Allergology International xxx (xxxx) xxx

Contents lists available at ScienceDirect

Allergology International
journal homepage: http://www.elsevier.com/locate/alit

Invited Review Article

Pathogenic helper T cells

Kiyoshi Hirahara a, b, *, Ami Aoki a, Toshinori Nakayama a, c, **
a
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
b
AMED-PRIME, AMED, Chiba, Japan
c
AMED-CREST, AMED, Chiba, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Intractable chronic inflammatory diseases, including autoimmune diseases, autoinflammatory diseases
Received 5 February 2021 and allergic diseases, are caused by disruption or failure of the immune system. Pathogenic immune cells
Available online xxx are presumed to be closely related to the pathogenesis of intractable diseases, but the precise cellular and
molecular mechanisms underlying the pathogenesis of these diseases remain unclear. The balance be-
Keywords: tween the T helper type 1 (Th1) and Th2 cell fractions has been believed to be responsible for the dif-
Allergy
ferences among inflammatory diseases. However, an analysis of the cells infiltrating inflammatory
Fibrosis
lesions in mice and humans revealed the generation of pathogenic Th cells with different characteristics
iBALT
Memory pathogenic T cells
at the memory T-cell stage in the peripheral tissues in various inflammatory diseases. In this review, we
Tissue resident memory T cells will summarize and discuss recent progress regarding the characteristics of pathogenic Th cells, their
mode of action, and the molecular mechanisms that regulate the pathology of intractable chronic in-
flammatory diseases, particularly those with tissue fibrosis. We hope this article will help clarify the
pathogenesis of these diseases and propose a future direction for research.
Copyright © 2021, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

What are pathogenic helper T (Tpath) cells?
The host immune system is able to eliminate pathogens more
efficiently when pathogens re-invade than on first encountering
them in a phenomenon called “immunological memory”.1 Adaptive
immunity, particularly memory helper T (Th) cells, is central to
shaping the immunological memory.1 Upon entry of the pathogen,
naïve CD4þ T cells are activated by specific antigens presented on
antigen-presenting cells in peripheral lymphoid organs and
differentiate into functional effector Th cells within a week or two.
Effector Th cells are divided into several functional subsets, such as
Th1, Th2, Th9 and Th17 cells, and each of the subsets produces
certain cytokines to eliminate the pathogens. For example, Th1 cells
produce large amounts of IFN-g to eliminate intracellular patho-
gens, including Mycobacterium tuberculosis and Leishmania major,
while Th2 cells produce Th2 cytokines, such as IL-4, IL-5 and IL-13,
which are crucial for protection against parasites.2,3 Th17 cells
* Corresponding author. Department of Immunology, Graduate School of Medi-
cine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
** Corresponding author. Department of Immunology, Graduate School of Medi-
cine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
E-mail addresses: hiraharak@chiba-u.jp (K. Hirahara), tnakayama@faculty.chiba-
u.jp (T. Nakayama).
Peer review under responsibility of Japanese Society of Allergology.
produce IL-17A and IL-17F and defend the host against fungi and
extracellular bacteria, such as Klebsiella pneumonia.4,5 These
effector Th cells direct other immune cells, such as neutrophils and
eosinophils, to local inflammatory sites and produce various func-
tional molecules, including proinflammatory cytokines to trigger an
inflammatory response, leading to the elimination of pathogens.
Although most effector Th cells die via apoptosis after pathogen
elimination, some are maintained in the body as memory Th cells
for years.6 Memory Th cells can be rapidly activated following the
re-entry of the same pathogen via antigen-specific TCR stimulation
and divide very quickly in response.1,3 Memory Th cells also pro-
duce large amounts of proinflammatory cytokines to induce an
inflammatory response, leading to the efficient elimination of the
pathogen in question.1,6 Memory Th cells thus play central roles in
the host protection during recall responses.1
However, memory Th cells also play pathogenic roles as drivers
of chronic allergic diseases and autoimmune diseases.1 For
example, memory Th2 cells are important in the pathogenesis of
bronchial asthma because they have ability to produce large
amounts of proinflammatory cytokines, including IL-5, which is a
key cytokine for the survival and activation of eosinophils.7 In 2011,
we found that memory Th2 cells could be divided into sub-
populations based on the expression of various cell surface mole-
cules, including CXCR3, a chemokine receptor preferentially
expressed on Th1 cells.8 A specific subpopulation of memory Th2

https://doi.org/10.1016/j.alit.2021.02.001
1323-8930/Copyright © 2021, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/
by/4.0/).

Please cite this article as: Hirahara K et al., Pathogenic helper T cells, Allergology International, https://doi.org/10.1016/j.alit.2021.02.001
2 K. Hirahara et al. / Allergology International xxx (xxxx) xxx
cells that show a unique phenotype, ST2hiCXCR3loCD62L-
lo
CCR4þCD44þSca-1þICOSþIL7Raþ, produces large amounts of IL-5
and induces eosinophilic inflammation.1 In humans, multiple
rounds of antigenic stimulation and functional differentiation can
efficiently generate IL-5-producing Th2 cells in vitro.9 These IL-5
hyper-producing memory Th2 cells have been recognized as a
novel pathogenic population of “pathogenic Th2 cells (Tpath2)”
that is responsible for eosinophilic inflammation in allergic dis-
eases, such as asthma and chronic dermatitis.1,8,10
Chronic airway inflammation, especially steroid-resistant airway
inflammation, is induced by not only Th2 cells but also Th17 cells.11
Furthermore, a unique cell subpopulation of memory/effector Th2
cells that express both GATA3 and RORgt, the master transcription
factors for Th2 cells and Th17 cells, respectively, and simultaneously
produce both Th2 and Th17 cytokines are involved in severe airway
inflammation.11,12 This IL-17-producing Th2 cell population is a new
Tpath2 cell population in both mice and humans in terms of the
induction of steroid-resistant severe asthma.
Induction and maintenance of Tpath2 cells
In 1989, an extracellular protein similar to the IL-1 receptor was
identified in fibroblasts.13,14 These proteins were later named T1,
ST2, Der4 and Fit1, but their detailed functions remained
unknown.13e16 In 2005, IL-33, a cytokine of the IL-1 family, was
identified as a ligand protein for ST2.17 In addition to IL-33, IL-1a, IL-
1b, IL-18, IL-36a, IL-36b, IL-36g and IL-37 are also members of the
IL-1 family.18
IL-33, like IL-1a and HMGB1, is localized in the nucleus of cells
but is also secreted extracellularly and acts as a cytokine.19 When
the normal mucosal barrier is damaged and the cells that form the
mucosa are destroyed, IL-33 is passively released extracellularly. In
myocardial endothelial cells and fibroblasts, mechanical stress in-
duces the release of IL-33.20 Thus, nuclear IL-33, also known as
alarmin or damage-associated molecular pattern (DAMP), responds
to various invasions of the body. In addition, various bioactive
substances induce the production and release of IL-33.21e23 For
example, extracellular ATP induces the production and secretion of
IL-33 in allergic inflammation.21e23
IL-33 protects the host from parasitic infections by inducing
type 2 immune responses. At the same time, IL-33 is also involved
in the pathogenesis of various diseases, such as bronchial asthma,
atopic dermatitis and anaphylactic reactions. For example, the
increased expression of IL-33 in lung tissue from patients with
bronchial asthma has been reported.24 A large-scale genome-wide
study revealed that IL33 and IL1RL1, which encodes ST2, are asso-
ciated with the development of asthma.25e27 In a mouse model,
direct administration of IL-33 to the lungs of mice induced eosin-
ophilic inflammation.28,29 Patients with chronic eosinophilic
sinusitis have a high expression of IL-33 in the epithelium and ST2
in the inflamed mucosa.30
In both mice and humans, IL-33 activates the p38-MAPK signaling
pathway in ST2-expressing memory Th2 cells and induces a func-
tional switch to Tpath2, which produces large amounts of IL-5.31
Furthermore, IL-33 stimulation enhances the ST2 expression on
ST2-expressing memory Th2 cells.31 However, the external stimuli
that induce the ST2 expression on ST2-negative Th cells have been
unclear.
The precise mechanisms underlying the maintenance of mem-
ory Th cells, including Tpath2, at inflammatory sites have not been
fully clarified. Lung inflammation causes the reconstruction of the
lung microenvironment, including the induction of IL-7-producing
lymphoid endothelial cells (LECs). In fact, inflammation induces the
ectopic formation of lymph node-like structures called inducible
bronchus-associated lymphoid tissue (iBALT) in the submucosa of
Please cite this article as: Hirahara K et al., Pathogenic helper T cells, Allergology International, https://doi.org/10.1016/j.alit.2021.02.001
the bronchi.32e35 In addition to so called B- and T-cell areas, iBALT
consists of dendritic cells, follicular dendritic cells and lymphatic
vessels. IL-7 is a key cytokine for the survival of memory T cells, and
IL-7-producing LECs within iBALT are important for the mainte-
nance of lung-resident antigen-specific memory Th2 cells.34
Furthermore, IL-7-producing LECs also have the ability to produce
IL-33, suggesting that IL-7þIL-33þ LECs are involved in the patho-
genesis of chronic lung inflammation by the induction and main-
tenance of memory Tpath2 cells1,34 (Fig. 1). Interestingly, not only
the allergic inflammation but also bacterial infection causes the
induction of IL-7-producing LECs, which are crucial for the main-
tenance of bacteria-specific memory Th17 cells in the lung.36
In humans, CD161hi IL-5-producing Tpath2 cells are detected in
around 1% of peripheral blood mononuclear cells (PBMCs) in patients
with eosinophilic gastrointestinal disease.37 In patients with eosino-
philic chronic rhinosinusitis (ECRS), IL-5-producing memory Tpath2
cells are rarely present among PBMCs, but a large number of memory
Tpath2 cells are found in the polyps in which ectopic lymphoid tissues
are formed.34 Thus, Tpath2 cells accumulate in the ectopic lymphoid
tissues of localized inflammatory tissues and are involved in shaping
the pathology of eosinophilic inflammation in ECRS patients.
Heterogeneity of memory Tpath2 cells
Uncontrolled tissue repair by chronic inflammation causes
fibrotic responses in various tissues.38 In fact, tissue fibrosis is
associated with chronic allergic inflammation, such as irreversible
bronchial asthma and cirrhosis of the liver.39,40 Tissue fibrosis
consists of excessive deposition of collagenous and non-
collagenous extracellular matrix (ECM) components as a result of
the proliferation and activation of fibroblasts, myofibroblasts and
immune cells.38e40 IL-5-producing Tpath2 cells and eosinophils
play crucial roles in the pathogenesis of allergic airway inflamma-
tion. A member of the epithelial growth factor family, amphir-
egulin, is involved in the tissue repair process in the muscle and
lung, thereby contributing to tissue maintenance.41e43 Another
Tpath2 cell population that specifically produces the tissue repair
factor amphiregulin was found to be involved in the pathogenesis
of tissue fibrosis during chronic allergic airway inflammation.44,45
Interestingly, IL-5-producing Tpath2 and amphiregulin-producing
Tpath2 are considered distinct cell populations, indicating that IL-
33-signaling induces heterogeneous Tpath2 populations.44,45
Furthermore, amphiregulin stimulation induces inflammatory
reprogramming with the increased expression of various proin-
flammatory genes and fibrosis-related genes in eosinophils.44 One
of the genes upregulated in eosinophils by amphiregulin stimula-
tion is osteopontin, a major component of the non-collagenous
ECM in fibrotic tissue involved in the pathogenesis of fibrosis.44
Refractory asthma is often associated with tissue fibrosis that
leads to a reduction in the lung function, inflammatory eosinophils
induced by amphiregulin-producing Tpath2 directly produce non-
collagenous ECM, suggesting that they are involved in tissue
fibrosis formation in allergic airway inflammation. An analysis of
the polyps of human ECRS patients has also revealed the presence
of two distinct memory Tpath2 cell populations among
CD161hiCRTH2hi memory CD4þ T cells: an IL-5-producing CD4þ T-
cell population and an amphiregulin-producing CD4þ T-cell pop-
ulation.44 To better understand the nature of this new pathogenic
helper T cell population, a detailed analysis of the amphiregulin-
producing T cell population is required.
Taken together, these results indicate that the IL-33-
amphiregulin-osteopontin pathway induces fibrosis in eosino-
philic airway inflammation and that this pathway may be a new
therapeutic target for tissue fibrosis associated with chronic allergic
diseases (Fig. 1).
 K. Hirahara et al. / Allergology International xxx (xxxx) xxx 3

Fig. 1. The cellular and molecular mechanisms involved in the pathology in chronic airway inflammation. Chronic allergic airway inflammation has a complicated pathology
involving inflammatory cell infiltration, especially eosinophils, fibrotic changes, inducible bronchus-associated lymphoid tissue (iBALT) formation and smooth muscle hyperplasia.
(A) One subpopulation of memory Tpath2 cells recruits eosinophils via IL-5. Another subpopulation of memory Tpath2 cells secretes amphiregulin and activates eosinophils that
produce osteopontin, a key profibrotic inflammatory protein. In addition, these memory pathogenic Th2 cells reside at local inflammatory sites. (B) Diverse populations of antigen-
specific memory pathogenic Th2 cells (Tpath2 cells) are maintained within iBALT. Tpath2 cells attach to the lymphatic endothelial cells that express both IL-7 and IL-33. ST2, IL-33
receptor; TCR, T cell receptor; Tpath2, Memory pathogenic Th2 cell;B, B cell;T, T cell; FDCs, Follicular dendritic cells; iBALT, Inducible bronchus associated lymphoid tissue.

Tissue-resident memory CD4þ T cells and tissue fibrosis
Lung fibrotic responses are induced by a variety of stimulants
and pathogens, including fungus. Aspergillus is the most common
environmental fungus, and inhalation of Aspergillus spores causes
allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) in
humans.46,47 Patients with ABPA/ABPM show bronchial dilatation
and fibrotic changes in the lung and suffer from recurrent bronchial
asthma attacks.46,47 In the lungs of mice with repeated exposure to
the Aspergillus fumigatus antigen, CD4þ tissue-resident memory T
(TRM) cells, a population that does not circulate throughout the
body but instead remains in the lung, are induced.48 TRM cells ex-
press CD69, a C-type lectin-like molecule, on their cell surface.49
CD103, an integrin E subunit molecule, has been reported as a
cell surface marker of TRM cells, but it is now known that the
expression of CD103 on TRM cells varies among organs.50 TRM cells
localize in the non-lymphoid tissue, such as the lung, skin, and liver,
for long periods of time and play an important role in maintaining

Please cite this article as: Hirahara K et al., Pathogenic helper T cells, Allergology International, https://doi.org/10.1016/j.alit.2021.02.001
4 K. Hirahara et al. / Allergology International xxx (xxxx) xxx
the homeostasis of the tissue function as well as a biological de-
fense against invasion of pathogenic microorganisms.50e52 In the
lungs of mice with repeated exposure to the A. fumigatus antigen,
these CD4þ TRM cells are also pathogenic helper T cells because they
play a significant role in the pathogenesis of fibrotic responses in
the lung.48 In fact, these CD4þ TRM cells express high levels of
fibrosis-related genes along with the enhanced production of
various proinflammatory cytokines, including IL-4, IL-5, IL-13 and
IL-17.48 Furthermore, the characteristic pathogenic features of these
CD4þ TRM cell populations are regulated at the chromatin level. An
assay for transposase-accessible chromatin using a sequencing
(ATAC-Seq) analysis revealed that the regulatory elements of
proinflammatory cytokines were specifically accessible in CD4þ
TRM cells.48
Pathogenic Th cell disease induction model
For many years, the imbalance between Th1/Th2 cells has been
considered to be responsible for the pathogenesis of autoimmune
and allergic diseases. Based on recent reports on the role of Tpath2
cells in the pathogenesis of chronic allergic diseases in various or-
gans, a pathogenic Th cell disease induction model has been pro-
posed by several groups, including our own.1,37,53 In this model,
Tpath cells with certain characteristics, such as the enhanced pro-
duction of cytokines and chemokines along with the unique
expression of cell surface molecules, are induced in peripheral non-
lymphoid tissues, and these Tpath cells, regardless of the balance of
the Th cell fraction, are responsible for the exacerbation and
maintenance of immune-related diseases.
Several subpopulations of Tpath2 have been identified in both
mice and humans. In mice, CD44hiCD62LloCXCR3loCCR4hiCCR8-
hi
IL7RahiST2hi Tpath2 cells and CCR8hi Tpath2 cells are important
pathogenic Th cell populations that induce chronic airway inflam-
mation and atopic dermatitis, respectively1 In humans,
CRTH2hiCD161hihPGDShi Tpath2 cells and CD45ROhiGPR15hi Tpath2
cells are pathogenic Th cell populations in eosinophilic gastroin-
testinal diseases and ulcerative colitis, respectively.37,54
CXCR3þTpath1 cells and IL23RþTpath17 cells are also involved in
type 1 diabetes and neuroinflammation, respectively.55,56 Further-
more, allergen-specific immunotherapy has revealed the
correlation between the presence of CD45ROhiCRTH2hiCCD49-
dhiCCR4hiCXCR3loCCR6loCD27lo Tpath2 cells and the disease activ-
ity.53 Recent technical advances regarding the genome-wide
analysis of single cell transcriptomes, regulomes, and proteomes
has uncovered the diversity and detailed characteristics of Tpath2
cells.57,58 Thus, the pathogenic Th cell disease induction model is
useful for understanding the pathogenesis of chronic allergic
diseases.
Concluding remarks
The identification of Tpath2 cells that induce allergic inflam-
mation has provided a breakthrough in understanding the patho-
genesis of chronic inflammatory diseases. The concept of
pathogenic Th-cell populations may also help expand our under-
standing of other inflammatory diseases, such as Th1- and Th17-
related tissue-specific autoimmune diseases. Therefore, we
believe that the pathogenic Th cell disease induction model is
useful for understanding the pathogenesis of various inflammatory
diseases and developing novel strategies for intractable immune-
related diseases.
Over the past decade, new Th cell populations, such as Th17, Th9
and Tfh cells, have been identified, and the developmental path-
ways and functions of each subset have been elucidated in detail.59
Recently, innate lymphoid cells (ILCs) have been identified.60
Please cite this article as: Hirahara K et al., Pathogenic helper T cells, Allergology International, https://doi.org/10.1016/j.alit.2021.02.001
Among the subpopulations of ILCs, ILC2 cells have particular simi-
larities to Th2 cells, especially Tpath2 cells.1,61 One potential future
research direction involves clarifying the molecular mechanisms
underlying the induction and maintenance of the function of
Tpath2 cells. The role of Tpath2 cells in the pathogenesis of chronic
intractable inflammatory diseases will be elucidated. Environ-
mental factors, such as allergens and microorganisms, are candi-
dates for the induction and activation of Tpath2 within
inflammatory lesions. As we mentioned, repeated exposure of the
airways of mice to A. fumigatus induces severe airway inflammation
and fibrotic responses accompanied by the infiltration of Tpath2
and Tpath17 cells that reside in the inflammatory sites. In humans,
filamentous fungi colonize the sinuses of patients with airway
allergic inflammatory diseases, including asthma. Furthermore,
since Tpath cell populations in various types of inflammatory dis-
eases have been identified, the development of antibodies specific
for these Tpath cell populations will be of great use in the treatment
of intractable chronic inflammatory diseases.
Acknowledgments
This work was supported by the following grants: Ministry of
Education, Culture, Sports, Science and Technology (MEXT Japan)
Grants-in-Aid for Scientific Research (S) JP19H05650, (B)
20H03685, (C) 17K08876, 18K07164 and 19K16683; Practical
Research Project for Allergic Diseases and Immunology (Research
on Allergic Diseases and Immunology) from the Japan Agency for
Medical Research and Development, AMED (Nos. JP20ek0410082,
JP20ek0410060 and JP19ek0410045); AMED-PRIME, AMED (No.
JP20gm6110005); AMED-CREST, AMED (No. JP20gm1210003);
Mochida Memorial Foundation for Medical and Pharmaceutical
Research, MSD Life Science Foundation, The Naito Foundation and
Takeda Science Foundation.
Conflict of interest
The authors have no conflict of interest to declare.
References
1. Nakayama T, Hirahara K, Onodera A, Endo Y, Hosokawa H, Shinoda K, et al. Th2
cells in health and disease. Annu Rev Immunol 2017;35:53e84.
2. Reiner SL, Locksley RM. The regulation of immunity to Leishmania major. Annu
Rev Immunol 1995;13:151e77.
3. Ruterbusch M, Pruner KB, Shehata L, Pepper M. In vivo CD4(þ) T cell differ-
entiation and function: revisiting the Th1/Th2 paradigm. Annu Rev Immunol
2020;38:705e25.
4. Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, et al.
Requirement of interleukin 17 receptor signaling for lung CXC chemokine and
granulocyte colony-stimulating factor expression, neutrophil recruitment, and
host defense. J Exp Med 2001;194:519e27.
5. Stockinger B, Veldhoen M, Martin B. Th17 T cells: linking innate and adaptive
immunity. Semin Immunol 2007;19:353e61.
6. Nakayama T, Yamashita M. Initiation and maintenance of Th2 cell identity. Curr
Opin Immunol 2008;20:265e71.
7. Takatsu K, Nakajima H. IL-5 and eosinophilia. Curr Opin Immunol 2008;20:
288e94.
8. Endo Y, Iwamura C, Kuwahara M, Suzuki A, Sugaya K, Tumes DJ, et al. Eome-
sodermin controls interleukin-5 production in memory T helper 2 cells through
inhibition of activity of the transcription factor GATA3. Immunity 2011;35:
733e45.
9. Upadhyaya B, Yin Y, Hill BJ, Douek DC, Prussin C. Hierarchical IL-5 expression
defines a subpopulation of highly differentiated human Th2 cells. J Immunol
2011;187:3111e20.
10. Islam SA, Chang DS, Colvin RA, Byrne MH, McCully ML, Moser B, et al. Mouse
CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5þ T(H)2
cells. Nat Immunol 2011;12:167e77.
11. Wang YH, Voo KS, Liu B, Chen CY, Uygungil B, Spoede W, et al. A novel subset of
CD4(þ) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine
and promote the exacerbation of chronic allergic asthma. J Exp Med 2010;207:
2479e91.
12. Irvin C, Zafar I, Good J, Rollins D, Christianson C, Gorska MM, et al. Increased
frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid
 K. Hirahara et al. / Allergology International xxx (xxxx) xxx
characterizes a population of patients with severe asthma. J Allergy Clin
Immunol 2014;134:1175e1186.e7.
13. Werenskiold AK, Hoffmann S, Klemenz R. Induction of a mitogen-responsive
gene after expression of the Ha-ras oncogene in NIH 3T3 fibroblasts. Mol Cell
Biol 1989;9:5207e14.
14. Tominaga S. A putative protein of a growth specific cDNA from BALB/c-3T3
cells is highly similar to the extracellular portion of mouse interleukin 1 re-
ceptor. FEBS Lett 1989;258:301e4.
15. Lanahan A, Williams JB, Sanders LK, Nathans D. Growth factor-induced delayed
early response genes. Mol Cell Biol 1992;12:3919e29.
16. Bergers G, Reikerstorfer A, Braselmann S, Graninger P, Busslinger M. Alterna-
tive promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms
coding for either secreted or membrane-bound proteins related to the IL-1
receptor. EMBO J 1994;13:1176e88.
17. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33,
an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein
ST2 and induces T helper type 2-associated cytokines. Immunity 2005;23:
479e90.
18. Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the
future. Immunity 2013;39:1003e18.
19. Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, et al. IL-33, the
IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear
factor in vivo. Proc Natl Acad Sci U S A 2007;104:282e7.
20. Chen WY, Hong J, Gannon J, Kakkar R, Lee RT. Myocardial pressure overload
induces systemic inflammation through endothelial cell IL-33. Proc Natl Acad
Sci U S A 2015;112:7249e54.
21. Hudson CA, Christophi GP, Gruber RC, Wilmore JR, Lawrence DA, Massa PT.
Induction of IL-33 expression and activity in central nervous system glia.
J Leukoc Biol 2008;84:631e43.
22. Kouzaki H, Iijima K, Kobayashi T, O'Grady SM, Kita H. The danger signal,
extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release
and innate Th2-type responses. J Immunol 2011;186:4375e87.
23. Byers DE, Alexander-Brett J, Patel AC, Agapov E, Dang-Vu G, Jin X, et al. Long-
term IL-33-producing epithelial progenitor cells in chronic obstructive lung
disease. J Clin Investig 2013;123:3967e82.
24. Prefontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ,
et al. Increased expression of IL-33 in severe asthma: evidence of expression by
airway smooth muscle cells. J Immunol 2009;183:5094e103.
25. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al.
A large-scale, consortium-based genomewide association study of asthma.
N Engl J Med 2010;363:1211e21.
26. Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE,
et al. Meta-analysis of genome-wide association studies of asthma in ethnically
diverse North American populations. Nat Genet 2011;43:887e92.
27. Bonnelykke K, Sleiman P, Nielsen K, Kreiner-Moller E, Mercader JM, Belgrave D,
et al. A genome-wide association study identifies CDHR3 as a susceptibility
locus for early childhood asthma with severe exacerbations. Nat Genet
2014;46:51e5.
28. Kurowska-Stolarska M, Stolarski B, Kewin P, Murphy G, Corrigan CJ, Ying S,
et al. IL-33 amplifies the polarization of alternatively activated macrophages
that contribute to airway inflammation. J Immunol 2009;183:6469e77.
29. Mato N, Hirahara K, Ichikawa T, Kumagai J, Nakayama M, Yamasawa H, et al.
Memory-type ST2þCD4þ T cells participate in the steroid-resistant pathology
of eosinophilic pneumonia. Sci Rep 2017;7:6805.
30. Shaw JL, Fakhri S, Citardi MJ, Porter PC, Corry DB, Kheradmand F, et al. IL-33-
responsive innate lymphoid cells are an important source of IL-13 in chronic
rhinosinusitis with nasal polyps. Am J Respir Crit Care Med 2013;188:432e9.
31. Endo Y, Hirahara K, Iinuma T, Shinoda K, Tumes DJ, Asou HK, et al. The inter-
leukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the
airway. Immunity 2015;42:294e308.
32. Moyron-Quiroz JE, Rangel-Moreno J, Hartson L, Kusser K, Tighe MP,
Klonowski KD, et al. Persistence and responsiveness of immunologic memory
in the absence of secondary lymphoid organs. Immunity 2006;25:643e54.
33. Randall TD. Bronchus-associated lymphoid tissue (BALT) structure and func-
tion. Adv Immunol 2010;107:187e241.
34. Shinoda K, Hirahara K, Iinuma T, Ichikawa T, Suzuki AS, Sugaya K, et al.
Thy1þIL-7þ lymphatic endothelial cells in iBALT provide a survival niche for
memory T-helper cells in allergic airway inflammation. Proc Natl Acad Sci U S A
2016;113:E2842e51.
35. Kuroda E, Ozasa K, Temizoz B, Ohata K, Koo CX, Kanuma T, et al. Inhaled fine
particles induce alveolar macrophage death and interleukin-1alpha release to
promote inducible bronchus-associated lymphoid tissue formation. Immunity
2016;45:1299e310.
Please cite this article as: Hirahara K et al., Pathogenic helper T cells, Allergology International, https://doi.org/10.1016/j.alit.2021.02.001
5
36. Amezcua Vesely MC, Pallis P, Bielecki P, Low JS, Zhao J, Harman CCD, et al.
Effector TH17 cells give rise to long-lived TRM cells that are essential for an
immediate response against bacterial infection. Cell 2019;178:1176e88.e15.
37. Mitson-Salazar A, Yin Y, Wansley DL, Young M, Bolan H, Arceo S, et al. He-
matopoietic prostaglandin D synthase defines a proeosinophilic pathogenic
effector human TH2 cell subpopulation with enhanced function. J Allergy Clin
Immunol 2016;137:907e18.
38. Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair
and regeneration. Science 2017;356:1026e30.
39. Gieseck 3rd RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and
fibrosis. Nat Rev Immunol 2018;18:62e76.
40. Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines.
Nature 2020;587:555e66.
41. Okumura S, Sagara H, Fukuda T, Saito H, Okayama Y. FcepsilonRI-mediated
amphiregulin production by human mast cells increases mucin gene expres-
sion in epithelial cells. J Allergy Clin Immunol 2005;115:272e9.
42. Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR. Amphiregulin, a
TH2 cytokine enhancing resistance to nematodes. Science 2006;314:1746.
43. Zaiss DM, Gause WC, Osborne LC, Artis D. Emerging functions of amphiregulin
in orchestrating immunity, inflammation, and tissue repair. Immunity 2015;42:
216e26.
44. Morimoto Y, Hirahara K, Kiuchi M, Wada T, Ichikawa T, Kanno T, et al.
Amphiregulin-producing pathogenic memory T helper 2 cells instruct eosin-
ophils to secrete osteopontin and facilitate airway fibrosis. Immunity 2018;49:
134e50.
45. Hirahara K, Aoki A, Morimoto Y, Kiuchi M, Okano M, Nakayama T. The
immunopathology of lung fibrosis: amphiregulin-producing pathogenic
memory T helper-2 cells control the airway fibrotic responses by inducing
eosinophils to secrete osteopontin. Semin Immunopathol 2019;41:339e48.
46. Knutsen AP, Bush RK, Demain JG, Denning DW, Dixit A, Fairs A, et al. Fungi and
allergic lower respiratory tract diseases. J Allergy Clin Immunol 2012;129:
280e91. quiz 92-3.
47. Asano K, Hebisawa A, Ishiguro T, Takayanagi N, Nakamura Y, Suzuki J, et al.
New clinical diagnostic criteria for allergic bronchopulmonary aspergillosis/
mycosis and its validation. J Allergy Clin Immunol 2020. https://doi.org/10.1016/
j.jaci.2020.08.029.
48. Ichikawa T, Hirahara K, Kokubo K, Kiuchi M, Aoki A, Morimoto Y, et al.
CD103(hi) Treg cells constrain lung fibrosis induced by CD103(lo) tissue-
resident pathogenic CD4 T cells. Nat Immunol 2019;20:1469e80.
49. Kimura MY, Hayashizaki K, Tokoyoda K, Takamura S, Motohashi S, Nakayama T.
Crucial role for CD69 in allergic inflammatory responses: CD69-Myl9 system in
the pathogenesis of airway inflammation. Immunol Rev 2017;278:87e100.
50. Masopust D, Soerens AG. Tissue-resident T cells and other resident leukocytes.
Annu Rev Immunol 2019;37:521e46.
51. Mueller SN, Mackay LK. Tissue-resident memory T cells: local specialists in
immune defence. Nat Rev Immunol 2016;16:79e89.
52. Paik DH, Farber DL. Anti-viral protective capacity of tissue resident memory T
cells. Curr Opin Virol 2020;46:20e6.
53. Wambre E, Bajzik V, DeLong JH, O'Brien K, Nguyen QA, Speake C, et al.
A phenotypically and functionally distinct human TH2 cell subpopulation is
associated with allergic disorders. Sci Transl Med 2017;9:eaam9171.
54. Nguyen LP, Pan J, Dinh TT, Hadeiba H, O'Hara 3rd E, Ebtikar A, et al. Role and
species-specific expression of colon T cell homing receptor GPR15 in colitis. Nat
Immunol 2015;16:207e13.
55. Antonelli A, Ferrari SM, Corrado A, Ferrannini E, Fallahi P. CXCR3, CXCL10 and
type 1 diabetes. Cytokine Growth Factor Rev 2014;25:57e65.
56. Ghoreschi K, Laurence A, Yang XP, Hirahara K, O'Shea JJ. T helper 17 cell het-
erogeneity and pathogenicity in autoimmune disease. Trends Immunol
2011;32:395e401.
57. Wen T, Rothenberg ME. Cell-by-cell deciphering of T cells in allergic inflam-
mation. J Allergy Clin Immunol 2019;144:1143e8.
58. Hewitt RJ, Lloyd CM. Regulation of immune responses by the airway epithelial
cell landscape. Nat Rev Immunol 2021. https://doi.org/10.1038/s41577-020-
00477-9.
59. O'Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity
of helper CD4þ T cells. Science 2010;327:1098e102.
60. Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, et al. Innate
production of T(H)2 cytokines by adipose tissue-associated c-Kit(þ)Sca-1(þ)
lymphoid cells. Nature 2010;463:540e4.
61. Kabata H, Moro K, Koyasu S. The group 2 innate lymphoid cell (ILC2)
regulatory network and its underlying mechanisms. Immunol Rev 2018;286:
37e52.