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nature publishing group
See REVIEW page 129
See REVIEW page 104
The increasing prevalence of diseases involving an allergic com-
ponent is of global concern, accounting for a significant por-
tion of annual healthcare expenditures worldwide. 1,2 The most
prevalent forms of allergic disease are allergic rhinitis, asthma,
atopic dermatitis (AD), and food allergies. In general, allergy is
characterized by an overreaction of the immune system to normally
harmless foreign protein substances, known as allergens, follow-
ing exposure through various routes such as inhalation, direct
contact, injection, or ingestion. The symptoms of allergic reac-
tions present themselves systemically and vary widely in their
severity, with the organs and tissues involved dependent upon
the point of contact with the allergen. 3 Although some aller-
gic conditions develop through IgE-independent pathways, 2,4
allergy is primarily viewed as an IgE-mediated response that
progresses from an immediate hypersensitivity reaction due
to products of mast cell and basophil degranulation, to a late-
phase reaction characterized by leukocyte infiltration and
The primary immune cell lineages involved in the initiation
and progression of allergic inflammation include dendritic cells
(DCs), mast cells, basophils, eosinophils, and type-2 helper T
(Th2) cells. The responses of these principal players in allergic
reactions are influenced by the local environments in which they
reside. Immune cells localized within the epithelium at mucosal
surfaces are at the site of primary exposure to pathogens and
allergens. Consistent with this, recent evidence has demon-
strated the importance of epithelial cross-talk with immune
cells in developing innate and adaptive immune responses. In
addition to providing a barrier to the external environment, epi-
thelial cells express a variety of cell-surface and secreted factors
in order to appropriately control immune responses. 7,8 Among
the various secreted factors epithelial cells are capable of produc-
ing, cytokines have emerged as having a broad influence on the
development of allergic inflammation and many are targets of
novel therapeutics currently in development. While several epi-
thelial cell-derived cytokines are capable of influencing immune
responses, one of the most thoroughly studied in the context of
allergic inflammation is thymic stromal lymphopoietin (TSLP).
The focus of this review will primarily be to discuss the role of
TSLP in the cascade of events leading to allergic inflammation,
the association of TSLP and gene variants with allergic disease,
and to highlight recent progress that has been made in the iden-
tification of novel cell sources, functions, species-specific differ-
ences, and regulation of this potent cytokine.
TSLP: AN EPITHELIAL CELL-DERIVED CYTOKINE
ASSOCIATED WITH HUMAN ALLERGIC DISEASE
TSLP is a member of the hematopoietic cytokine family that
includes interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-13, IL-15, and
IL-21. The initial studies to elucidate the biological activities of
TSLP were focused on lymphopoiesis and similar to IL-7, TSLP
was found to support mouse B-cell expansion both in vitro and
in vivo. 9 – 12 Using a variety of methods several groups identified
a TSLP-binding protein in mouse, referred to as TSLP recep-
tor (TSLPR), and showed that it was a low-affinity receptor for
TSLP. Sequence analysis showed that TSLPR was similar to the
common cytokine-receptor ? -chain ( ? c ). 13 – 15 Further analysis of
The influence of TSLP on the allergic response
MR Comeau 1 and SF Ziegler 2
Exposure to allergens first occurs at body surfaces in direct contact with the environment such as the skin, airways, and
gastrointestinal tract, and compelling evidence suggests that allergic inflammatory responses are profoundly influenced
by the products of epithelial cells located at these sites. One such product is thymic stromal lymphopoietin (TSLP),
which is capable of affecting multiple cell lineages involved in allergic reactions. In this review we discuss recent work
that has provided insight into the role TSLP plays in both aberrant and protective allergic inflammatory responses, as
well as regulation, associations with disease, sources, and functions of this important cytokine.
1 Inflammation Research, Amgen Inc. , Seattle , Washington , USA . 2 Immunology Program, Benaroya Research Institute , Seattle , Washington , USA. Correspondence:
MR Comeau ( email@example.com ) .
Received 25 September 2009; accepted 16 November 2009; published online 16 December 2009. doi:10.1038 / mi.2009.134
MucosalImmunology | VOLUME 3 NUMBER 2 | MARCH 2010
the TSLP-receptor complex showed that the interleukin 7 recep-
tor alpha ( IL-7R ? ) chain was a component of the high-affin-
ity receptor, further linking these four-helix bundle cytokines.
Later, in silico methods were used to isolate clones of human
TSLP and TSLPR. 16 – 18 The human proteins were found to be
quite divergent from those in mouse at the sequence level, but, as
described below, functionally they behave in a similar manner.
Epithelial cells were found to be the principle source of TSLP, 19
while several hematopoietic lineage cells were found to express
both TSLPR and IL-7R ? , including DCs, monocytes, and
Studies of TSLP in humans demonstrated a potential role in
Th2 inflammatory responses. The first supporting data along
these lines were provided by a series of elegant experiments
demonstrating several key findings: Primary human CD11c +
myeloid DCs were found to coexpress the IL-7R ? and TSLPR
chains, and respond to TSLP stimulation by producing the CCR4-
binding, Th2 T-cell-attracting chemokines CCL17 and CCL22.
Unlike other common DC-activating factors, TSLP-treated DCs
are capable of priming na ï ve CD4 + helper T-cells to differentiate
into proinflammatory Th2 T cells producing IL-4, IL-5, IL-
13, and tumor necrosis factor- ? (TNF- ? ), but lower levels of
interferon- ? and IL-10. 19 Additionally, TSLP was shown to be a
potent DC survival and maturation factor inducing upregulation
of surface HLA-DR, CD40, CD80, CD83, and CD86. 17 Uniquely,
TSLP induces OX40-L on DCs in the absence of IL-12, and the
interaction between OX40 and OX40-L was identified as the
molecular signal TSLP uses to prime na ï ve T-cells for Th2
differentiation. 20,21 TSLP-treated DCs were also found to interact
with CRTH2 + CD4 + Th2 memory T-cells to support their main-
tenance and further polarization, 22 partially through upregulation
of IL-17RB, conferring Th2-T-cell responsiveness to IL-25. 23
It was established that in the steady-state TSLP is primarily
expressed by epithelial cells in the skin, gut, and lungs; how-
ever, under inflammatory conditions, several addition cell types,
including bronchial smooth-muscle cells and lung fibroblasts,
express TSLP. 19,24 In addition, TSLP protein was found to be
highly expressed in the lesional skin of patients with AD, but
absent in normal skin or in skin samples from patients with
Th1-type skin diseases, providing the first human disease asso-
ciation identified for TSLP. 19 TSLP expression in acute and
chronic lesions of AD skin is also associated with DC activation
and migration. 19 Together these seminal findings established
TSLP as the first epithelium-derived cytokine with the capacity
to skew the developing immune response toward a proallergic
state through its direct actions on DCs.
TSLP EXPRESSION INITIATES THE DEVELOPMENT OF
ALLERGIC INFLAMMATORY DISEASE IN VIVO
Human TSLP is found on chromosome 5q22.1, neighboring the
atopy and asthma-associated cytokine cluster on 5q31, 25 which
encodes IL-3, IL-4, IL-5, IL-9, IL-13, and the IL-4 receptor. 26
Like other Th2 cytokines its expression is associated with aller-
gic inflammation in both mice and humans. The development
of TSLP transgenic mice demonstrated that aberrant expres-
sion of this potent cytokine has dramatic local and systemic
effects. Transgenic TSLP expression under the control of the lck -
proximal promoter, which is preferentially active during early
lymphocyte development, 27 results in systemic inflammatory
disease involving the kidney, liver, spleen, lungs, and skin, and
formation of cryoglobulins. Interestingly, these mice demon-
strated progressive ulcerative lesions of the ears and a mixed
perivascular leukocyte infiltrate in the lungs, ultimately leading
to occlusion of the alveoli and death. 28 Mice expressing TSLP
under the control of the ubiquitous ? -actin promoter also devel-
oped lethal systemic inflammation involving the bone marrow,
spleen, thymus, and lungs. These mice display elevated serum
IL-5 levels and myeloid hyperplasia as evidenced by the pres-
ence of myeloperoxidase-positive granulocytes in the spleen.
As observed in lck -TSLP transgenic mice, the principal cause of
death in ? -actin TSLP transgenic mice was attributed to severely
compromised lung function. 29
Keratin-specific overexpression of TSLP in the skin under
control of inducible K5 30 or constitutive K14 31 promoters lead
to an AD-like phenotype, with the development of skin lesions
containing inflammatory cell infiltrate, increased Th2 cyok-
ines and chemokines in affected skin, and systemic increases
in IgE. The results from inducible K5-TSLP transgenic animals
are notable in their demonstration that mice born with normal
TSLP levels may develop severe allergic inflammatory disease
upon induction of TSLP. Similarly, in non-transgenic models,
aberrant TSLP expression can be induced by keratinocyte-spe-
cific ablation of retinoid X receptors (RXR) or topical application
of vitamin D3 and its low-calcemic analogues. This expression
leads to the development of an AD-like phenotype comparable
to that seen in TSLP transgenic mice. 31,32 Interestingly, the phe-
notype seen in both TSLP transgenic and vitamin D3-driven
models was reported to be independent of T and B-cells, 30,32
suggesting that the in vivo targets of TSLP at the sites of inflam-
mation are likely myeloid-derived cells, which are then capable
of initiating the disease process. 30
As overexpression of TSLP in the skin leads to an AD-like
phenotype, lung-specific overexpression of TSLP results in
severe allergic airway inflammatory responses with asthma-
like features. Mice overexpressing TSLP under the control of
the lung-specific surfactant protein-C promoter (SPC-TSLP)
develop Th2-biased CD4 + T-cell airway infiltrates, eosinophilia,
increased serum IgE, airway hyper-responsiveness, and remod-
eling. 33 A substantial reduction in airway inflammation and
remodeling was observed in IL-4- or STAT6-deficient mice
crossed with SPC-TSLP mice, or following blockade of IL-4 and
IL-13 in SPC-TSLP mice with established airway disease. These
results demonstrate that intact Th2 responses are necessary for
the development of TSLP-induced airway inflammatory disease
in this system. 34
TSLP also plays a role in allergen-driven models of airway
inflammation. In the ovalbumin-induced model of mouse
asthma (OVA-asthma), TSLP expression is increased in response
to antigen challenge and correlates with inflammatory cell infil-
trates 33 and IL-5 levels in the broncho-alveolar lavage fluid. 35
In this model TSLPR-deficient mice display greatly reduced
airway inflammatory responses 33,36 unless reconstituted with
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wild-type CD4 + T-cells. 36 As well, blockade of TSLP using a
TSLPR-Fc fusion protein 36 or a TSLPR-blocking antibody 35 sig-
nificantly alleviated the allergic airway inflammatory response.
Together these results highlight the involvement of TSLP signal-
ing in this common model of asthma.
The profound phenotypes observed in mice overexpressing
TSLP demonstrate the consequences of aberrant TSLP expres-
sion in vivo . Interestingly, administration of recombinant
TSLP protein to normal mice reveals differences in systemic
inflammatory responses and required mediators when com-
pared with endogenous TSLP-induced phenotypes. Repeated
intradermal TSLP administration over a 2-week time frame
resulted in the development of a systemic Th2 response and
a significant, diffuse inflammatory cell infiltrate in the skin
containing eosinophils and mast cells, with subcutaneous fibro-
sis. 37 In contrast to mice with dysregulated TSLP expression in
the skin, 30 – 32 in this model no skin lesions developed even after
6 weeks of TSLP administration (unpublished observations).
Interestingly, while T-cells were found to be unnecessary for the
phenotypes observed in mice expressing TSLP in the skin, 30,32
they were a required component for the response induced
following TSLP injection in the skin. 37 In an acute model of
lung inflammation, intranasal TSLP administration over a
2-week period induced only a mild inflammatory response in
the lung, unless co-administered with OVA as a model antigen 38
upon which mice develop a robust airway inflammatory
response. As well, OVA administration to SPC-TSLP trans-
genic mice prior to onset of spontaneous disease resulted in
accelerated disease development. Taken together these results
demonstrate the capacity of TSLP to drive the development of
allergic inflammatory responses upon exposure to normally
innocuous antigens. As observed in experiments involving
injection of recombinant TSLP in the skin, 37 T-cells were
found to be required for the TSLP + OVA-induced responses
and contribute significantly to the phenotype that develops in
the SPC-TSLP transgenic mice, indicating the requirement of
an adaptive immune response for the complete TSLP-driven
inflammatory response to develop in this model. 38 Multiple
factors could account for the differential responses seen in mice
expressing native TSLP versus those receiving recombinant
protein. Native mouse TSLP protein may have intrinsically
different activities as compared with recombinant protein, as
has been demonstrated with human TSLP. 39 As well, the recom-
binant TSLP used in both exogenous administration studies
contains 10 histidine residues at the C-terminus of the protein,
which may be seen as antigenic in mice repeatedly exposed to
the protein. Alternatively, the constant systemic exposure to
high levels of TSLP that occurs in transgenic and overexpres-
sion models may drive innate responses not seen with pulsatile
delivery of recombinant protein. We have observed that intra-
peritoneally administered TSLP protein is no longer detect-
able in the circulation 2 h post injection (unpublished results).
These caveats aside, both chronic and acute exposure to TSLP
above homeostatic levels influences multiple aspects of the
in vivo immune response, leading to the development of
inappropriate allergic inflammatory responses.
Eczema in early life is often associated with the development
of asthma and allergic rhinitis later in life, and this progres-
sion is referred to as the “ atopic march ” . 40 As demonstrated
in transgenic mice, dysregulated TSLP expression can lead to
the development of widespread and multi-focal inflammation,
which may initiate in one organ and ultimately lead to disease
in another tissue. The first data implicating TSLP with human
asthma pathogenesis was provided by in situ hybridization stud-
ies. Increased numbers of TSLP-expressing cells were found in
the epithelium and sub-mucosa of bronchial biopsies of patients
with asthma as compared with normal controls, and this expres-
sion correlated with disease severity. 41 An additional study of
broncho-alveolar lavage fluid from moderate-to-severe asth-
matics demonstrated elevated TSLP protein levels in asthma
patients as compared with normal controls, 42 suggesting that
TSLP mRNA expression may translate into the presence of pro-
tein in patients with asthma.
Recently, a large international study of four heterogeneous
asthma populations identified a genetic variant in the promoter
region of the TSLP gene that was associated with protection
from asthma, atopic asthma, and airway hyper-responsiveness.
Associations between TSLP and asthma-related phenotypes were
the most statistically significant observation in the study, which
included over 5,500 genotyped individuals. 43 An additional study
identified a TSLP-gene variant associated with lower levels of
allergen-specific IgE and total IgE in a gender-specific manner. 44
Collectively, these studies provide compelling human disease
association data and demonstrate that TSLP is necessary and
sufficient for the initiation and development of allergic inflam-
mation in rodents in vivo . The possibility that genetic variations
affecting TSLP expression may influence asthmatic and allergic
phenotypes across widespread populations, suggests an essential
and central role for TSLP in the development of allergic inflam-
REGULATION OF TSLP EXPRESSION IN THE PERIPHERY
Factors modulating TSLP expression encompass a wide variety
of stimuli, which may be of cellular, microbial, or environmen-
tal origin, many of which are relevant to allergic inflammation.
Constitutive TSLP expression is increased by the classic proin-
flammatory cytokines TNF- ? and IL-1 ? (or IL-1 ? ) in multiple
cell types and tissues, 19,39,45 – 49 and Th2 cytokines have also
been shown to influence TSLP expression. When used alone,
IL-4 and IL-13 are minimally effective at inducing TSLP expres-
sion, but when added in combination with either TNF- ? or IL-1
demonstrate considerable synergy in human skin, lung, and gut
samples. 45,48,50 In contrast, IL-13 stimulation alone has recently
been shown to induce robust TSLP production in mouse skin,
lung, and nasal tissue cultures, suggesting that TSLP may be
a downstream target of IL-13. 51 Interestingly, IL-13 does not
induce significant TSLP production in cultures of mouse small
and large intestine. 52 The promoters of both mouse and human
TSLP contain nuclear factor- ? B-binding sites that were found to
be critical for TNF- ? and IL-1 ? -induced TSLP transcription, 46
and mice with intestinal epithelial cell-specific deletion of IKK- ?
show reduced TSLP expression, 53 highlighting the importance of
MucosalImmunology | VOLUME 3 NUMBER 2 | MARCH 2010
the nuclear factor- ? B pathway in the regulation of TSLP expres-
sion. Additionally, members of the nuclear receptor superfamily
are involved in the regulation of TSLP expression. In the skin,
keratinocytes-specific ablation of the retinoid X nuclear receptor
? and ? chains was shown to result in increased TSLP produc-
tion in mice, leading to an AD-like phenotype, a response also
seen in mice topically treated with RXR agonists, vitamin D3,
or its low-calcemic analogues. 31,32
Microbial infections, pollution, and allergens are all known
to exacerbate allergic responses. Consistent with this, epithe-
lial TSLP expression has been shown to be increased following
incubation with bacteria, 24 infection of mice with the intesti-
nal nematode Trichuris , 54 stimulation with ligands for toll-like
receptors (TLR) TLR2, TLR3, TLR8, and TLR9, 39,45,46 rhino-
virus infection, 45 diesel exhaust particles, 55 or cigarette smoke
extract. 56 While IgE-activated mast cells induce TSLP produc-
tion from airway smooth-muscle cells in a TNF- ? -dependent
manner, other products of mast cell activation, as well as com-
mon allergens and TLR ligands, fail to induce TSLP from these
cells. 49 Mediators of allergic responses are also known to regu-
late TSLP expression. Mast cells express TSLP mRNA, which
is upregulated upon cross-linking of the IgE receptor, 19 and
pre-incubation with IL-4 results in significant upregulation of
IgE-mediated TSLP protein and mRNA expression. 57 Recently,
the contribution of proteases in regulating TSLP expression
from both epithelial and hematopoetic cells has been reported.
Proteases are a component of certain allergens and are also
secreted by helminths. 58 Proteases promote the development
of Th2 reactions, 59 and they are thought to provide a key link
between Th2 immune responses in anti-helminth immunity
and allergic responses. 60 A study using the model protease
allergen papain demonstrated its capacity to activate mouse
basophils and induce TSLP mRNA and protein expression from
these cells. 61 Similarly papain and trypsin were shown to induce
TSLP production from a human airway epithelial cell line. TSLP
expression in this system was amplified in the presence of IL-4
and dependent upon the protease-activated receptor, PAR-2. 60
Airborne allergens such as house dust mite are also associated
with protease activity and administration of house dust mite to
the airways of mice results in significant accumulation of TSLP
in the broncho-alveolar lavage fluid. 62
These recent advances in the understanding of factors and
pathways that regulate TSLP have provided significant insight
into scenarios that may lead to dysregulated TSLP expression
in allergic disease, and demonstrate that numerous microor-
ganisms and their products, known to be exacerbating factors
for allergic disease, may induce TSLP in sufficient amounts to
activate innate immune responses.
TSLP AND EFFECTOR CELLS OF THE ALLERGIC
Initially the contributions of TSLP to the development of Th2-
biased immune responses were focused on its DC-specific
activities. It is now clear that several other cell types involved in
the allergic response are capable of responding to TSLP under
permissive conditions ( Figure 1 ).
TSLP AND Th2 T CELL RESPONSES
Allergic inflammatory responses involve Th2 cell-derived
cytokines and a common hallmark of affected tissues is the infil-
tration of CD4 + Th2 cells. 2 In addition to influencing Th2-T-cell
differentiation indirectly through activation and programming
of DCs, TSLP directly influences CD4 + T-cell differentiation
into Th2 cells. TSLP was initially shown to induce prolifera-
tion of CD4 − CD8 − adult mouse thymocytes synergistically
with IL-1 ? 10 and TSLPR has been cloned from a Th2-skewed
mouse T-cell library. 15 Subsequently it was demonstrated that
upon T-cell receptor (TCR) engagement mouse and human
CD4 + T-cells respond to TSLP stimulation, 63 – 65 a response
likely mediated through TCR-mediated upregulation of TSLPR
expression. 65 In experiments using cells sorted to greater than
99 % purity, TSLP was shown to induce the differentiation of
mouse splenic CD62L high CD4 + na ï ve T-cells into Th2 cytokine-
producing cells that rapidly induced STAT5 phosphorylation
and IL-4 production in response to TSLP. 64 These data convinc-
ingly demonstrate that in the mouse, T-cells are direct targets
of TSLP capable of responding in the absence of DCs. A recent
study showed that TSLPR mRNA is not expressed in freshly
isolated na ï ve, central memory, CRTH2 + CD4 + memory Th2, or
effector memory human T-cell populations. 66 In this study the
authors did not determine whether TCR engagement conferred
responsiveness to TSLP with these isolated T-cell populations as
demonstrated in previous reports 63 – 65 Although the contribu-
tion of contaminating DCs in T-cell experiments has recently
been called into question, 67,68 collectively these data suggest that
T-cell activation is an additional mechanism by which TSLP is
able to contribute to the developing immune response in the
absence of DCs.
BEYOND DCs; TSLP IS A POTENT ACTIVATOR OF HUMAN
Along with DCs, mast cells are located at sites exposed to the
external environment such as the skin, airways, and gut, where
they serve as crucial sentinel cells in host defense. 69 Originally
thought of only in terms of their contributions to immediate
Figure 1 The constellation of TSLP-responsive cell types. TSLP
derived from epithelial, stromal, and granulocytic cells acts on a variety
of human and mouse cell populations, influencing multiple aspects of the
allergic inflammatory response. TSLP, thymic stromal lymphopoietin.
VOLUME 3 NUMBER 2 | MARCH 2010 | www.nature.com/mi
hypersensitivity reactions, the involvement of mast cells in innate
and adaptive immune responses is now evident. 70 – 74 Mast cell
numbers in normal tissues vary depending on their anatomic
location, and the severity of allergic responses are influenced by
their concentration in tissues. 3 Additionally, increased numbers
of mast cells have been demonstrated in a variety of autoimmune
and inflammatory conditions. 75 – 77 Among human hematopoietic
cells examined to date, mast cells are one of the only identified
non-epithelial sources of TSLP. In addition to providing a poten-
tial source of TSLP in response to IgE-receptor cross-linking, 19,57
mast cells express the functional TSLPR complex and respond to
TSLP in the presence of IL-1 and TNF- ? 39 or IL-33, 78 suggesting
that a proinflammatory environment is necessary to confer mast
cell responsiveness to TSLP. Interestingly, native TSLP protein
derived from both primary lung epithelial cells and lesional skin
samples from AD patients has been shown to potently activate
mast cells without inducing degranulation. TSLP stimulation
induced the release of several cytokines (IL-5, IL-6, IL-13, TNF- ? ,
and granulocyte – macrophage colony-stimulating factor) and
chemokines (CCL1 and CXCL8), but did not induce the release
of pre-formed, granule-associated mediators such as ? -hexosami-
nidase, histamine, leukotriene C 4 , and prostaglandin-D 2 . 39 These
data implicate TSLP in IgE-independent forms of asthma and
eczema, and suggest that in addition to DCs, mast cells at epithelial
surfaces may be activated by TSLP, thereby contributing to both
the initiation and perpetuation of innate immune responses.
Extending these findings, a potential role for TSLP as a media-
tor of cross-talk between bronchial smooth-muscle and mast
cells was identified. In asthmatic patients, mast cells are the
predominant inflammatory cells that accumulate within airway
smooth-muscle-cell bundles. 79 Mast cells play a key role in the
orchestration of airway inflammation through their release of
mediators capable of inducing bronchoconstriction, smooth-
muscle-cell proliferation, and recruitment and activation of
inflammatory cells. 80,81 TSLP mRNA is expressed constitutively
in cultured human bronchial airway smooth-muscle cells, 19
while protein expression is increased upon stimulation with
the proinflammatory cytokines TNF- ? and IL-1, 47 but not with
Th2 cytokines IL-4 and IL-13. 49 Additionally, individually or in
combination, TNF- ? and IL-1 induce TSLP production from a
variety of primary human cell types and tissues 19,39,47 – 49 Unlike
other cellular sources of TNF- ? in allergic inflammation, mast
cells are known to contain abundant pre-formed TNF- ? stores,
which are available for immediate release upon appropriate stim-
ulation, 6,82 suggesting that in IgE-dependent reactions mast cells
may represent a critical initial source of this proinflammatory
cytokine. 5 Supernatants from IgE-activated mast cells induce
bronchial smooth-muscle cell production of TSLP in a TNF- ? -
dependent manner and in turn bronchial smooth-muscle cell
-derived TSLP is sufficient to induce mast cell production of
IL-5 and IL-13. 49 Consistent with these data, mast cells were
shown to be necessary for TSLP expression in a model of allergic
rhinitis using mast cell-deficient mice. 83 Collectively these data
suggest a potential feedback loop where in an allergic state, IgE-
activated mast cells may provide the proinflammatory environ-
ment necessary for TSLP production possibly through release of
TNF- ? . In this environment TSLP may activate bystander mast
cells contributing to the exacerbation of allergic inflammatory
responses ( Figure 2 ).
THE EFFECTS OF TSLP ON PROGENITOR CELLS IN THE
The bone marrow is an active participant in systemic allergic
inflammatory responses as several granulocytic effector cell
types involved in allergic inflammation develop from CD34 +
bone marrow-derived progenitor cells. 84 While differentiation
and maturation of eosinophils and basophils from these progeni-
tors primarily occurs within the bone marrow, mast cell matura-
tion typically occurs in peripheral tissues. 5 CD34 + progenitor
cells are normally present in circulation due to constant release
from the bone marrow, 85 and in allergic individuals increased
numbers of progenitor cells are present in both the bone marrow
and peripheral blood. Upon allergen exposure these progenitors
traffic into local tissues where they are capable of maturing into
mast cells, eosinophils, and basophils depending on their local
environments. 84,86,87 In mouse, TSLPR mRNA is expressed in
hematopoietic progenitor cells and is upregulated in response to
granulocytic differentiation signals. 88 In humans, CD34 + pro-
genitor cells express TSLPR mRNA 78 and protein. 89 As observed
with mature mast cells, 39 these progenitors respond to TSLP
in the presence of co-stimulation with TNF- ? and IL-1 or IL-
33, 78 and rapidly produce abundant amounts of cytokines (IL-5,
IL-13, granulocyte – macrophage colony-stimulating factor, IL-6)
and chemokines (CXCL8, CCL1, CCL17, CCL22). Supernatants
from nasal explant cultures of chronic rhinosinusitis patients
have also been shown to induce the production of IL-5 from
CD34 + progenitor cells in a TSLP-dependent manner. 89 CD34 +
progenitor cells residing in or recruited to tissues exposed
to allergens may, therefore, contribute to proinflammatory
Figure 2 TSLP-mediated cross-talk between mast cells and airway
epithelial and smooth-muscle cells in both IgE-dependent and independent
inflammatory responses. Proinflammatory stimuli leading to epithelial
cell production of TSLP directly activates mast cells, inducing release of
multiple proinflammatory cytokines and chemokines independently of
IgE, whereas IgE-mediated mast cell activation leads to release of TNF- ? ,
which may drive TSLP production from smooth-muscle cells in the airway.
TNF- ? , tumor necrosis factor- ? ; TSLP, thymic stromal lymphopoietin.
MucosalImmunology | VOLUME 3 NUMBER 2 | MARCH 2010
processes following exposure to locally expressed, epithelium-
derived cytokines such as TSLP and IL-33. 89
BASOPHILS AND EOSINOPHILS
Along with mast cells, basophils and eosinophils are the primary
effector cells of immediate hypersensitivity reactions and allergic
disease. 3 In addition, basophils and eosinophils are implicated in
the pathogenesis of numerous inflammatory processes, includ-
ing parasitic helminth infections. Present as mature cells found
primarily in circulation, these cells can respond to a variety of
activating stimuli and rapidly migrate to sites of inflammation.
Both cell types are capable of a variety of immune functions and
release an array of cytokines, chemokines, toxic granule proteins,
and lipid mediators, thus participating as potent effector cells
in the exacerbation of inflammatory responses. 90 – 92 That TSLP
is capable of activating mast cells and the common progenitors
of eosinophils and basophils in the presence of proinflamma-
tory signals, suggests there may be similar cofactors or scenarios
where eosinophil and basophil responses to TSLP might occur.
Indeed two recent reports have emerged describing direct activi-
ties of TSLP on human eosinophils. Peripheral blood eosinophils
were found to express TSLPR and IL-7R ? at the message and
protein level, and respond to TSLP in a dose-dependent and
specific manner. 93 As well, eosinophil responses to TSLP were
synergistically enhanced in the presence of IL-3 and TNF- ? . 94
Interestingly, although TSLP induced the release of inflam-
matory cytokines (TNF- ? IL-6, IL-8) and chemokines (CCL2,
CCL3, CCL4, CXCL1, CXCL8), it did not induce degranulation
of eosinophils, 93,94 similar to what has been observed with mast
cells. 39 Additionally, both local and systemic allergic inflam-
matory responses to exogenous TSLP administration in the
mouse were shown to involve eosinophils. Repeated intradermal
administration of TSLP protein induces a systemic inflamma-
tory response that is largely Th2 in nature 37 and is characterized
by systemic increases in circulating IgE, local inflammatory cell
infiltrates, and increased Th2 cyokines and chemokines in the
skin. Eosinophil-deficient dblGATA 95 mice failed to develop
both local and systemic responses to TSLP 37 in this system.
Collectively these recent data imply that in both humans and
mice, eosinophils have the capacity to contribute to TSLP-driven
Although basophils constitute less than 1 % of circulating leu-
kocytes, these rare cells have potent effects on multiple aspects
of the allergic inflammatory response. Recent findings have pro-
vided new insight into the role of basophils in allergic disease
and immunity to helminths, suggesting that these cells may pro-
vide unique functions unmet by other hematopoietic cells. 92,96
Although no direct responses to TSLP have yet been described,
basophils have been identified as a potentially important source
of TSLP in vivo. Mice exposed to the model protease allergen
papain developed Th2 inflammatory responses with increased
systemic IgE levels and transient appearance of IL-4 and TSLP-
producing basophils in lymph nodes. Depletion of basophils
in this model demonstrated their necessity in the differentia-
tion of na ï ve CD4 T cells to Th2 cells. Additionally, basophils
stimulated in vitro with papain expressed TSLP mRNA, while
neutralization of TSLP in vivo inhibited papain-induced Th2
responses. 61 As well delivery of recombinant TSLP protein leads
to robust elicitation of basophils and their accumulation in the
periphery unlike other epithelium-derived cytokines such as IL-
25 and IL-33. 97 Taken together, these results suggest that in the
context of protease allergens, basophil-derived TSLP is neces-
sary for initiation of Th2 responses along with IL-4, and ascribe
a potentially unique attribute to TSLP in comparison with other
epithelium-derived cytokines that influence allergic inflamma-
tory responses. Although no examination of basophils in mice
overexpressing TSLP has been reported, these results suggest
that they are likely a component of the lethal systemic phenotype
observed in these animals. Thus, expansion of basophils under
conditions that lead to dysregulated expression of TSLP may be
a crucial early cellular response in the cascade of events leading
to allergic inflammation.
A role for CD1d-restricted natural killer (NK)T cells has been
proposed in asthma and although their contribution remains
controversial, a significant body of supporting data provides
a compelling case. 98 Mouse invariant NKT (iNKT) cells were
found to express both chains of the TSLPR and in the presence
of TCR stimulation, proliferate in response to TSLP. 99 While
the proliferative response required TCR stimulation, similar
to the TCR engagement required to confer TSLP responsive-
ness to CD4 + T-cells, 63 – 65 TSLP alone was able to induce IL-13
production from iNKT cells. 99 While iNKT cells preferentially
produced IL-13 upon TCR engagement, IL-4 and interferon- ?
were also abundantly produced in the presence of TSLP. When
SPC-TSLP transgenic mice were crossed with mice lacking
iNKT cells, no difference in the spontaneous development of
allergic inflammatory responses was observed, suggesting that
iNKT cells are not required for the phenotype observed in the
TSLP transgenic mice. Interestingly, in a standard OVA-asthma
model iNKT-deficient SPC-TSLP mice demonstrated signifi-
cantly reduced airway hyperresponsiveness and IL-13 pro-
duction, but no difference in pulmonary eosinophilia or IgE
when compared with controls. 99 It was therefore concluded that
iNKT cells are required for SPC-TSLP mice to develop AHR in
response to allergen challenge. Future studies will be required
to determine whether human iNKT cells respond to TSLP in a
A ROLE FOR TSLP IN GUT HOMEOSTASIS
Although allergic reactions to normally innocuous antigens can
result in damaging inflammation, Th2 immune responses are
thought to have developed partially in order to protect the host
from parasitic helminths, 100 clearly a beneficial aspect of this
arm of the immune response. TSLP is constitutively expressed
by epithelial cells in the intestine, with the highest levels found
in the proximal large intestine. 24,53,54,101 A critical role for TSLP
in the development of protective immunity to Trichuris muris
infection was identified in mice with reduced TSLP expression
due to an intestinal epithelial cell-specific deletion of IKK- ? . 53
Reduced epithelial TSLP expression in these mice was associated
VOLUME 3 NUMBER 2 | MARCH 2010 | www.nature.com/mi
with increases in pathogen-specific IL-12 / 23p40, IL-17, and
interferon- ? , and increased worm burdens as compared with
those in control mice. Similar Th1 responses were observed
in TSLPR-deficient mice, which also failed to expel worms. 53
Extending these observations, it was reported that TSLP neu-
tralization in normally genetically resistant mice also resulted
in increased susceptibility to Trichuris infection and reduced
Th2 cytokine production in the gut. Notably, blockade of inter-
feron- ? in TSLPR-deficient mice restored Th2 responses and
immunity to Trichuris , demonstrating that TSLP is dispensible
for the generation of protective Th2 cytokine responses in the
intestine. 101 Although the contribution of TSLP was less pro-
nounced, similar results were obtained in two additional stud-
ies using helminth infection models. 102,103 Consistent with a
role for TSLP at limiting inflammation in the intestine, TSLPR-
deficient mice develop more severe inflammation, increased
weight loss, and elevated Th1 cytokines in the dextran sodium
sulfate model of colitis. 101 Interestingly, TSLPR-deficient mice
also demonstrate reduced Th2 responses coupled with exag-
gerated IL-12 mRNA expression in the OVA-asthma model. 36
Collectively these results suggest a principal function of TSLP
in the intestine is to limit the production of non-protective Th1
cytokines and inflammation.
The IL-7R ? chain is required for TSLP and IL-7 signaling as
it is used by both cytokines in their receptor complexes. Mice
deficient in the IL-7R ? chain demonstrate impaired T and B-cell
development, 104 leading to deficiencies in both populations, and
treatment of mice with neutralizing antibodies to IL-7 results
in a similar phenotype. 105 In contrast, mice lacking the TSLPR
exhibit normal T and B-cell development and cellularity. 63,106
IL-7 uses the common cytokine-receptor ? -chain ( ? c ) as an
additional component of its receptor complex. 107,108 Injection
of TSLP into ? c -deficient mice enhances the expansion of both
T and B-cells, and interestingly, mice lacking both the TSLPR
and ? c display more severe lymphoid defects than ? c -deficient
mice. 63 As IL-7 and TSLP both use the IL-7R ? chain, these
results suggest there may be a role for TSLP in mouse T and
B-cell lymphopoiesis, although IL-7 likely plays the dominant
role. Additionally, humans with severe combined immunode-
ficiency due to IL-7R ? mutations lack T-cells but have normal
B-cell numbers, 109 a significant difference when compared with
mice lacking the IL-7R ? chain. While most of the identified
TSLP activities have been demonstrated in both mouse and
human systems, these findings suggest that like IL-7, species-
specific activities exist for TSLP.
At the amino-acid level there are additional differences in
TSLP to note between species. While the position of the six
cysteine residues involved in disulfide bond formation are con-
served across species, mouse and human TSLP share only 43 %
amino-acid identity overall. 10,16 We have determined that this
low level of conservation is also seen in additional rodent TSLP
sequences, including rat (45 % ) and rabbit (58 % ) ( Figure 3 ).
Not surprisingly, non-human primate TSLP displays a much
higher level of sequence conservation, with an amino-acid
identity of 93 % for chimpanzee and 90 % for the cynomol-
gus monkey. A comparison of TSLP amino-acid sequences
from several species reveals an interesting conservation in the
primate sequences of seven basic amino acids (KKRRKRK)
upstream of the final cysteine residue near the C-terminal end
of the protein 16 that is not present in any rodent sequence
identified to date ( Figure 3 ). This stretch of amino acids
encodes a putative furin cleavage site. 110 Furin is a proprotein
convertase enzyme that is typically involved in the post-trans-
lational processing of inactive precursor proteins into their
biologically active forms, an ancient mechanism that enables
cells to regulate the levels of bioactive proteins. 110 The pres-
ence of this conserved furin site in primate TSLP leads one to
speculate on what purpose it may serve, if any, in the proteins
biological activity. In an inflammatory state, furin cleavage
may be a mechanism used by the primate immune system to
limit the levels of bioactive TSLP protein in order to prevent
inappropriate inflammatory responses. In order to determine
whether this cleavage occurs and has any effect on TSLP activ-
ity, native TSLP expression would need to be examined both
in the steady state and under inflammatory conditions where
TSLP is thought to play a role.
Much progress has been made in the understanding of the
biological responses mediated by TSLP in the approximately
10 years since this cytokine was first cloned. Future studies
of the interplay of TSLP with additional epithelium-derived
cytokines such as IL-25 and IL-33 will likely reveal additional
cellular targets and exciting novel findings. The regulation of
TSLP by disease-relevant environmental factors, endogenous
proinflammatory cytokines, and effector cells of the allergic
response highlight the relevance of this epithelium-derived
cytokine in innate and adaptive immunity ( Figure 4 ) and make
it an especially attractive target to consider for therapeutic
intervention under both atopic and non-atopic conditions.
Figure 3 Species differences in the amino-acid sequences of TSLP.
Primate TSLP contains a putative furin cleavage site upstream of the
final conserved cysteine residue that is not present in rodent sequences.
TSLP, thymic stromal lymphopoietin.
MucosalImmunology | VOLUME 3 NUMBER 2 | MARCH 2010
We thank Heidi K. Jessup for excellent scientific contributions and critical
review of the manuscript.
Michael R. Comeau is an employee and shareholder of Amgen Inc.
© 2010 Society for Mucosal Immunology
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Figure 4 TSLP activation of key immune cells supports the
development of allergic inflammatory responses. Multiple environmental
and pathogenic factors are capable of inducing TSLP production from
epithelial cells, which may act as both an upstream and downstream
mediator of inflammatory responses through activation of inflammatory
cells of the innate and adaptive immune response. Recently, activated
basophils have been identified as an early source of IL-4 and TSLP,
which may serve to influence the differentiation of Th2 cells from na ï ve
T-cells. IL, interleukin; Th2, type-2 helper T-cells; TSLP, thymic stromal
VOLUME 3 NUMBER 2 | MARCH 2010 | www.nature.com/mi
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