involved analysis for single nucleotide
polymorphisms (SNPs) associated with GVHD in
IL-23 or the IL-23 receptor (IL-23R). Previous work
had shown a very strong association between an SNP
present in the IL-23R (G to A change at 1142 leading
to a substitution of glycine for arginine, R381G, and
Crohn’s disease. This SNP is located in the IL-23
receptor chain of the IL-23 receptor. A group in
Germany evaluated the G.A change in a cohort of
221 transplant recipients and their HLA identical
donors [34]. The gene variant occurred in 13.1% of
recipients and 11.3% of donors. Severe grade III-IV
aGVHD was found less frequently in recipients trans-
planted with donor cells with the IL-23R SNP (22%
versus 4%). In this evaluation, all but 1 donor and
recipient were heterozygous for the SNP. A second
cohort undergoing unrelated transplantation was also
Biol Blood Marrow Transplant 18:S56-S61, 2012
evaluated in which all donors and recipients who
had the SNP were heterozygous. Again, recipients
transplanted with donors having the IL-23R SNP
had a significant decrease in grade III-IV aGVHD
compared with those receiving donor cells with the
wild-type SNP (3.8% versus 25.5%). However, in
this analysis there was no beneficial effect if only the
recipients had the IL-23R G.A change. Overall sur-
vival was not impacted by the presence of the IL-23R
polymorphism.
Two other groups have evaluated the interaction
between polymorphisms in the IL-23R and outcome
posttransplantation, with 1 group focusing on children
and young adults [35]. The IL-23R SNP was found in
7.8% of patients and 11% of donors with, again, none
of the patients being homozygous for this. Patients
receiving donor grafts with the G.A SNP had a signif-
icantly decreased risk of aGVHD (5% versus 33.3%
for grade II or greater); however, in this analysis unlike
in the previous analysis, the frequency of severe
GVHD was not affected by the occurrence of the poly-
morphism in the patient. When this group confined
their analysis only to patients under the age of 16, there
was still a statistically significant decreased incidence
of aGVHD when the donor had the G.A polymor-
phism in the IL-23R. Again, no association with the
G.A polymorphism and the incidence of chronic
GVHD (cGVHD) or overall survival was found.
However, 1 recent paper has questioned whether
the G.A polymorphism in the IL-23R is implicated
in a diminished risk of aGVHD [36]. A total of 390 pa-
tients who underwent T-replete transplants for the
treatment of acute or chronic leukemia or myelodys-
plastic syndrome using primarily myeloablative condi-
tioning were included. Two SNPs in the IL-23R,
including the G.A SNP, and a second polymorphism
associated with ankylosing spondylitis were evaluated.
A total of 13% of the donors and 16% of the recipients
had the variant SNPs. No association between either
of the SNPs and the incidence or severity of aGVHD
was found. Thus, it is not clear at this time if these dif-
ferences are because of differences in the (1) transplan-
tation approaches, (2) methods used to prevent
GVHD, or (3) perhaps ethnic differences in the activ-
ity of the IL-23 axis between these cohorts.
Finally, it is now clear that our perceived under-
standing of the lineage fidelity of T cells needs to be
altered. Our group and a number of others has found
that Th17 cells rapidly undergo epigenetic modifica-
tions in the presence of IL-12, which mediates the
loss of expression of IL-17A, and IL-17F and the
increased expression of IFN-g. We have found that
a substantial number of IFN-g producing T cells in
recipient mice after transplantation come from a popu-
lation of donor T cells that were initially skewed to
a Th17 lineage, but later posttransplantation are indis-
tinguishable from Th1 cells (Carlson, Ott, and Serody,
IL-17 in BMT S59
unpublished). Thus, early Th17 T cell polarization
may not be identified when tissue biopsies are per-
formed at the time of GVHD involvement. If this is
true clinically, it would suggest that aGVHD might
best be termed a Th1/Th17 process.
IL-17 and cGVHD
Chronic GVHD is the major cause of late nonre-
lapse death following stem cell transplantation
(SCT). Its presentation may be progressive (active or
aGVHD merging into chronic), or de novo (occurring
without prior aGVHD). Older recipient age and a his-
tory of aGVHD are the greatest risk factors for
cGVHD [37], and strategies to prevent aGVHD may
help to prevent cGVHD. However, scleroderma, the
primary manifestation of cGVHD, can also develop
in a de novo fashion, late after BMT in the absence
of prior clinical aGVHD. It is also noteworthy that
cGVHD develops with high frequency in recipients
of T cell–depleted transplants, suggesting that non–
T cell pathways exist, or alternatively, that bone
marrow–derived and pathogenic autoreactive T cell
development occurs [38]. The majority of clinical
transplants are currently undertaken using G-CSF
mobilized peripheral blood stem cells, and it is now
clear that cGVHD is significantly enhanced in this
setting [39]. Importantly, unlike aGVHD, effective
therapy options are very limited for cGVHD.
In contrast to aGVHD, the pathophysiology of
cGVHD still remains poorly defined. Chronic
GVHD manifests with features characteristic of auto-
immune disease, including sclerodermatous skin dis-
ease, and does not fit easily into either Th1 or Th2
paradigms [12,40], although IFN-g can clearly play
a causal role [32,41]. Recently, the Th17 pathway of
T cell differentiation has been demonstrated to
promote pathogenic autoimmune-mediated organ
damage in conditions such as multiple sclerosis, rheu-
matoid arthritis, inflammatory bowel disease, and
psoriasis [1]. Notably, in systemic sclerosis, a condition
closely resembling scleroderma, the predominant
clinical feature of cGVHD after SCT, fibrosis is
mediated by Th17 cells infiltrating the skin and serum
IL-17 levels positively correlate with disease severity
[42,43]. In preclinical studies where true cause
and effect can be delineated, most publications
demonstrate pathogenic effects of donor-derived IL-
17A on GVHD, particularly in skin and lung [16,19].
However, as a whole, these effects are limited early
after BMT, consistent with the established notion
that the dominant aspects of aGVHD, particularly
that found in the GI tract are most associated with
a Th1 process [39]. In the setting of cGVHD, recent
preclinical and clinical data support a role for IL-17A
as a central mediator of pathology, particularly within
the skin [16,19,31]. We have demonstrated that
S60 J. S. Serody and G. R. Hill
G-CSF promotes type-17 differentiation within both
conventional CD41 and CD81 populations, and that
this effect is downstream of IL-21. Importantly, the
majority of IL-17A generated late after BMT when
scleroderma manifests in these systems is from
CD81 T cells and the disease process was confirmed
to be CD8-dependent. How IL-17A induces sclero-
derma remains unclear, but is likely to be because of
the control of the cellular migration of fibrogenic
populations, particularly granulocytes and mono-
cytes/macrophages [19] and perhaps T cells.
FoxP31 regulatory T cells (Tregs) are critical for the
maintenance of peripheral tolerance, and disruption of
the development or function of Tregs leads to develop-
ment of autoimmune disease [44]. Equally, Tregs are
crucial for the establishment and maintenance of toler-
ance after SCT. Notably, Treg populations are dimin-
ished in the clinical setting of aGVHD and cGVHD
[45-47]; however, the factors that contribute to their
absence and the mechanism by which their absence
results in pathology is not entirely clear. The fact that
these cells are thymic dependent and that this organ
is a target of GVHD, together with impairment of
peripheral T cell homeostasis, are likely to be
important. In addition, the requirement of the highly
fibrogenic cytokine TGF-b [48] in the expansion and
homeostasis of both Treg and IL-17 differentiation
suggests a ‘‘ying and yang’’ type pathogenic versus
protective relationship between IL-17 and Tregs differ-
entiation in cGVHD.
Importantly, clinical studies that have linked
IL-17A to aGVHD have shown concurrent links to
Th1 cytokines [31,49]. What is clear both preclinically
[17,19] and clinically [31] is that during aGVHD,
IL-17A producing cells can also coproduce IFN-g,
making attempts to correlate disease with the genera-
tion of IL-17A alone very difficult. In contrast to the
posttransplantation setting, IL-17A and IFN-g genera-
tion are generated independently by T cells from
healthy donors [19], and so in theory, the induction of
a single cytokine may be informative. We have shown
that G-CSF administration promotes the induction of
type 17 cells [2], and Sun et al. [50] confirmed this in
healthy donors. A subsequent study demonstrated a re-
duction in the proportion of IL-17A producing cells
within the CD4 compartment during G-CSF adminis-
tration; however, this work also demonstrated an induc-
tion of IL-17A producing and RORgt expressing T cells
following G-CSF [51]. Importantly, stem cell mobiliza-
tion with G-CSF results in an increase in the total num-
bers of CD31 T cells in peripheral blood, and we have
noted that the numbers of CD81IL-171 T cells (but
not any IFN-g1 T cell subset) are significantly in-
creased (unpublished data).
Thus, although there is little doubt IL-17A can
contribute to GVHD, effects early after BMT are
somewhat modest in our hands (and others [8,50])
Biol Blood Marrow Transplant 18:S56-S61, 2012
and IL-17A generation is augmented by the use of
G-CSF mobilized grafts. Although the pathogenic ef-
fects of IL-17A on cutaneous and particularly cGVHD
are clear [19,31], they are still difficult to interpret
independently of coexpressed Th1 cytokines with
current technology. It is also clear that Th17 cells
generate a number of important cytokines (IL-21,
IL-22, TNF, GM-CSF, IL-17F) that may be critical
to the pathogenesis of aGVHD and/or cGVHD.
Thus, the absence of an effect by targeting IL-17A
alone does not indicate the absence of a role for
Th17 cells. Additionally, given the plasticity of the
Th17 lineage and the ability of those cells to convert
to conventional Th1 cells, it is likely that both Th1
and Th17 pathways contribute to aGVHD and/or
cGVHD. How these differentiation pathways interact
to cause disease will likely be an important issue for the
development of rational therapy. In the future, armed
with this information, the field will need to progress to
well-designed prospective clinical studies using active
clinical grade IL-17 inhibitors currently in early phase
trials in inflammatory diseases such as psoriasis. It will
be critical to base these studies on informative preclin-
ical studies that demonstrate when and how IL-17A
[17-19], similar to IFN-g [13,52], might mediate
protective versus pathogenic effects after BMT.
ACKNOWLEDGMENTS
Financial disclosure: The authors did not supply any
financial disclosure.
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