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Discoveries made over the past two decades have mark‑ Specifically, IL‑17A produced within 4–8 hours after
Recombination-activating
gene edly changed the way we study immunological processes. microbial infection was shown to enhance neutrophil
(RAG). Expressed by Not the least of these was the identification and clon‑ chemotaxis by promoting IL‑6, granulocyte colony‑stim‑
developing lymphocytes, mice ing of several new cytokines, including interleukin‑17A ulating factor (G‑CSF) and CXC‑chemokine ligand 8
that are deficient for either
(IL‑17A)1 (BOX 1). These discoveries provided compelling (CXCL8; also known as IL‑8) production and to trigger
Rag1 or Rag2 fail to produce
B or T cells owing to a
reasons to explore outside the T helper 1 (TH1)– TH2 cell rapid, nonspecific immunity to infectious agents12.
developmental block in the paradigm in search of answers to explain the effector T cell So, what cell types are driving these early IL‑17‑
gene rearrangement that is responses that occur independently of known TH1 and TH2 dependent innate immune responses? It is notable that
necessary for receptor cell signalling pathways. It was clear that a strong T cell‑ the organ systems that protect the host from the environ‑
expression.
dependent response can occur even in the absence of the ment, specifically the lungs, intestinal mucosa and skin,
TH1 cell promoting factors interferon‑γ (IFNγ), IL‑12p35, seem to contain most of the IL‑17‑producing ‘sentinel’
signal transducer and activator of transcription 1 cells16. Because, these sentinel cells would not have time
(STAT1) and STAT4 or the TH2 cell promoting factors to sense processed antigens, undergo developmental and
IL‑4, STAT6 and GATA binding protein 3 (GATA3)2. expansion programmes and traffic to the site of injury,
Through the study of the role of IL‑23 in autoimmu‑ they probably reside in barrier tissues at the interface of
nity, it was discovered that an alternative T cell subset host and environment, possess a pre‑activated pheno‑
can promote chronic inflammation and tissue damage3–6. type and express an array of sensory receptors that
A rapid succession of studies defined the TH17 cell para‑ allow them to sample their surrounding milieu. Innate
digm, in which IL‑6–STAT3 activation of the transcrip‑ IL‑17‑producing cells can also interact with memory
tional regulator retinoic acid receptor‑related orphan cells during chronic inflammation17,18. The importance
receptor‑γt (RORγt) controls the lineage fate of IL‑17A‑, of TH17 cells in immune responses and diseases has been
IL‑17F‑, IL‑21‑ and IL‑22‑producing T cells (known as reviewed in detail elsewhere2,19,20, so we focus here on the
TH17 cells) that are highly responsive to IL‑1 receptor 1 innate sources of IL‑17 and how these cells are involved
Merck Research (IL‑1R1) and IL‑23R signalling 4–10. However, the TH17 in sensing stress and injury.
Laboratories, DNAX cell pathway was inadequate to explain the early IL‑17‑
Discovery Research,
mediated immune responses that have crucial roles Evidence for innate sources of IL‑17
901 California Avenue,
Palo Alto, California 94304, during stress responses and host defence. The IL‑17‑ Following the discovery that IL‑23 promotes the secre‑
USA. mediated immune pathway is induced within hours tion of IL‑17 by memory CD4+ T cells21,22, we observed
Correspondence to D.J.C. following epithelial cell injury or activation of pattern that IL‑23 also induced IL‑17 expression in recombination-
e-mail: recognition receptors (PRRs)8,11–13, which is not enough activating gene (RAG)‑deficient mice, which lack both
daniel.cua@spcorp.com
doi:10.1038/nri2800
time for the development of TH17 cells. It is important B and T cells, suggesting that innate IL‑17‑producing
Published online 18 June 2010; to remember that the earliest reported functions of cells are an integral part of IL‑17‑mediated immune
corrected online 25 June 2010 IL‑17A were its effects on innate immune responses 14,15. responses23. Using a T cell‑independent inflammatory
killer (NK) cells and myeloid cells26,28,36,37. Not surpris‑ epithelial cells, therefore CD27+ γδ T cells are thought to
ingly, each of these populations has an important role emerge from the thymus already ‘preactivated’ to make
in tissue surveillance, most notably in the gut, lung IFNγ38. CD25 (also known as IL‑2Rα) and CD122 (also
and skin. These cell populations share some common known as IL‑2Rβ) are also expressed by IL‑17‑ and IFNγ‑
activating signals, as well as unique pathways, and their producing γδ T cells, respectively 40,41. CD25 expression
function is vital to maintain the integrity of the target may be downregulated on γδ T cells that experience their
tissue (TABLE 1). How these distinct subsets of innate antigen in the thymus41, making them less sensitive to
cell populations help shape T cell effector and memory endogenous IL‑2 production. As IL‑2 is known to inhibit
responses and promote rapid antimicrobial immunity early TH17 cell development42, maintaining expression of
remains an area of active research. CD25, the high‑affinity receptor for IL‑2, on this subset
of thymic γδ T cells may also help to regulate the homeo‑
γδ T cells. The γδ T cell subset is an innate immune cell stasis of peripheral IL‑17‑secreting γδ T cells41 (FIG. 1). IFNγ‑
population that has an important role at the mucosal bar‑ secreting γδ T cells in the periphery also express NK1.1,
rier. However, the functional characteristics of γδ T cells whereas IL‑17‑secreting γδ T cells express CC‑chemokine
have been difficult to elucidate. It is now becoming clear receptor 6 (CCR6), which is also known to be expressed
that the function of γδ T cells, in addition to their anti‑ by TH17 cells40. Finally, a recent study showed that the
genic specificity, is influenced by a unique thymic selec‑ scavenger receptor SCART2 was exclusively expressed
tion process38. Because peripheral γδ T cells can recognize by peripheral γδ T cells that could be stimulated to pro‑
both self and non‑self ligands, it is thought that they can be duce IL‑17A43. As the phenotype of IL‑17A‑producing
divided into two broad categories of ‘antigen experienced’ γδ T cells becomes more clearly defined, we should gain
and ‘antigen naive’ γδ T cells38. In turn, these subsets can a better understanding of the role of these first‑responder
also be sorted based on several cell surface markers and cells to stress and injury.
according to whether they readily produce IFNγ or IL‑17
(FIG. 1). Consistent with this hypothesis, fetal thymocytes LTi cells. Seminal work establishing the importance of
can be segregated into IL‑17‑ or IFNγ‑producing γδ T cells Rorc (which encodes RORγt) in promoting IL‑17 pro‑
based on their expression of CD27 (a TNF family mem‑ duction by CD4+ T cells was paramount to our under‑
Common cytokine-receptor ber). CD27– γδ T cells from the thymi of e18 mouse standing of the biology of the TH17 cell developmental
γ-chain embryos were shown to constitutively express RORγt and programme. As a result, it led to the investigation of
A chain common to type I
runt‑related transcription factor 1 (RUNX1) and could be other cells that were already known to express the tran‑
cytokine receptors. It was first
discovered as the γ-chain of stimulated with phorbol 12‑myristate 13‑acetate (PmA) scription factor RORγt, such as LTi cells44,45, which
the IL-2 receptor and was and ionomycin to produce IL‑17 (REF. 39). By contrast, reside in peripheral lymph nodes, spleen and gut lam‑
subsequently shown also to be CD27 co‑stimulation of γδ T cells seems to be required ina propria. In general, LTi cells depend on expression
present in the receptors for for the generation of IFNγ‑producing γδ T cells, as well as of the transcription factor inhibitor of DNA binding 2
IL-4, IL-7, IL-9, IL-15 and
IL-21. It is mutated in humans
NKT cells. CD27+ γδ T cells were found to express Tbx21 (ID2)46, common cytokine-receptor γ-chain signalling and
with X-linked severe combined (which encodes T‑bet) and thus, in turn, make IFNγ39. The IL‑7R expression47–49 for their development and homeo‑
immunodeficiency. CD27 ligand CD70 is expressed constitutively by thymic stasis (TABLE 1). LTi‑like cells in the spleen28 share many
Thymus iNKT cells. iNKT cells are part of the innate immune
system and are activated in response to self and non‑self
No or weak glycolipid antigens presented by the non‑polymorphic
TCR engagement TCR engagement
mHC class I‑like molecule CD1d. iNKT cells rapidly
produce immunoregulatory cytokines following acti‑
CD44 vation by foreign or self glycolipids57. iNKT cells have
CD44 CD122 a key role in immune surveillance, as well as immune
CCR6 suppression, and have been divided into subsets that
TCR TCR produce either IL‑4 or IFNγ. Recently, a new IL‑17‑
NK1.1 producing iNKT cell subset that develops in the thymus
RORγt
Stress
T-bet has been described58. Treatment of CD44hiNK1.1–CD4–
IL-1R1 receptor iNKT thymocytes with the glycolipid α‑galactoceramide
(α‑GalCer) stimulated IL‑17 production, indicating that
γδ T cell γδ T cell a subset of iNKT thymocytes are already committed to
IL-23R SCART2
IL-18R IL-12R making IL‑17 (REF. 58). Furthermore, NKT cells in the
peripheral blood of simian immunodeficiency virus‑
IL-17 IFNγ infected rhesus macaques were found to secrete IL‑17
Figure 1 | Developmental programming of γδ T cell and express CD161 and CCR6 (REF. 59), consistent with
subsets. Certain subsets of γδ Nature
T cells may leave
Reviews the
| Immunology other IL‑17‑producing populations. IL‑17+ iNKT cells
thymus programmed to secrete either interleukin‑17 express RORγt and IL‑23R but not T‑bet (TABLE 1).
(IL‑17) or interferon‑γ (IFNγ) once they enter the By contrast, T‑bet + iNKT cells express NK1.1 and
periphery. It is hypothesized that the predilection towards
produce IFNγ36. Of note, IL‑6, which is important for
a particular functional programme by a γδ T cell is
determined in part by the strength of signal as it develops lineage commitment of T H17 cells, is not required
within the thymus. T cell receptor (TCR) engagement and/ for IL‑17‑producing iNKT cell development and func‑
or coincident co‑stimulation in the thymus will bias the tion60. However, the precise signals that induce RORγt
cell towards an IFNγ‑secreting programme. By contrast, expression and lineage commitment of IL‑17‑producing
lack of TCR engagement or weak TCR signalling will iNKT cells are not known.
promote an IL‑17‑secreting programme. Whether or not
these subsets are truly mutually exclusive has yet to be NK cells. NK cells have also drawn considerable interest;
shown. However, several surface receptors have been however, to date, only one report has shown evidence
identified by various laboratories as being associated with for the ability of NK cells to produce IL‑17 (REF. 37).
either IL‑17‑ or IFNγ‑producing γδ T cells. CCR6,
Peritoneal NK1.1+ NK cells isolated from Toxoplasma
CC‑chemokine receptor 6; R, receptor; RORγt, retinoic
acid receptor‑related orphan receptor‑γt. gondii‑infected mice were shown to produce IL‑17A in
an IL‑6‑ and IL‑23‑dependent manner 37. However, it
has been suggested that mucosal NK cell populations
phenotypic similarities with LTi cells. Although LTi cells expressing NKp46 or NKp44 markers are a different
have been shown to be required for lymph node develop‑ lineage from the classical NK cell population found
ment 50–53, it is unknown whether LTi‑like cells can also in the periphery 27, and they may instead be related to
induce lymph node organogenesis; therefore, they cannot LTi cells61,62. whether or not these cells can produce
yet be termed true LTi cells. when stimulated with either IL‑17 has yet to be determined; however, several studies
exogenous IL‑23 or the TLR2‑agonist zymosan, LTi‑like have reported that CD3–NKp46+ cells can constitutively
cells can produce IL‑17 (REF. 28); however, expression of secrete substantial amounts of the TH17 cell‑associated
specific TLRs by these cells has not been shown. In addi‑ cytokine IL‑22 (REFs 26,63–65). This NK cell subset is
tion, both mouse and human LTi cell populations can dependent on both RORγt and ID2 and are poor IFNγ
produce IL‑22 following stimulation ex vivo with PmA producers61,66 (TABLE 1). Further investigation of NK
and ionomycin or with TLR agonists54,55. cells that can rapidly produce IL‑17 and/or IL‑22 is
In mice, LTi and LTi‑like cells have been defined as warranted, given that they will probably be an impor‑
leukocyte lineage marker (LIN)–CD4+CD127+ cells that tant population for mediating efficient early immunity
express lymphotoxin‑α (LTα) and LTβ and the chemo‑ under various conditions.
kine receptors CCR7 and CXC‑chemokine receptor 5
(CXCR5)56. By contrast, human LTi cells are LIN–CD4– Paneth cells. Paneth cells are highly specialized epi‑
CD127+CD45mid cells54. Following more rigorous exam‑ thelial cells thought to be involved in mucosal homeo‑
ination, other disparities between human and mouse stasis and immunity. Known for their production of
LTi cell surface markers have been noted: both CD7 antimicrobial peptides, they have been intimately
and CD161 (also known as KLRB1) are expressed by linked with innate immune responses in the gut 67,68.
human LTi cells, markers that are more characteristically In addition, Paneth cells have been shown to produce
expressed by human NK cells54. In fact, the development various pro‑inflammatory mediators, such as TNF and
of CD56+ NK cells expressing Rorc transcripts could be nitric oxide, and can respond to inflammatory stim‑
induced from human LTi precursor cells27,54, suggesting uli through cytokine receptors or intracellular PRRs,
a common lineage for these IL‑17‑ and IL‑22‑producing such as nucleotide‑binding oligomerization domain 2
populations. (NOD2)69–73. Thus, Paneth cells may actively promote
chronic inflammation after exposure to inflammatory diverse anatomical locations — mainly in the lungs, liver,
cytokines such as TNF through a positive feedback skin, gut and secondary lymphoid organs — suggests
loop that induces increased pro‑inflammatory cytokine that they have a broad range of immune regulatory func‑
production in the mucosa. tions that has yet to be fully elucidated. The gut mucosal
Paneth cells activated in a model of TNF‑induced tissue seems to harbour the highest numbers and types
shock have been shown to rapidly secrete IL‑17 (REF. 74) of innate IL‑17‑producers77,78. Indeed, a new subset of
and are therefore another innate source of this cytokine. innate lymphoid cells has been recently described that
Furthermore, IL‑17 expression detected at the bottom is characterized as THy1hiSCA1+LIN–KIT–CD3–CD4–
of crypts in the jejunum of naive mice was found to co‑ (REF. 79) (TABLE 1). These cells are CCR6+ and reside in the
localize with Paneth cells74. These specialized epithelial intestinal lamina propria and can readily expand more
cells constitutively express intracellular IL‑17 and can than 100‑fold during microbial infection. Following
efficiently release cytokine stores following stimula‑ stimulation with IL‑23, this innate population pro‑
tion. IL‑17 could then feed forward to promote more duces high levels of IL‑17, IL‑22 and IFNγ and seems
TNF production followed by increased IL‑6 and nitric to be uniquely regulated by RORγt and T‑bet but not
oxide. In addition, IL‑17‑encoding mRNA is rapidly by the TH17 cell‑associated transcription factor aryl
upregulated to replace the spent store of IL‑17 (REF. 74). hydrocarbon receptor (AHR) (see below)79.
Paneth cell‑derived IL‑17 was shown to be responsible Although many innate lymphoid subsets are found
for increased chemokine production and recruitment in the tissues with barrier functions, during a tissue‑
of neutrophils74. Taken together, these data provide an specific inflammatory response these cells can also
additional mechanism for acute production of IL‑17. migrate from secondary lymphoid organs to immune‑
Given the role of these specialized epithelial cells in privileged sites, such as the central nervous system
immune surveillance, it is conceivable that these stores (CNS), where they participate in the disease process17.
of IL‑17 could provide a rapid and efficient mechanism we now have a fundamental understanding of how
to respond to mucosal pathogens. the IL‑17R signalling pathway, through the adaptor
molecule ACT1 (also known as CIKS) and the tran‑
Neutrophils. A recent report75 suggests that myeloid cells scription factor nuclear factor‑ κB (NF‑κB), induces
can produce IL‑17 in response to ‘sterile’ injury such as downstream mediators, including IL‑6, CXCL8 and
ischaemia, in which there is recruitment of neutrophils CC‑chemokine ligand 20 (CCL20)80. we next discuss
into the damaged tissue. In a model of acute kidney the common activating signals shared among the innate
ischaemia–reperfusion injury, early production of IL‑23 acti‑ IL‑17 producing cells, as well as the unique pathways
vates downstream IL‑17‑mediated pathways, including that regulate them.
chemokine production and recruitment of neutrophils.
most of the initial IL‑17 in the kidney was produced by Regulation of innate IL‑17‑producing cells
bone marrow‑derived CD11b+GR1+ cells and not by Transcriptional regulation by RORγt and AHR. The
lymphocytes75. This IL‑17 production directly promoted orphan nuclear receptor RORγt has been shown to induce
kidney damage as measured by serum creatinine levels after the transcription of genes encoding IL‑17. Although IL‑6‑
injury induction. Furthermore, transfer of CD11b+GR1+ dependent STAT3 activation is thought to be crucial for
cells to Il17a–/– mice promoted an injury response, which RORγt expression and development of TH17 cells, careful
could be subsequently blocked by IL‑17‑specific anti‑ examination of IL‑6‑deficient mice revealed several sub‑
body75. Interestingly, IFNγ production was also decreased sets of IL‑17‑producing cells that arise independently of
in the absence of IL‑17, suggesting that IL‑17 promoted this cytokine60,81,82, including iNKT cells, γδ T cells, LTi‑
pathogenic levels of IFNγ that exacerbated tissue injury. like cells and NK‑like cells (FIG. 2). The fact that these cells
An earlier study also shows that Il17 mRNA can be do not require IL‑6 stimulation raises an interesting ques‑
detected in purified neutrophils after administration of tion: what promotes preferential RORγt expression in
anti‑neutrophil cytoplasmic autoantibodies (ANCA) to these innate populations? In αβ TCR thymocytes, RORγt
induce arthritis76. GR1hiCD11bmidF4/80– neutrophils iso‑ is first induced as a crucial survival factor83 for CD4+CD8+
lated after ANCA injection could be stimulated ex vivo (double positive) thymocytes; as these cells mature and go
with PmA and ionomycin in the presence or absence through the TCR selection process, RORγt is repressed.
of myeloperoxidase‑specific ANCA to produce IL‑17 Subsequent activation with TGFβ and IL‑6 is required
(REF. 76), suggesting these cells may be contributors to the to induce the re‑expression of RORγt for TH17 cell dif‑
pathogenesis of the disease. However, there remain many ferentiation10. By contrast, the subsets of γδ T cells and
open questions; for example, it is unknown whether iNKT cells that exit the thymus without going through
Ischaemia–reperfusion neutrophils express IL‑23R, through which signalling TCR selection do not repress RORγt expression and seem
injury
is required for most IL‑17‑producing cells, or whether to preferentially develop into IL‑17‑producing cells58,84.
An injury in which the tissue
first suffers from hypoxia as a these cells exhibit IL‑17‑inducing transcription factors, Interestingly, the subsets of γδ T cells and iNKT cells that
result of severely decreased, such as RORγt or RORα. whether these cells respond do go through TCR selection preferentially express T‑bet
or completely arrested, blood to stimuli distinct from those already known to induce and produce IFNγ38. However, more work is needed to
flow. Restoration of normal IL‑17 production also remains to be determined. confirm this TCR selection hypothesis for the ‘default’
blood flow then triggers
inflammation, which
Although we have described many subsets of innate development of innate IL‑17‑producing cells. Another
exacerbates the tissue IL‑17‑producing cells, it is likely that more will be uncov‑ hypothesis that may be more applicable for CD3– LTi
damage. ered. The observation that these innate cells reside in and NKp46+ cells is that other STAT3 activators, such as
STAT3 IL-17
↑ STAT3
Antigen- RORγt IL-22
Differentiation RORγt
presentation and AHR
in lymph node
co-stimulation
Naive CD4+ Polarized effector
T cell TH17 cell
3–5 days
IL-1β
IL-23
IL‑21 and IL‑23, could initiate the RORγt‑mediated pro‑ owing to their proximity to the environment. However
gramme (FIG. 2). Further studies are needed to formally it is conceivable that this sensor capable of detecting
test whether IL‑21‑ and/or IL‑23‑induced STAT3 signal‑ toxic pollutants may predispose individuals to chronic
ling is necessary and sufficient for LTi and NKp46+ cells inflammatory disorders.
to turn on RORγt expression.
AHR is another transcriptional regulator that con‑ Cytokines that regulate innate IL‑17‑producing cells. A
trols IL‑17‑associated immune responses85. It is a nuclear common characteristic of many of these innate IL‑17‑
receptor that senses environmental toxins, such as dioxin producing cells is the constitutive expression of IL‑1R1
and FICZ (6‑formylindolo[3,2‑b]carbazole)86,87. Recently, and IL‑23R36,82,89,92–94, both of which are also important
AHR was shown to be expressed by TH17 and regulatory to potentiate the TH17 cell differentiation programme
T cells, suggesting a link between toxic environmental (FIG. 2). Studies have now shown that in vitro stimula‑
pollutants and tissue inflammation18,88. Importantly, AHR tion of γδ T cells with IL‑1β or IL‑23 can promote rapid
is also expressed by γδ T cells, LTi cells and NK cells and IL‑17 secretion17,89; optimal IL‑17 production is induced
is important for their effector functions, including IL‑22 following culture with both IL‑1β and IL‑23 (REF. 17).
production26,89 (TABLE 1). whether other IL‑17‑producing Furthermore, 4 hours after injection of IL‑1β and IL‑23
myeloid cells also express AHR is currently unknown. It into the footpad of mice, γδ T cells in the draining lymph
has been suggested that AHR can cooperate with RORγt node were already stimulated to secrete IL‑17 (REF. 17).
to induce maximal amounts of IL‑17 and IL‑22 produc‑ Ex vivo stimulation of LTi cells with IL‑23 also induced
tion and to inhibit TGFβ‑induced FOXP3 expression90. the secretion of IL‑17 (REFs 28,54). Similar results were
In addition, AHR was shown to co‑immunoprecipitate obtained in studies culturing iNKT cells, from the drain‑
with STAT1 and STAT5. This interaction was thought ing lymph nodes of type II collagen‑immunized mice,
to be relevant for suppressing STAT1‑ and STAT5‑ with IL‑23 (REF. 93). Furthermore, human NKT cells
mediated signalling and thus enhancing the effects of treated with IL‑23 in vitro produced IL‑17 (REF. 82).
IL‑23‑ and RORγt‑dependent functions91. The expres‑ Although not strictly dependent on CD1d ligation, co‑
sion of AHR by innate sentinel cells seems fortuitous activation of iNKT cells with IL‑23 and α‑GalCer was
production can be detected a few hours after exposure production of ReG3γ is maintained at low levels by com‑
and can be maintained for days, suggesting that these mensal flora and is strongly induced by pathogens such
cells may be required for enhancing the antimicrobial as C. rodentium and L. monocytogenes 8,116,117.
response105. IL‑17‑producing γδ T cells are also found One intriguing implication of these studies is that
in the liver during the first three days of infection the composition of gut commensal species can skew
with intracellular pathogens such as Listeria mono- the mucosal immune effector cell balance. For exam‑
cytogenes and T. gondii 107,108. This early IL‑17 produc‑ ple, a recent study has shown that a single group of
tion is required for optimal neutrophil recruitment to commensal bacteria, segmented filamentous bacteria
the liver and resistance to the infection. It is important (SFB), preferentially induced intestinal IL‑17‑producing
to note that innate IL‑17 populations not only interact cells77. mice that are free of SFB have few gut‑resident
with pathogens during infection, but also interact with IL‑17‑producing cells and were shown to be more sus‑
the commensal flora to maintain mucosal homeostasis. ceptible to Citrobacter spp. infection. Transfer and coloni‑
Recent studies have suggested that this interaction with zation of SFB in these mice increased the number of gut‑
the intestinal microbiota is an important defining fea‑ resident IL‑17‑producing cells and enhanced resistance
ture of IL‑17‑producing cells — the sentinels of the to the inflection77. These findings suggest that increases
mucosal barrier. in mucosal IL‑17 and IL‑22 production — which induce a
subset of antimicrobial peptides that target specific groups
Early IL‑17 and surveillance. Although there is compel‑ of bacteria — may ‘re‑shape’ the gut microbiota. In turn,
ling evidence in the literature of the destructive nature of gut commensal organisms can specifically promote IL‑17‑
dysregulated IL‑17‑mediated inflammation, it has long secreting cells by inducing IL‑1R1 expression on their sur‑
been known that IL‑17 also has an important role in main‑ face92. During SFB colonization, it is likely that the sentinel
taining mucosal barrier integrity both during homeostasis innate IL‑17 producing cells, such as LTi cells, NKp46+
and pathogenic insults109,110. One way IL‑17 can preserve cells and γδ T cells, are the first responder populations and
tissue integrity is by enhancing synthesis of tight junction influence the development of TH17 cells. These innate
proteins, such as claudin111. These tight junction proteins and memory cells would act in concert to produce a basal
form interconnecting ultra‑structures between epithelial level of IL‑17 and IL‑22, which then maintain a consti‑
cells to keep out gut luminal contents and commensal tutive level of antimicrobial proteins. In addition, there
organisms (FIG. 3). The importance of IL‑17 in sustaining are many checks and balances in this system to maintain
the integrity of the intestinal cell wall was shown in stud‑ mucosal homeostasis, and FOXP3+ regulatory T cells have
ies where neutralization of IL‑17 exacerbated epithelial an important role in opposing the effects of the IL‑17‑
destruction in a colonic injury model112. producing cells118. Given the pro‑inflammatory activities
Another mechanism for the protective effects of of IL‑17 and IL‑22 in this model, it is conceivable that a
IL‑17 is the induction of antimicrobial agents such as dysregulated interaction between sentinel IL‑17‑producers
β‑defensins, regenerating (ReG) proteins, S100 proteins, and pathogenic organisms could lead to skewing of the
lipocalins and lactoferrins (FIG. 3). These microbicidal effector versus regulatory cell balance and predispose an
agents are predominantly produced by epithelial cells, individual to chronic inflammatory diseases.
as well as neutrophils and macrophages that constitu‑
tively express IL‑17R. It is notable that IL‑17 often works Early IL‑17 and autoimmunity. Recent studies have
cooperatively with IL‑22. These two cytokines can be co‑ begun to elucidate the role of innate IL‑17‑producing cells
produced by γδ T cells, LTi cells and THy1hiSCA1+ cells, in priming and perpetuating autoimmunity. Although
although they may preferentially produce only IL‑17 or innate cells do not recognize specific peptide antigens
IL‑22 at a given time point17,26–28,79. exactly what regulates presented by accessory cells and cannot, therefore, initi‑
differential IL‑17 and IL‑22 production is not known. ate an immune response against self antigen, they may still
In the airways, IL‑17 and IL‑22 have been shown to have an important role in shaping the cytokine milieu in
work together to promote the secretion of β‑defensin 2, a target organ to favour the induction of chronic inflam‑
β‑defensin 3 and calgranulin by bronchial epithelial mation. The immune ‘feedforward’ loop between mucosal
cells25,113. Induction of lipocalin‑2 expression by IL‑17 and pathogens and an inflammatory ‘TH17‑type’ response is a
IL‑22 in tracheal epithelial cells is essential for killing of good example. Among the many subsets of innate IL‑17
the Gram‑negative pathogen K. pneumoniae25,114. producing cells, γδ T cells have received the most atten‑
In the gut mucosa, IL‑17 and IL‑22 have synergistic tion regarding their participation in both the induction,
effects on the induction of antimicrobial proteins such as as well as the effector, phase of autoimmune inflamma‑
ReG3γ by gastrointestinal epithelial cells, which has an tion17,29,30,31. For example, in a model of collagen‑induced
important role in the control of pathogens and limits dis‑ arthritis, γδ T cells were found to be an important source
Tight junction
semination of commensal bacteria that could penetrate a of early IL‑17 produced in response to IL‑1β and IL‑23
A belt-like region of adhesion
between adjacent epithelial or disrupted epithelial barrier 8,115. ReG3γ is a soluble C‑type signalling 30. It is thought that γδ T cells are activated
endothelial cells that regulates lectin produced by Paneth cells and interacts directly directly by complete Freund’s adjuvant (CFA), which is
paracellular flux. Tight junction with the bacterial cell wall to promote its anti‑microbial used in the protocol to help induce collagen‑induced
proteins include the integral activity 116. mice lacking IL‑22 and IL‑23 have reduced arthritis 29. Cooperation between IL‑17‑producing
membrane proteins occludin
and claudin, in association with
amounts of S100A8, S100A9, ReG3β and ReG3γ and γδ T cells and antigen‑specific CD4+ αβ T cells was
cytoplasmic zonula occludens were highly susceptible to C. rodentium infection but can shown to enhance the pathogenesis of experimental auto‑
proteins. be rescued by treatment with recombinant ReG3γ8. The immune uveitis after immunization with the autoantigen
Blood–brain barrier interphotoreceptor retinoid‑binding protein31. In a CNS receptor complexes (reviewed in REF. 80) — which are
A physiological barrier autoimmune model, when γδ T cells were depleted dur‑ highly expressed by epithelial cells — recruits neu‑
between blood vessels and ing immune priming, fewer myelin‑oligodendrocyte trophils, promotes secretion of defensin‑like factors
brain parenchyma. It is formed glycoprotein (mOG)‑derived antigen specific TH17 cells and maintains tight junction structure of the intestinal
by specialized tight junctions
between endothelial cells of
develop in vivo, suggesting that γδ T cells may promote wall; together, these factors maintain mucosal tissue
the blood vessel wall, which is the expansion of antigen‑specific TH17 cells17. In addition, barrier functions. Despite these important insights,
surrounded by a basement treatment with IL‑1β and IL‑23 could induce γδ T cell we still do not fully understand the effects of IL‑17 in
membrane and an additional secretion of IL‑17 without the need for TCR engagement. immune privileged sites such as the CNS, where IL‑17 is
membrane formed from
Remarkably, in vivo injection of IL‑1 and IL‑23 could produced by both adaptive TH17 cells and innate γδ
astrocyte feet and microglial
cells, known as the glial limitin.
induce γδ T cell expression of Il17 mRNA in just 4 hours17. T cells17. A recent report suggested that the IL‑17R
Together, these results indicate that early production of complex is expressed by astrocytes that form part of the
IL-23ReGFP and RORγteGFP cytokines by innate IL‑17‑producers may enhance devel‑ blood–brain barrier and that these cells are an important
reporter mice opment of pathogenic TH17 cells, although the precise initial IL‑17‑responder population that control inflam‑
Mice expressing enhanced
green fluorescent proteins
mechanism has not been elucidated. One suggestion was matory responses in the CNS123. whether additional
(eGFP) under the control of the that innate cell‑produced IL‑17 could act as a paracrine subsets of glial cells also express the IL‑17R complex and
IL-23R (encoded by Il23a) or factor to promote activation of TH17 cells17. whether how early IL‑17 signalling affects brain inflammation
RORγt (encoded by Rorc) IL‑17 can signal and activate CD4+ T cells as an autocrine remain important areas of research.
promoter. These mice can be
and/or paracrine factor remains controversial. A recent we still do not fully appreciate the roles of
used to track the
differentiation, proliferation,
study, using surface plasmon resonance analysis, showed IL‑23R+RORγt+ innate cells in the mucosal tissues.
migration and effector function that once an IL‑17 molecule is bound by an IL‑17RA mol‑ One issue is that many of these cells lack lineage mark‑
of IL-17-producing cells. Gene ecule, the binding affinity for a second IL‑17RA is reduced ers, making it difficult to study their developmental
targeting vectors are generated by three logs, whereas the affinity of IL‑17RC for IL‑17 pathway and function. It is likely that they are impor‑
by introducing eGFP sequences
into bacterial artificial
remains high, thereby promoting heterodimeric rather tant tissue‑resident first responders during microbial
chromosome (BAC) clones than homodimeric receptor formation119. Fibroblasts, or toxin insults. with the availability of IL-23ReGFP and
containing the Il23a or Rorc epithelial cells and endothelial cells express both IL‑17RA RORγteGFP reporter mice, it may be possible to dissect the
gene. The targeting constructs and IL‑17RC, whereas T cells express IL‑17RA but not in vivo functions of these lineage marker‑negative cells.
are introduced into embryonic
IL‑17RC120. These findings raise the possibility that T cells, The fact that LTi‑like and NK‑like cells are also found
stem cells and injected into
mouse blastocysts to generate
which bear the homodimeric IL‑17RA receptor complex, in the spleen and other lymphoid tissue is interesting.
eGFP transgenic mice. The may have a lower affinity for IL‑17 than macrophages and Perhaps these cells produce early IL‑17 and induce APCs
eGFP is co-expressed with epithelial cells that express high‑affinity heterodimeric to secrete IL‑1, IL‑6 and IL‑23, thereby enhancing TH17
IL-23R or RORγt, which allows IL‑17RA–IL‑17RC receptor complexes119,120. cell priming 17,120. Are these LTi‑like and NK‑like cells
cell fate analysis of
IL-17-producing cells during an
An alternative suggestion for the mechanism by which part of the same population of mucosal residents that
immune response. innate cell‑produced IL‑17 can enhance autoimmune then migrate throughout the host organism? If so, what
inflammation, is that early IL‑17 can act on antigen‑pre‑ factor (or factors) controls their decision to reside in
senting cells (APCs), such as macrophages and subsets of the peripheral tissue or to migrate to lymphoid organs?
dendritic cells17, which could express both IL‑17RA and These are important areas of research that will shed light
IL‑17RC120. IL‑17 has been shown to directly induce APC on the complex regulation and function of these cells.
production of IL‑23, IL‑1, IL‑6 and TGFβ17, which are the Finally, the clinical relevance of innate IL‑17‑
crucial factors for development of pathogenic TH17 cells. producing cells is now better understood. IL‑23R poly‑
In this way, innate IL‑17 produced early during immune morphisms are associated with psoriasis, ankylosing
priming could influence the generation of antigen‑specific spondylitis and inflammatory bowel disease124,125,126 — a
TH17 cells and exacerbate autoimmunity. In humans, γδ cluster of diseases with a well recognized clinical asso‑
T cells have been found to accumulate in acute multiple ciation and overlap. It has become evident that animal
sclerosis lesions121, as well as in cerebrospinal fluid of models of these inflammatory diseases can be induced
patients with recent‑onset multiple sclerosis122, suggesting in the complete absence of adaptive immune cells. This
that innate cells may also have a role in human disease. is likely to have important consequences for therapeutic
treatments as current clinical studies have shown efficacy
Conclusions and future directions for targeting IL‑17 and IL‑23 in human autoimmune dis‑
It is evident that both adaptive T cells and innate cell orders127,128. Understanding these early innate immune
populations can produce IL‑17, and this has crucial roles responses will be the key to designing rational therapies
in mucosal tissues. Signalling through IL‑17RA–IL‑17RC targeting these important immune pathways.
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