It is well established that IL-4 is a key cytokine for the differentiation of Th2 cells from naïve CD4+ T cells. ST2 is predominantly expressed on Th2 cells but not naïve T cells, Th1 cells, Th17 cells or regulatory T cells.18-20 On the other hand, ST2 is not essential for Th2 cell differentiation, as shown in studies using ST2-deficient mice: ST2-deficient mice showed normal development of Th2 cells.21, 22 In support of that, although IL-33 did not induce differentiation of Th2 cells from naïve CD4+ T cells in vitro,23, 24 it enhanced IL-5 and IL-13, but not IL-4, production by in vitro-skewed Th2 cells which highly express ST2.3, 7, 23, 25, 26 In humans, IL-33 potentiates not only Th2-type cytokine production but also production of a Th1-type cytokine, IFN-γ, by peripheral blood-derived Th2 cells,27 although IFN-γ production is only slightly increased by peripheral blood-derived human Th1 cells.26 In addition, IL-33 acts as a chemoattractant for Th2 cells, but not Th1 cells, in both humans and mice.28
In contrast to the role of IL-33 in Th2 cell differentiation, Kurowska-Stolarska et al. reported that IL-33 induces differentiation of IL-5-positive IL-4-negative CD4+ T cells (IL-5+IL-4- Th cells) from naïve CD4+ T cells independently of IL-4, STAT-6 and GATA-3, which are important factors for the typical Th2 cell differentiation.24 While ST2-expressing Th cells are also observed in IL-4-, IL-5- or IL-10-deficient mice,19, 29 two distinct populations of IL-4-producing Th cells were found: ST2-positive Th2 cells, which produce IL-4, IL-5 and IL-10, and ST2-negative Th2 cells, which produce IL-4 and IL-10, but not IL-5, in mice during Leishmania major infection.30 Further evidence regarding the role of IL-33 in the differentiation of typical and atypical Th2 cells may provide new insight into the molecular mechanisms in Th2-type cytokine-mediated disorders such as allergic asthma.
In addition to CD4+ Th2 cells, it has been shown that type II CD8+ cytotoxic T cells (Tc2 cells) and IL-10-producing Tr1 cells also express ST2 on their cell surface.31, 32 However, the precise roles of IL-33 in Tc2 and Tr1 cells remain unclear.
MAST CELLS (MCs)
MCs, which express c-Kit and high-affinity IgE receptors (FcεRI) and are predominantly localized in mucosal and connective tissues, are major effector cells in the induction of IgE-mediated immune responses. After binding of antigens (Ags) to IgE-bearing MCs via FcεRI, MCs rapidly release a large variety of inflammatory mediators from their granules, thereby provoking local and systemic inflammation. Mouse MCs (i.e., BMCMCs and connective tissue-type MCs from the peritoneal cavity) and MC/basophil precursor cells and human MCs (i.e., cord blood and peripheral blood stem cell-derived cultured MCs) constitutively express ST2.33-36 Except for IL-3 and stem cell factor (SCF, a ligand for c-kit), which are required for mast cell development at least in mice, IL-33 is the only cytokine among 45 different cytokines which can directly induce cytokine and chemokine (IL-1β, IL-6, IL-13, TNF and MCP-1) secretion from mouse BMCMCs without effecting their degranulation.37, 38 Like its murine counterpart, human IL-33 can induce cytokine and chemokine production, prolong survival and promote cell-adhesion in human cord blood stem cell-derived cultured MCs.35, 36 In addition, IL-33 can augment IgE-mediated cytokine production and degranulation by mouse BMCMCs and/or human cord blood stem cell-derived cultured MCs.35-37, 39 IL-33-mediated cytokine production by mouse BMCMCs and human cord blood stem cell-derived cultured MCs is enhanced in the presence of IL-3 and thymic stromal lymphopoietin (TSLP), respectively.23, 36
Although the levels of phorbol ester + ionophore-induced IL-4 production and IgE + antigen-mediated histamine release from ST2-deficient BMCMCs are comparable to those from wild-type BMCMCs,21 ST2-deficient BMCMCs do not produce cytokines in response to IL-33.23 Therefore, IL-33-induced mast cell-derived cytokines are not involved in IL-4 production or IgE-dependent histamine release.
Basophils, which express FcεRI, but not c-Kit, on their cell surface, are considered to be a potential primary source of IL-4 in certain allergic immune responses.40, 41 Supporting this, it was recently reported that basophils express MHC class II and present Ags to naïve T cells as an Ag-presenting cell, inducing Ag-specific Th2 cell differentiation in lymph nodes that is dependent on IL-4 production and Ag-presentation by activated basophils.42-44
In comparison with Th2 cells and MCs, human and mouse basophils constitutively express ST2 at a relatively low level on their cell surface.23, 26, 45, 46 On the other hand, expression of ST2 on the cell surface of basophils is promoted by stimulation with IL-3.26 Like the effect of IL-33 on Th2 cells and MCs, IL-33 alone can induce production of cytokines, including Th2-type cytokines, and chemokines by basophils and promote cell-adhesion and CD11b expression by human and murine basophils.26, 27, 45, 46 IL-33 does not induce degranulation of basophils directly, but it synergistically enhances IgE-mediated degranulation of human basophils.26, 45 In addition, IL-33 augments immune responses of human and murine basophils in humans and mice: eotaxin-mediated migration,45 cytokine secretion in the presence of IL-3, which is a growth factor for basophils as well as mast cells,23, 26, 27, 45-47 and prolonged survival in the presence of IL-3 or GM-CSF.45-47 These observations suggest that IL-33 is a potential activator of basophils by enhancing their cytokine and chemokine secretion, recruitment and adhesion.
Eosinophilia is found in local inflammatory sites in patients with certain IgE-mediated allergic disorders, such as asthma. Although ST2 expression was barely detectable on the cell surface of human peripheral blood eosinophils, ST2 mRNA and intracellular ST2 protein were detectable in them.26, 48, 49 IL-33 can directly induce production of superoxide and IL-8 and enhance IL-3-, IL-5- or GM-CSF-mediated IL-8 production by human eosinophils.26, 48 As in the case of MCs and basophils, IL-33 enhances adhesion of eosinophils by promoting CD11b expression and survival independently of IL-4, IL-5 and GM-CSF.49 Unlike the case of basophils, IL-33 does not influence eotaxin-mediated migration of eosinophils.49 The role of IL-33 in the degranulation of eosinophils remains controversial. One group demonstrated that IL-33 alone could enhance degranulation (EDN release) of human eosinophils,48 whereas another showed that IL-33 could not (assessed by EDN and LTC4 release).49 These observations strongly suggest that IL-33 may contribute to the pathogenesis of certain allergic disorders accompanied by marked accumulation of eosinophils.
NATURAL KILLER (NK) CELLS AND NKT CELLS
As in the case of Th2 and Tc2 cells, ST2 expression was observed on the cell surface of IL-4-producing NK cells (NK2 cells), but not IFN-γ-producing NK cells (NK1 cells), which were derived in vitro from a freshly-isolated NK cell population of human PBMCs under Th1/Th2 cytokine-skewed culture conditions.31 Smithgall et al. demonstrated that freshly-isolated NK cells from human PBMCs could produce IFN-γ in response to IL-33 in the presence, but not absence, of IL-12 or IL-23, since IL-12 and/or IL-23 enhanced the expression of ST2 mRNA in NK cells.27 However, that study did not elucidate the role of IL-33 in Th2-type cytokine secretion by NK cells.
Smithgall et al. also detected ST2 mRNA expression in human invariant NKT (iNKT) cells and demonstrated a role for IL-33 in these cells: IL-33 enhanced TCR-dependent cytokine production (i.e., IFN-γ, IL-2, IL-4, IL-5, IL-13 and TNF) by iNKT cells after stimulation with α-galactosylceramide (α-GalCer).27 Moreover, IL-33 enhanced IFN-γ, but not IL-4, production by iNKT cells in the presence, but not absence, of IL-12, independently of TCR stimulation.27 As in the case of NK cells, IL-12 enhances ST2 mRNA expression in human iNKT cells.27
Administration of IL-33 to mice results in increased expansion of iNKT cells in the spleen and liver.50 Thymic iNKT cells constitutively express ST2 on their cell surface, and IL-33 enhances IL-7-mediated thymic iNKT cell proliferation.50 IL-33 alone could not induce cytokine secretion by naïve mouse iNKT cells. On the other hand, similar to the study in human iNKT cells,27 IL-33 enhanced both IL-4 and IFN-γ production by TCR-stimulated mouse iNKT cells and IFN-γ, but not IL-4, production by mouse iNKT cells in the presence of IL-12, independently of TCR stimulation.50 In contrast to the findings for human iNKT cells,27 IL-12 could not enhance ST2 expression in mouse iNKT cells. These observations suggest that IL-33 may have a non-Th1/Th2 cytokine-restricted role in certain NK cell- and NKT cell-mediated immune responses.
DENDRITIC CELLS (DCs)
IL-33 is considered to promote the development of DCs from bone marrow cells.51 It has been shown that DCs derived by cultivation of murine bone marrow cells in the presence of GM-CSF and IL-4 (that is, bone marrow-derived DCs; BMDCs) express ST2.52 IL-33 enhances the production of IL-6, but not IL-12, by BMDCs and augments the expression of MHC class II and CD86, but not CD80, CD40 and "OX40 ligand (OX40L)", on the cell surface of BMDCs.52 When naive CD4+ T cells were co-cultured with BMDCs in the presence of IL-33 for 6 to 10 days, IL-5 and IL-13, but not IL-4 or IFN-γ, were detected in the culture supernatant even without TCR engagement. Since such cytokine secretion was not induced by IL-33 in the culture of naïve CD4+ T cells alone, the effect of IL-33 seemed to be mediated by factors derived from IL-33-stimulated BMDCs through a TCR/Ag-MHC class II-independent pathway. However, the secreted cytokine profiles (IL-5 and IL-13, but not IL-4, production) in the setting (BMDCs + naïve CD4+ T cells + IL-33, no Ag) are similar to those by the IL-5-positive, IL-4-negative atypical Th2 cell population observed in the culture of naïve CD4+ T cells stimulated by TCR engagement plus IL-33, as described above. Thus, these observations suggest that IL-33 can enhance induction of an IL-5-positive, IL-4-negative atypical Th2 cell population from naïve CD4+ T cells directly and/or indirectly from DCs via the effects of certain factors.
Like IL-33, IL-25 and TSLP are known to be Th2-prone cytokines and contribute to the induction of Th2-type cytokine-mediated immune responses.53 In contrast to the case of IL-33, TSLP-activated DCs promote IL-4-producing Th2 cell differentiation from naïve CD4+ T cells in the presence of TCR engagement through OX40L-OX40 interaction, at least in part.54, 55 IL-25 can enhance TSLP-stimulated DC-mediated Th2 cell expansion.56 Unlike IL-33, both TSLP and IL-25 can induce differentiation of IL-4-producing Th2 cells from naïve CD4+ T cells after TCR engagement, dependent on the IL-4-IL-4Rα-STAT6 pathway.57, 58 Therefore, these observations suggest that the roles of IL-33, TSLP and IL-25 in T cells and DCs may be different in Th2-type cytokine-mediated immune responses. That is, TSLP and IL-25 may be preferentially involved in the induction of antigen-specific IL-4/IL-5/IL-13-producing Th2 cell-mediated immune responses, while IL-33 may contribute, at least in part, to the induction of antigen-non-specific Th2 cell-mediated immune responses by inducing IL-5/IL-13-, but not IL-4-, and thereby producing atypical Th2 cells.
Constitutive expression of ST2 mRNA/proteins was detected in mouse bone marrow cell-derived cultured macrophages and mouse alveolar macrophage cell lines.59, 60 Soluble ST2 expression was increased in macrophages in response to LPS and proinflammatory cytokines such as TNF, IL-1 and IL-6.60-62 IL-33 promoted the expression of LPS receptor components, such as MD2, TLR4, soluble CD14 and MyD88.63 Although IL-33 alone did not induce TNF, IL-1 or IL-6 production by thioglycolate-induced mouse peritoneal macrophages, it did in the presence of LPS.63 Such effects of IL-33 on LPS-mediated activation were abolished in anti-ST2 Ab-treated and ST2-deficient macrophages. Therefore, IL-33 may be a potential activator of macrophages during bacterial infections.
In addition, both naïve and thioglycolate-induced mouse peritoneal macrophages produced IL-33 upon LPS stimulation,4 suggesting that macrophage-derived IL-33 may autocrinely enhance LPS-mediated macrophage activation. Supporting this, LPS-mediated production of cytokines, such as IL-1, IL-6, IL-12 and/or TNF, by mouse bone marrow cell-derived cultured macrophages or mouse alveolar macrophage cell lines was inhibited by addition of soluble ST2-Fc fusion proteins.59, 60
It is well known that macrophages are key effector cells during septic shock. It was shown that mice treated with polyclonal anti-ST2 antiserum, which had potential activity to deplete ST2-expressing cells, including macrophages,64 were highly susceptible to LPS-induced endotoxin shock,59 suggesting the importance of ST2-expressing macrophages for protection against this event. Consistent with the effect of soluble ST2-Fc fusion proteins on macrophage activation by LPS, mice treated with soluble ST2-Fc fusion proteins were resistant to endotoxin shock and showed reduced serum IL-6 and TNF levels after intraperitoneal LPS injection.59
However, in contrast with the effect of soluble ST2-Fc fusion proteins,59, 60 IL-6, IL-12 and TNF productions by ST2-deficient thioglycolate-induced peritoneal macrophages were increased in response to LPS.65 In addition, ST2-deficient mice showed high susceptibility to LPS-induced endotoxic shock.65 The apparent discrepancy between the results using macrophages treated with soluble ST2-Fc fusion proteins and macrophages deficient in ST2 may be explained as follows. Perhaps ST2-deficiency results in increased formation of other IL-1R family molecules, such as IL-1R (IL-1R1 and IL-1RAcP), due to the failure of formation of IL-33R1 (ST2 and IL-1RAcP), causing cytokine hyperproduction by ST2-deficient macrophages in response to IL-1, which can be produced by these macrophages after LPS stimulation. Indeed, ST2-deficient macrophages produced larger amounts of cytokines than wild-type macrophages after IL-1β treatment.65 Although IL-1R1-deficient mice showed normal susceptibility to LPS-induced endotoxic shock,66 IL-1R antagonist-deficient mice, which have excessive IL-1-signaling, showed high susceptibility.67 This suggests that IL-1 is not required for induction of LPS-induced endotoxic shock, but excessive IL-1 production leads to amplified susceptibility to LPS, as seen in ST2-deficient mice.
Macrophages are phenotypically divided into two distinct populations: "classically activated macrophages (CAMφ)/type 1 macrophages (M1)" and "alternatively activated macrophages (AAMφ)/type 2 macrophages (M2)." CAMφ/M1s are generated in response to IFN-γ and LPS (or TNF induced by bacterial components) and are involved in Th1-type immune responses such as host defense against viral and bacterial infections and tumor rejection by producing IL-12, IL-23 and nitric oxide. M2 macrophages are further subdivided into at least three populations by in vitro stimulation with distinct factors: IL-4- and/or IL-13-stimulated M2a (also called AAMφ), immune complex plus IL-1β- or LPS-stimulated M2b (also called typeIIMφ) and IL-10-, TGF-β- or glucocorticoid-treated M2c (also called deactivated Mφ).68-71
IL-13 enhances ST2 expression in mouse bone marrow cell-derived cultured macrophages, and IL-33 amplifies polarization of M2a/AAMφs in the presence, but not absence, of IL-13, contributing to the induction of Th2-type immune responses.72
CD34-POSITIVE HEMATOPOIETIC PROGENITOR CELLS
CD34+ hematopoietic progenitor cells are capable of differentiating into various types of cells in the bone marrow and peripheral tissues. Recently, it was shown that mRNA and cell surface expression of ST2 as well as TSLPR were found in CD34+ hematopoietic progenitor cells derived from human umbilical cord blood cells.73 IL-33 enhances the production of various cytokines and chemokines, including IL-5, IL-13, CCL17 and CCL22, by human umbilical cord blood cell-derived CD34+ hematopoietic progenitor cells in cooperation with TSLP in the presence of IL-3 and SCF.73 Interestingly, the number of CD34+ hematopoietic progenitor cells was increased in peripheral blood from allergic patients.73 In addition, IL-5- and IL-13-producing CD34+ hematopoietic progenitor cells were also detected in sputum from patients with asthma. These observations suggest that CD34+ hematopoietic progenitor cells may themselves be potential effector cells by responding to IL-33 and TSLP even in the undifferentiated state and contributing to the development of allergic diseases.
NATURAL HELPER CELLS
Adipose tissue-associated Lin- c-Kit+ Sca-1+ natural helper cells are a newly identified population distinct from lymphoid progenitors and lymphoid tissue inducer cells.74 Natural helper cells constitutively express ST2 and can produce larger amounts of IL-5 and IL-13 than basophils and mast cells in response to IL-33. IL-33-mediated natural helper cell activation was shown to be important for development of goblet cell hyperplasia during Nippostrongylus brasiliensis infection.74
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