Memory-type pathogenic TH2 cells and ILC2s in type 2 allergic inflammation

Abstract

Type 2 immunity is characterized by the production of signature cytokines, such as IL-4, IL-5, and IL-13, which regulate various biological responses.1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google Scholar Type 2 immunity is important for the host defense response against parasitic infection.1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google Scholar Type 2 immunity is also involved in shaping the pathogenesis of allergic diseases, such as bronchial asthma and atopic dermatitis.1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google Scholar In bronchial asthma, type 2 immunity is involved in not only IL-4–induced IgE class switching, IL-5–induced induction and activation of eosinophils, and IL-13–induced eosinophilic airway inflammation but also amphiregulin-induced peri-airway fibrosis and aseptic inflammation induced by Charcot-Leyden crystals.2Morimoto Y. Hirahara K. Kiuchi M. Wada T. Ichikawa T. Kanno T. et al.Amphiregulin-producing pathogenic memory T helper 2 cells instruct eosinophils to secrete osteopontin and facilitate airway fibrosis.Immunity. 2018; 49: 134-150.e6Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar,3Gause W.C. Rothlin C. Loke P. Heterogeneity in the initiation, development and function of type 2 immunity.Nat Rev Immunol. 2020; 20: 603-614Crossref PubMed Scopus (19) Google Scholar Furthermore, the pathogenic interaction between the nervous system and immune cells in type 2 inflammation causes various allergic diseases, such as bronchial asthma and atopic dermatitis.4Chu C. Artis D. Chiu I.M. Neuro-immune interactions in the tissues.Immunity. 2020; 52: 464-474Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Besides the induction of allergic inflammation, type 2 immunity regulates tissue homeostasis and tissue repair responses.3Gause W.C. Rothlin C. Loke P. Heterogeneity in the initiation, development and function of type 2 immunity.Nat Rev Immunol. 2020; 20: 603-614Crossref PubMed Scopus (19) Google Scholar It is induced by both the acquired and innate immune systems. In the acquired immune system, TH2 and B cells are major cell populations that produce type 2 cytokines, whereas group 2 innate lymphoid cells (ILC2s) are the main source of type 2 cytokines in the innate immune system. The organ-specific environment affects the function of both memory-type TH2 cells and ILC2s because subpopulations of memory-type TH2 cells and ILC2s are known to reside in specific mucosal organs, such as the lung and skin.3Gause W.C. Rothlin C. Loke P. Heterogeneity in the initiation, development and function of type 2 immunity.Nat Rev Immunol. 2020; 20: 603-614Crossref PubMed Scopus (19) Google Scholar For example, the respiratory tract is covered by the tracheal mucosa formed from goblet cells, clara cells, ciliated cells, and tuft cells to prevent the invasion of various foreign antigens. On exposure to various stimuli, the airway epithelial cells release epithelial cytokines, such as IL-25, IL-33, and thymic stromal lymphopoietin, which activate tissue-resident immune cells in the airway mucosa and elicit a type 2 immune response in the local inflammatory sites.3Gause W.C. Rothlin C. Loke P. Heterogeneity in the initiation, development and function of type 2 immunity.Nat Rev Immunol. 2020; 20: 603-614Crossref PubMed Scopus (19) Google Scholar Epithelial cells and chemosensory epithelial cells called tuft cells produce IL-25 and thymic stromal lymphopoietin.3Gause W.C. Rothlin C. Loke P. Heterogeneity in the initiation, development and function of type 2 immunity.Nat Rev Immunol. 2020; 20: 603-614Crossref PubMed Scopus (19) Google Scholar When the mucosal barrier is broken down and the epithelial cells that form the mucosa are destroyed, IL-33 is released from the cell and transmits signals to other neighboring cells. Indeed, multiple genome-wide association studies have shown that IL33 and IL1RL1 are genes associated with the pathogenesis of bronchial asthma.1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google Scholar Regarding the main target cell populations for epithelial cytokines in vivo, certain subpopulations of memory TH2 cells express high levels of ST2, which is a receptor of IL-33, and produce inflammatory cytokines, such as IL-5 and amphiregulin, following IL-33 stimulation.2Morimoto Y. Hirahara K. Kiuchi M. Wada T. Ichikawa T. Kanno T. et al.Amphiregulin-producing pathogenic memory T helper 2 cells instruct eosinophils to secrete osteopontin and facilitate airway fibrosis.Immunity. 2018; 49: 134-150.e6Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Because the ST2hi memory-type TH2 cells are involved in the pathogenesis of various allergic inflammatory diseases via producing large amounts of inflammatory cytokines, this subpopulation is referred to as memory-type pathogenic TH2 (Tpath2) cells.1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google Scholar Memory-type Tpath2 cells, with their unique expression of cell surface molecules, TCRβ+CD44hiCD62LlowIL-7RahiST2hiIL-17RBhi, are involved in the induction of antigen-specific allergic inflammatory responses and the pathogenesis of various human diseases, such as eosinophilic sinusitis, hay fever, and peanut allergy1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google Scholar (Table I, left). ILC2s are another target cell population for epithelial cytokines, because ILC2s express high levels of ST2 and other cell surface molecules, including IL-7Rα, CD90.2, and ICOS5Meininger I. Carrasco A. Rao A. Soini T. Kokkinou E. Mjosberg J. Tissue-specific features of innate lymphoid cells.Trends Immunol. 2020; 41: 902-917Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,6Kabata H. Moro K. Koyasu S. The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms.Immunol Rev. 2018; 286: 37-52Crossref PubMed Scopus (89) Google Scholar (Table I, right). In fact, Tpath2 cells and ILC2s share various important characteristics, including the expression of lineage-determining transcription factors (eg, GATA3); the production of proinflammatory cytokines, such as amphiregulin, IL-5, and IL-13; and the expression of cell surface molecules (eg, ST2 and IL-7Rα).1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google Scholar,6Kabata H. Moro K. Koyasu S. The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms.Immunol Rev. 2018; 286: 37-52Crossref PubMed Scopus (89) Google Scholar,7Yamamoto T. Endo Y. Onodera A. Hirahara K. Asou H.K. Nakajima T. et al.DUSP10 constrains innate IL-33-mediated cytokine production in ST2(hi) memory-type pathogenic Th2 cells.Nat Commun. 2018; 9: 4231Crossref PubMed Scopus (16) Google Scholar Furthermore, an assay for transposase-accessible chromatin using sequencing revealed similarities in the chromatin landscapes between Tpath2 cells and ILC2s in the lung.8Shih H.Y. Sciume G. Mikami Y. Guo L. Sun H.W. Brooks S.R. et al.Developmental acquisition of regulomes underlies innate lymphoid cell functionality.Cell. 2016; 165: 1120-1133Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar However, despite these similarities, ILC2s can be directly activated by IL-33 and IL-25 stimulation and can rapidly produce proinflammatory cytokines, such as IL-5 and IL-13. In contrast, memory-type Tpath2 cells have little ability to produce IL-5 or IL-13 by epithelial cytokine stimulation alone. Interestingly, in memory Tpath2 cells, dual-specificity phosphatase 10, a mitogen-activated protein kinase phosphatase, inhibits IL-33–induced p38-mitogen-activated protein kinase phosphorylation and the reduction in the phosphorylation of p38-mitogen-activated protein kinase that confers the inability of memory-type Tpath2 cells to produce cytokines in an innate-like fashion.7Yamamoto T. Endo Y. Onodera A. Hirahara K. Asou H.K. Nakajima T. et al.DUSP10 constrains innate IL-33-mediated cytokine production in ST2(hi) memory-type pathogenic Th2 cells.Nat Commun. 2018; 9: 4231Crossref PubMed Scopus (16) Google Scholar Another important difference between these 2 cell populations is that ILC2s respond to various external stimuli, including neuronal biomolecules, to regulate immune responses.5Meininger I. Carrasco A. Rao A. Soini T. Kokkinou E. Mjosberg J. Tissue-specific features of innate lymphoid cells.Trends Immunol. 2020; 41: 902-917Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,6Kabata H. Moro K. Koyasu S. The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms.Immunol Rev. 2018; 286: 37-52Crossref PubMed Scopus (89) Google Scholar For example, the neuropeptide neuromedin U (NMU) induces the activation of ILC2s and exacerbates allergic lung inflammation.4Chu C. Artis D. Chiu I.M. Neuro-immune interactions in the tissues.Immunity. 2020; 52: 464-474Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar In the case of Tpath2 cells, whether or not Tpath2 cells anticipate neuronal-derived factors is unclear.Table ICharacteristics of memory-type Tpath2 cells and ILC2sAntigenMemory-type Tpath2 cells1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google ScholarILC2s5Meininger I. Carrasco A. Rao A. Soini T. Kokkinou E. Mjosberg J. Tissue-specific features of innate lymphoid cells.Trends Immunol. 2020; 41: 902-917Abstract Full Text Full Text PDF PubMed Scopus (17) Google ScholarDependentIndependentCell surface markers (mouse)CD4+CD44hiCD62LloCXCR3loCD127hiST2hi (lung tissues from mice with induced chronic airway inflammation)CD45+Lineage-Sca1+CD90+CD127+ andST2hi IL17RBloIL18R1+/-KLRG1+/- (lung)ST2loIL17RBloIL18R1hiKLRG1+ (skin)ST2hiIL17RBloIL18R1-KLRG1+ (fat) ST2loIL17RBhiIL18R1-KLRG1hi (gut)Cell surface markers (human)CD4+CD45ROhiCD69hiST2hiIL17RBhi (nasal polyps from patients with ECRS)CD4+CD45ROhiCRTH2hiCCR4hiCXCR3loCCR6loCD27lo (PBMCs from patients with pollen allergy)CD4+CRTH2hiCD161hihPGDShi (PBMCs from patients with EGID and AD)CD4+CD45ROhiGPR15hi (PBMCs and colons from patients with UC)CD45+Lineage-CD127+CD161+CRTH2+ andICOS+ CD69+ (skin, tonsil, lung from healthy subjects)ICOS- CD69- (PBMCs from healthy subjects)elevated expressed ST2, IL17RB, TSLPR, and KLRG1 (skin tissues from patients with AD)AD, Atopic dermatitis; CD62L, CD62 ligand; CD127, IL-7 receptor subunit α; CRTH2, chemoattractant receptor-homologous molecule on TH2 cells; CXCR3, C-X-C motif chemokine receptor 3; ECRS, eosinophilic chronic rhinosinusitis; EGID, eosinophilic gastrointestinal disease; GPR15, G protein–coupled 15; hi, highly expressed; hPGDS, hematopoietic prostaglandin D synthase; ICOS, inducible costimulator; IL17RB, IL-17 receptor B (IL-25 receptor); IL18R1, IL-18 receptor 1; KLRG1, killer cell lectin-like receptor G1; lo, low expression; Sca1, stem cells antigen-1; ST2, IL-1 receptor-like1 (IL-33 receptor); TSLPR, thymic stromal lymphopoietin receptor; UC, ulcerative colitis; +/-, heterogeneous expression. Open table in a new tab AD, Atopic dermatitis; CD62L, CD62 ligand; CD127, IL-7 receptor subunit α; CRTH2, chemoattractant receptor-homologous molecule on TH2 cells; CXCR3, C-X-C motif chemokine receptor 3; ECRS, eosinophilic chronic rhinosinusitis; EGID, eosinophilic gastrointestinal disease; GPR15, G protein–coupled 15; hi, highly expressed; hPGDS, hematopoietic prostaglandin D synthase; ICOS, inducible costimulator; IL17RB, IL-17 receptor B (IL-25 receptor); IL18R1, IL-18 receptor 1; KLRG1, killer cell lectin-like receptor G1; lo, low expression; Sca1, stem cells antigen-1; ST2, IL-1 receptor-like1 (IL-33 receptor); TSLPR, thymic stromal lymphopoietin receptor; UC, ulcerative colitis; +/-, heterogeneous expression. ILC2s reside in nonlymphoid mucosal tissues from the neonatal period. Disruption of the airway epithelial cells followed by the release of IL-33 causes the activation of local tissue-resident immune cells, including ILC2s. Activated ILC2s induce local inflammation by producing type 2 cytokines. However, ILC2s have no ability to respond to antigenic stimulation because they do not express receptors for antigen recognition, which is the fundamental difference between ILC2s and memory-type Tpath2 cells. In contrast, naive CD4+ T cells are largely absent in nonlymphoid tissues. During the initiation phase of inflammation, antigen-specific naive CD4+ T cells are activated by certain antigens for priming and expansion in the lymph nodes followed by exposure of type 2 cytokines and migration into the inflammatory tissue (Fig 1, left). Therefore, in the early phase of inflammation, ILC2s and TH2 cells show distinct responses with unique kinetics and magnitude via different stimuli, although ILC2s and TH2 cells share a similar effector functional program. Once inflammation occurs in the mucosal tissue, a subpopulation of memory T cells known as tissue-resident memory T (TRM) cells is induced and resides in the postinflammatory tissues (Fig 1, right). At the same time, inflammation causes the induction of ectopic lymphoid tissue, such as inducible bronchus-associated lymphoid tissue and conjunctiva-associated lymphoid tissue, both of which have separate B-cell areas, containing follicular dendritic cells, dendritic cells, high endothelial venules, and lymphatics. TRM cells are maintained within inducible bronchus-associated lymphoid tissue in the nonlymphoid tissue.1Nakayama T. Hirahara K. Onodera A. Endo Y. Hosokawa H. Shinoda K. et al.Th2 cells in health and disease.Annu Rev Immunol. 2017; 35: 53-84Crossref PubMed Scopus (142) Google Scholar Of note, the subpopulation of CD4+ TRM cells shows an enhanced expression of ST2 upon IL-33 stimulation. Under conditions of chronic allergic inflammation, these subpopulations of ST2high CD4+ TRM cells are involved in the pathogenesis of chronic inflammation and are maintained in the ectopic lymphoid tissue. Through IL-33-ST2 signaling accompanied by TCR stimulation, these memory-type Tpath2 cells can produce large amounts of IL-5, which recruits eosinophils to the inflamed tissue. Another subpopulation of memory-type Tpath2 cells has the ability to produce amphiregulin, an epithelial growth factor family member, via IL-33-ST2 signaling accompanied by TCR stimulation. Amphiregulin induces the activation of eosinophils, which secrete osteopontin, an extracellular matrix component; its deposition causes fibrotic responses in both mice and humans (Fig 1, right). In the eosinophils, amphiregulin upregulates the expression of CD101, which is a cell surface marker of activated eosinophils.2Morimoto Y. Hirahara K. Kiuchi M. Wada T. Ichikawa T. Kanno T. et al.Amphiregulin-producing pathogenic memory T helper 2 cells instruct eosinophils to secrete osteopontin and facilitate airway fibrosis.Immunity. 2018; 49: 134-150.e6Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar CD4+ TRM cells induce antigen-specific secondary immune responses in the mucosal tissue. Thus, CD4+ TRM cells in the airway mucosa are involved in the pathogenesis of chronic allergic airway inflammation and fibrosis of lung tissue induced by specific antigen stimulation, such as house dust mite and Aspergillus fumigatus.9Hondowicz B.D. An D. Schenkel J.M. Kim K.S. Steach H.R. Krishnamurty A.T. et al.Interleukin-2-dependent allergen-specific tissue-resident memory cells drive asthma.Immunity. 2016; 44: 155-166Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar,10Ichikawa 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: 1469-1480Crossref PubMed Scopus (33) Google Scholar In fact, CD103-negative CD4+ TRM cells produce various types of inflammatory cytokines, including IL-4, IL-5, and IL-13, in the lungs of mice with repeated exposure to A fumigatus.10Ichikawa 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: 1469-1480Crossref PubMed Scopus (33) Google Scholar Thus, memory-type Tpath2 cells reside in the mucosal tissue as CD4+ TRM cells and are involved in the pathogenesis of allergic airway inflammation. Given the above, both memory-type Tpath2 cells and ILC2s are shown to be involved in the pathogenesis of type 2 inflammation, but they contribute to shaping the pathogenesis in different phases via different stimuli (Fig 1). The discussion of the similarities and differences between CD4+ T cells and ILCs is interesting from an evolutionary perspective. To develop new therapeutic strategies for intractable allergic diseases, it will become increasingly important for immunologists and clinicians to understand the precise features of Tpath cells and ILCs.