Abstract
Mast cells and basophils are associated with T helper 2 (Th2) immune responses. Newly developed mast cell-deficient mice have provided evidence that mast cells initiate contact hypersensitivity via activating dendritic cells. Studies using basophil-deficient mice have also revealed that basophils are responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Recently, several studies reported the existence of innate lymphoid cells (ILCs), which differ from classic T cells in that they lack the T cell receptor. Mast cells and basophils can interact with ILCs and play some roles in the pathogenesis of Th2 responses. Basophil-derived interleukin (IL)-4 enhances the expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in ILC2s, leading to the accumulation of eosinophils in allergic reactions. IL-33-stimulated mast cells can play a regulatory role in the development of ILC2-mediated non-antigen-specific protease-induced acute inflammation. In this review, we discuss the recent advances in our understanding of mast cells and basophils in immunity and inflammation.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Both mast cells and basophils produce the same effector molecules, including histamine, various cytokines, pro-inflammatory chemokines, and lipid mediators. Mast cells and basophils are associated with T helper 2 (Th2) immune responses. Mast cells are involved in the protection of the host against a range of parasitic and bacterial infections, the induction of tolerance to skin transplants, and tumor rejection [1, 2]. Basophils contribute to the pathogenesis of allergic skin and airway inflammation and contribute to immunity against parasites in both the gut and the skin [3, 4]. Mast cells also cause detrimental inflammatory responses to allergens and may exacerbate autoimmunity [5].
Recently, newly developed mast cell-deficient mice have provided evidence that mast cells initiate contact hypersensitivity via activating dendritic cells. In addition, studies using basophil-deficient mice have revealed that basophils are responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Moreover, human basophils infiltrate different skin lesions and have been implicated in the pathogenesis of a variety of skin diseases ranging from atopic dermatitis (AD) to autoimmune diseases [3, 4].
Recent studies have reported the existence of innate lymphoid cells (ILCs) in both mice and human subjects, which differ from classic T cells in that they lack the T cell receptor [6]. Mast cells and basophils can interact with ILCs and play some roles in the pathogenesis of Th2 responses. In this review, we summarize these recent studies on mast cells and basophils and focus on their role in immunity and inflammation.
Newly generated mast cell-specific depletion model
The selective depletion of mast cells in vivo is a useful tool to address the role of these cells in immune responses. Classic models for the investigation of mast cell functions are based on Kit-mutant mouse strains. In addition to their mast cell defect, Kit W/Wv mice that are Kit-mutant mouse strains have multiple hematopoietic abnormalities that include compromised fitness of the hematopoietic stem and progenitor cells [7], severe macrocytic anemia [8], impaired T development in the thymus [8], and a shift in intraepithelial T cells in the gut in favor of T cell receptor (TCR) αβ+ cells and against TCR γδ+ cells [9]. In addition, the Kit mutant is neutropenic, and this may be a major factor affecting immune responses in this strain [10].
Recently, new mouse models have been developed, which have marginal effects on other immune cells. These studies have reported the generation of mice expressing Cre recombinase under the control of mast cell protease genes [11–13]. Several groups developed their mice or generated lines to obtain Kit-independent mast cell-deficient mouse strains [14–17]. The differences among these strains are the selected gene loci and the methods used to drive ectopic gene expression in mast cells (targeted knock-in or transgenic overexpression) and depletion mechanisms. Dudeck et al. generated a mast cell depletion model in which mast cell protease (Mcpt)5-Cre transgenic mice were crossed to inducible diphtheria toxin receptor (iDTR) line [13]. In these mice, peritoneal mast cells were completely depleted by a single injection of diphtheria toxin (DT), but skin-resident mast cells were not. For the depletion of mast cells in the skin, Mcpt5-Cre + iDTR + mice require an additional local injection of DT [14]. Using Mcpt5-Cre mice crossed with the R-DTA line, the constitutive mast cell depletion model was generated [18]. These models do not have any effects on other cell types. Lilla et al. crossed mice carrying the Cpa3-Cre transgene with mice in which the first exon of myeloid cell leukemia sequence 1 (Mcl-1) is flanked by LoxP sites [16] and generated constitutive mast cell deficiency. Although these mice exhibit reductions in mast cell number in all tissues, they also exhibit a marked reduction in basophils, splenic neutrophilia, and macrocytic anemia. Using Cpa3-Cre transgenic mice, Feyerabend et al. also generated a mast cell deficiency model [15]. These mice exhibit reductions in mast cells and basophils. Considering the phenotype of these mast cell depletion models, Cpa3 may play some roles in the development of both mast cells and basophils. We also generated Mas-TRECK Tg mice using the DTR transgene under the control of 5′ enhancer, promoter, and intronic enhancer of interleukin (IL)-4 and demonstrated the role of mast cells in contact hypersensitivity [17]. Both mast cells and basophils in Mas-TRECK Tg mice are depleted after DT treatment, but basophils are restored sooner than mast cells.
Newly generated basophil-specific depletion model
Although no natural mouse mutants with basophil deficiencies have been reported yet, antibodies have often been used to study the contribution of basophils in different experimental settings. MAR-1 and Ba103 antibodies recognize FcεRI and the orphan activating receptor CD200 receptor 3 (CD200R3), respectively. They are both mainly expressed by basophils and mast cells. Both antibody clones can efficiently deplete basophils, and they can also activate mast cells [19, 20]. Furthermore, the depletion of basophils by Ba103 is FcR-dependent and has a potential to activate myeloid cells and natural killer (NK) cells [21]. In addition, MAR-1 also depletes a subset of FcεRI-expressing dendritic cells (DCs) [22]. Recently, several new mouse strains with a constitutive or inducible depletion of basophils have been generated. Mcpt8 is a basophil-specific gene in the conserved chymase locus [23]. Taking advantage of this gene regulation, three groups generated basophil depletion models [19, 24, 25]. Basophils, but not mast cells or other cell types, were depleted in the blood and spleen in these mice. Another group generated a different basophil depletion model [26] in which the N-terminal sequences for P1-Runx were replaced with the neor gene, resulting in the absence of both P1-Runx1 transcriptions and protein. A severe reduction in basophils was observed in these mice without any effects on eosinophils, neutrophils, or mast cells. Bas-TRECK Tg mice using the DTR transgene under the control of 5′ enhancer, promoter, and intronic enhancer of IL-4 were reported by another group [27]. New mast cell depletion models exhibited marginal effects on basophil depletion, while new basophil depletion models seemed to have no effect on the depletion of other immune cells.
The role of mast cells and basophils in contact hypersensitivity
Contact hypersensitivity (CHS) has been widely used as a model to study cutaneous immune responses, as a prototype of delayed-type hypersensitivity [28, 29]. CHS is classified into a sensitization phase and an elicitation phase. An essential step in the sensitization phase of CHS is the migration of hapten-bearing cutaneous DCs, such as epidermal Langerhans cells (LCs) and dermal DCs, into the skin-draining lymph nodes (LNs). In the draining LNs, mature DCs present antigens to naïve T cells, thus establishing the sensitization phase. In the elicitation phase, re-exposure to the same hapten induces the recruitment of antigen-specific T cells and other non-antigen-specific leukocytes into the lesional skin.
Several studies have demonstrated that mast cells modulate the DC function. It has been reported that activated human cord blood-derived mast cells induce DC maturation in vitro [30]. In addition, IgE-stimulated mast cell-derived histamine induces murine LC migration in vivo [31]. Furthermore, mast cell-derived tumor necrosis factor (TNF)-α promotes cutaneous murine DC migration in vivo in an IgE-independent manner [32], and coculture of mast cells and DCs results in upregulation of DC maturation markers, such as CD40, CD80, and CD86 [33]. Moreover, mast cells were required for the migration of plasmacytoid and CD8+ subsets of DCs into the draining LNs [34]. In contrast, prostaglandin (PG) D2 is abundantly produced by mast cells in response to allergens [35] and inhibits LC migration [36]. Therefore, mast cells might have bi-directional effects on DC activity in a context-dependent manner.
While basophils are essential to CHS development [37], the role of mast cells in CHS is controversial. Although mast cell-deficient mice have exhibited reduced inflammation in trinitrochlorobenzone (TNCB)-induced CHS in several studies [38, 39], other studies showed undiminished CHS induced with TNCB or 2, 4-dinitrofluorobenzene (DNFB) [40, 41]. To date, the reason for this discrepancy between reports using stem cell factor-deficient or c-Kit-deficient models and those using conditional mast cell ablation models is unknown. One of the differences between these two models is the existence of melanocytes and hematopoietic stem cells. Recently, melanocytes were shown to express toll-like receptors (TLRs) to modulate immune responses and to produce IL-1α and IL-1β [42, 43]. In addition, because of the congenital absence of mast cells in Kit W/Wv and Kit W−sh/W−sh mice, a compensatory mechanism may exist such as the repopulation of the skin with basophils [44]. Therefore, Kit W/Wv and Kit W−sh/W−sh mice may not necessarily be appropriate for evaluating the exclusive roles of mast cells.
Newly mast cell-deficient mice were developed as mentioned previously [14, 37]. Using these mice, it was reported that the CHS response induced by several haptens was attenuated [14, 37]. Using Mas-TRECK Tg mice, we demonstrated that the skin DC migration and/or maturation and T cell priming in the sensitization phase were impaired [17]. Consistently, the CHS response was reduced in DT-treated Mcpt5-Cre + iDTR + mice [14], which showed attenuation of the CHS response using DNFB and FITC as haptens. Thus, newly generated mast cell depletion mouse models provided evidence that mast cells promote the development of CHS irrespective of the type of haptens. Mast cell-derived TNF-α is considered to play an essential role in the modulation of DC function. A recent study showed the critical role of mast cell-derived TNF in CD8+ DC maturation, migration, and T cell-priming efficiency and, consequently, in efficient hapten-specific skin inflammation using the Mcpt5-CreTNFFL/FL mouse line [45]. Our studies showed that mast cells stimulated DCs via ICAM-1 or lymphocyte function-associated antigen 1 interaction and by membrane-bound TNF-α on mast cells [17]. Interestingly, activated DCs in turn increased Ca2+ influx in mast cells [17], suggesting that mast cells and DCs interact to activate each other. In the elicitation phase, mast cell deficiency resulted in an impaired CHS response, probably as a result of reduced vascular permeability caused by a loss of histamine release from mast cells [14].
The role of basophils in cutaneous allergic response
Recent studies reported that basophils migrate into draining LNs from the site of papain injection or helminth infection and act as antigen-presenting cells (APCs) by taking up and processing antigens [46–48]. Basophils are capable of expressing MHC class II and costimulatory molecules such as CD40, CD80, and CD86. They also secrete several cytokines critical for Th2 development, including IL-4 and thymic stromal lymphopoietin (TSLP). In addition, it has been demonstrated that basophils are capable of inducing Th2 upon exposure to ovalbumin (OVA) proteins complexed with specific IgE [48]. Thus, under certain conditions, basophils alone, without DCs, can cause Th2 induction from naïve T cells. However, the role of basophils in Th2 skewing has once more been questioned since several of the above experiments used bone marrow-derived basophils (BMBaso) containing FcεRI-expressing inflammatory DC [22].
Basophils contribute to the strength of the Th2 response in the lungs, but they cannot present the antigens or express the chaperones involved in antigen presentation [22]. Therefore, it was suggested that DCs are necessary and sufficient for inducing Th2 immunity to house dust mites in the lungs, and basophils are not required. Recently, we demonstrated that basophils play a role in Th2 skewing in response to haptens and peptide antigens, but not protein antigens because of the lack of processing ability [37]. Because basophils are not able to take up or process protein antigens efficiently, DCs may prepare peptides from protein antigens for antigen presentation by basophils or may promote IL-4 production from basophils to skew Th2. Consistently, we had previously demonstrated that LCs, an epidermal DC subset, plays an essential role in epicutaneous sensitization with OVA protein antigen to induce Th2-type immune responses through TSLP production [49].
Recently, two different groups have shown that Th2 skewing in response to infection with a gastrointestinal nematode parasite depends on dermal CD301b+ DCs [50, 51]. Depletion of CD301b+ DCs prior to infection reduces the number of IL-4-producing CD4+ T cells [50, 51]. CD301b+ DCs also express programmed death ligand-2 (PDL2), and a subset of PDL2+CD301b+ DCs that express the transcription factor interferon regulatory factor 4 (IRF4) was shown to be required for Th2 induction in vivo [51]. Based on these findings, CD11c+MHC class II+ dermal DCs expressing PDL2 and CD301b were identified as a Th2-inducing DC subset in gastrointestinal nematode parasite infection [52]. However, CD301b+ DCs alone cannot induce Th2 response in vitro [51] or in vivo [50]. Furthermore, basophils were found in the vicinity of T cells in the T cell zone of draining LNs by epicutaneous sensitization with haptens [53]. In addition, reactive oxygen species (ROS) were generated in dermal DCs and in LN DCs upon subcutaneous exposure to papain plus antigen. ROS promoted the Th2 response via the formation of oxidized lipids that triggered TSLP production by epithelia cells. In addition, ROS enhanced Th2 induction by inducing the release of CCL7 from DCs, leading to the recruitment of basophils to the draining LNs [54]. These studies support the hypothesis that DCs prepare peptides from protein antigens for antigen presentation by basophils and promote Th2 skewing.
Several studies show that murine basophils can serve as APCs, although the situation is less clear for human basophils. Human basophils express MHC class II [55, 56] but are not able to induce antigen-specific T cell activation or proliferation in response to exposure to house dust mite allergen [56]. Another group reported that human leukocyte antigen—antigen D related (HLA-DR) in human basophils—is upregulated by IL-3 and interferon (IFN)-γ, but that the basophils cannot work as APCs for pollen allergen [57]. It has been confirmed that human basophils lack some features of APCs [58, 59]. Additional studies are needed to determine whether human basophils can act as APCs under various pathophysiological conditions.
Cooperation of basophils and ILC2
Recent studies have reported the existence of ILCs in both mice and human subjects, which differ from classic T cells in that they lack the TCR [60]. ILCs can be distinguished into the three groups, ILC1, ILC2, and ILC3, according to their cytokine production (Fig. 1a) [60]. ILC2s produce type 2 cytokines including IL-5 and IL-13 and are responsive to IL-25 or IL-33 [61, 62]. These cells express the IL-7R, CD25, IL-33 receptor (T1/ST2), and the IL-25 receptor [61, 63]. In humans, ILC2s also express CRTH2 and CD161 (Fig. 1b) [64]. ILC2 development requires GATA-3 and RORα [64] and has been identified in various tissues such as the skin, lungs, and intestine [63]. ILC2s in the gut produce both IL-5 and IL-13, which are regulated in response to feeding. On the contrary, ILC2s in the lungs produce IL-13 only after cytokine stimulation and helminth infection [65]. IL-25, IL-33, and TSLP are the main cytokines produced by epithelial cells after certain stimuli, such as tissue damage, allergic inflammation, and helminth infections. These cytokines promote cytokine production from ILC2 [61, 63]. ILC2s have the potential to produce IL-4, especially in response to TSLP and leukotriene D4 rather than IL-33 (Fig. 1b) [66].
Recent studies have demonstrated that basophils and ILC2s infiltrated the atopic dermatitis (AD)-like lesional skin in a TSLP-dependent manner and play an essential role in Th2-type inflammation in a murine model [63, 67]. Basophils produced IL-4 and TNF-α in contact with fibroblasts and promoted the expression of eotaxin/CCL11 from fibroblasts, which promotes the infiltration of innate cells such as eosinophils [68]. In contrast, ILC2s express IL-5 and IL-13 [61, 63]. The differential effector cytokine expression profiles of basophils and ILC2s define their specialized functions in vivo [69]. IL-13 production was largely confined to Th2 cells and ILC2 cells in the lungs and was associated with large amounts of cellular transcription factor GATA-3. Conversely, follicular helper T cells (TFH cells) and basophils produced only IL-4 in vivo and did not have a high expression of GATA-3 [69]. In addition, recent studies have demonstrated that basophils and ILC2s accumulate in close proximity to each other in the dermis of lesional skin in AD patients and in AD-like murine lesions [67]. Basophil–ILC2 clusters significantly accumulated in AD-associated skin compared to those in healthy control skin. In murine AD-like inflammation, basophils accumulated into the lesional skin and then eosinophils infiltrated there. Basophils and IL-4 were necessary for the accumulation of ILC2s and the induction of AD-like inflammation. In addition, ILC2s expressed IL-4Rα and depended on the IL-4 produced by basophils for their proliferation in AD-like inflammation. Collectively, these studies demonstrate that basophils are early regulators of ILC2 responses in the AD-like inflammation.
Although ILC2s have been reported to be at least IL-33-independent [67], another study demonstrated that the skin-specific expression of IL-33 in transgenic mice causes AD-like cutaneous manifestations with the accumulation of eosinophils and ILC2s [70]. IL-33 stimulates the production of IL-4 by eosinophils [71], which in turn can promote the proliferation of ILC2 via IL-4Rα.
IL-4 from basophils is also considered to play an essential role in allergic asthma. Proteases such as papain cause barrier disruption in epithelial cells, leading to the production of multiple cytokines including IL-25, IL-33, and TSLP due to the stress of tissue injury. A recent study showed that the conditional deletion of basophils caused a resolution of the papain-induced eosinophilia and mucus production in an allergic asthma model [72]. Basophil-derived IL-4 enhanced the expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in ILC2s, leading to the accumulation of eosinophils. IL-33-deficient mice, but not TSLP receptor-deficient mice, failed to develop papain-induced lung inflammation [73]. Furthermore, antibody neutralization of IL-33 blocked IL-13 production [74]. Therefore, it has been speculated that lung ILC2 cells respond to the IL-33 produced by activated lung stromal cells, which directly induces IL-5 and IL-13 production by ILC2 cells, resulting in lung eosinophilia, goblet cell hyperplasia, and mucus production [73, 74]. Above all, basophil-derived IL-4 seems to be the main regulator of ILC2s in allergic conditions (Fig. 2). The mechanism of the induction or accumulation of ILC2s may depend on the organ specificity or the stimuli.
Bi-directional effects of mast cells and ILC2
Original studies have reported that ILC2 exists in fat-associated lymphoid tissue and mucosa-associated tissues [62, 75–77]. A recent study identified dermal ILC2s as producing IL-13 in steady-state conditions and depending on IL-7 for their survival [78]. Dermal ILC2 preferentially interacts with skin-resident mast cells [78]. In addition, dermal ILC2 responds to IL-2–anti-IL-2 complexes to proliferate and produce IL-5, leading to the promotion of eosinophil influx [78]. Collectively, dermal ILC2s are considered to play some roles with other immune cells in cutaneous immune reactions.
Activated mast cells produce prostaglandin D2 (PGD2), which binds to their receptor, a chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on eosinophils, basophils, and Th2 cells [79]. The allergic response mediated by mast cells was significantly attenuated in mice in which CRTH2 is genetically ablated [80]. A recent report showed that PGD2 promoted IL-13 production from ILC2s through activation of CRTH2 in a synergistic manner with IL-25/IL-33 [76]. Another study showed that CRTH2 also played an essential role in the proinflammatory responses of ILC2s, including cell migration and diverse cytokine production [81]. Therefore, ILC2s can contribute to adaptive type 2 immunity via IgE-mediated mast cell degranulation. In addition, it has been reported that IL-25-mediated collaborations between ILC2s and Th2 cells can enhance the allergic reactions to ingested antigens in the effector phase of IgE-mediated food allergy through mast cells [82, 83].
Mast cells can also negatively regulate innate or adaptive immune responses. Mast cells have been reported to promote peripheral tolerance to skin allografts using mast cell-deficient Kit W-sh/W-sh mice [84]. This research showed that IL-9 represents the functional link through which activated regulatory T cells recruit and activate mast cells to mediate regional immune suppression [84]. In addition, mast cells have been reported to exert anti-inflammatory or immunosuppressive effects via the production of histamine [85]. Furthermore, IgG-stimulated mast cell-derived IL-10 or IL-2 can suppress the chronic phase of local inflammation during CHS [86, 87]. A recent study identified another mechanism of mast cell-dependent negative regulation for inflammation. They showed that mast cell-deficient Kit W-sh/W-sh mice exhibited exacerbated protease-induced lung inflammation associated with a reduced number of regulatory T (Treg) cells [88]. IL-33-activated mast cells produced IL-2 which suppressed the Treg expansion. The IL-10 produced by Treg inhibited the proliferation of ILC2s which play an essential role in papain-induced lung inflammation. Although IgE-stimulated mast cells are considered to have potent effector cell functions in the pathology of allergic disorders, the study provided multiple lines of evidence that IL-33-stimulated mast cells can play a regulatory role in the development of ILC2-mediated non-antigen-specific protease-induced acute inflammation (Fig. 3) [88].
Conclusion
The establishment of newly developed mast cell-deficient or basophil-deficient mice revealed the novel mechanisms of immunity and inflammation. However, several key questions remain unanswered, such as what role basophils play in pathogenic processes where they are detected in the lesional skin and how DCs present peptides to basophils during Th2 skewing. In addition, there remains a compelling need to determine whether these findings in mouse models are relevant to humans. Especially for basophils, most of the current knowledge in vivo is based on the murine model. Further studies are needed to investigate the counterpart in human skin diseases. In addition, recent studies have demonstrated the strong relationship between ILC2s and mast cells/basophils in allergic reactions. The newly developed mast cell-deficient and basophil-deficient models are expected to provide us with valuable information on the mechanisms of allergic diseases. Future studies focusing on these topics will enable the development of novel therapeutic approaches to controlling immunity and inflammation.
References
Migalovich-Sheikhet H, Friedman S, Mankuta D, Levi-Schaffer F (2012) Novel identified receptors on mast cells. Front Immunol 3:238
Schneider E, Thieblemont N, De Moraes ML, Dy M (2010) Basophils: new players in the cytokine network. Eur Cytokine Netw 21:142–153
Otsuka A, Kabashima K (2015) Mast cells and basophils in cutaneous immune responses. Allergy 70:131–140
Otsuka A, Kabashima K (2015) Contribution of basophils to cutaneous immune reactions and Th2-mediated allergic responses. Front Immunol 6:393
Gilfillan AM, Beaven MA (2011) Regulation of mast cell responses in health and disease. Crit Rev Immunol 31:475–529
Sonnenberg GF, Artis D (2015) Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med 21:698–708
Russell ES (1979) Hereditary anemias of the mouse: a review for geneticists. Adv Genet 20:357–459
Waskow C, Terszowski G, Costa C, Gassmann M, Rodewald HR (2004) Rescue of lethal c-KitW/W mice by erythropoietin. Blood 104:1688–1695
Puddington L, Olson S, Lefrancois L (1994) Interactions between stem cell factor and c-Kit are required for intestinal immune system homeostasis. Immunity 1:733–739
Zhou JS, Xing W, Friend DS, Austen KF, Katz HR (2007) Mast cell deficiency in Kit(W-sh) mice does not impair antibody-mediated arthritis. J Exp Med 204:2797–2802
Feyerabend TB, Terszowski G, Tietz A, Blum C, Luche H, Gossler A et al (2009) Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms. Immunity 30:67–79
Musch W, Wege AK, Mannel DN, Hehlgans T (2008) Generation and characterization of alpha-chymase-Cre transgenic mice. Genesis 46:163–166
Scholten J, Hartmann K, Gerbaulet A, Krieg T, Muller W, Testa G et al (2008) Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res 17:307–315
Dudeck A, Dudeck J, Scholten J, Petzold A, Surianarayanan S, Kohler A et al (2011) Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 34:973–984
Feyerabend TB, Weiser A, Tietz A, Stassen M, Harris N, Kopf M et al (2011) Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity. Immunity 35:832–844
Lilla JN, Chen CC, Mukai K, BenBarak MJ, Franco CB, Kalesnikoff J et al (2011) Reduced mast cell and basophil numbers and function in Cpa3-Cre; Mcl-1fl/fl mice. Blood 118:6930–6938
Otsuka A, Kubo M, Honda T, Egawa G, Nakajima S, Tanizaki H et al (2011) Requirement of interaction between mast cells and skin dendritic cells to establish contact hypersensitivity. PLoS One 6:e25538
Voehringer D, Liang HE, Locksley RM (2008) Homeostasis and effector function of lymphopenia-induced “memory-like” T cells in constitutively T cell-depleted mice. J Immunol 180:4742–4753
Ohnmacht C, Schwartz C, Panzer M, Schiedewitz I, Naumann R, Voehringer D (2010) Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 33:364–374
Kojima T, Obata K, Mukai K, Sato S, Takai T, Minegishi Y et al (2007) Mast cells and basophils are selectively activated in vitro and in vivo through CD200R3 in an IgE-independent manner. J Immunol 179:7093–7100
Obata K, Mukai K, Tsujimura Y, Ishiwata K, Kawano Y, Minegishi Y et al (2007) Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood 110:913–920
Hammad H, Plantinga M, Deswarte K, Pouliot P, Willart MA, Kool M et al (2010) Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med 207:2097–2111
Poorafshar M, Helmby H, Troye-Blomberg M, Hellman L (2000) MMCP-8, the first lineage-specific differentiation marker for mouse basophils. Elevated numbers of potent IL-4-producing and MMCP-8-positive cells in spleens of malaria-infected mice. Eur J Immunol 30:2660–2668
Sullivan BM, Liang HE, Bando JK, Wu D, Cheng LE, McKerrow JK et al (2011) Genetic analysis of basophil function in vivo. Nat Immunol 12:527–535
Wada T, Ishiwata K, Koseki H, Ishikura T, Ugajin T, Ohnuma N et al (2010) Selective ablation of basophils in mice reveals their nonredundant role in acquired immunity against ticks. J Clin Invest 120:2867–2875
Mukai K, BenBarak MJ, Tachibana M, Nishida K, Karasuyama H, Taniuchi I et al (2012) Critical role of P1-Runx1 in mouse basophil development. Blood 120:76–85
Sawaguchi M, Tanaka S, Nakatani Y, Harada Y, Mukai K, Matsunaga Y, et al. Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness. J Immunol 2012.
Honda T, Egawa G, Grabbe S, Kabashima K (2013) Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. J Invest Dermatol 133:303–315
Honda T, Otsuka A, Tanizaki H, Minegaki Y, Nagao K, Waldmann H et al (2011) Enhanced murine contact hypersensitivity by depletion of endogenous regulatory T cells in the sensitization phase. J Dermatol Sci 61:144–147
Kitawaki T, Kadowaki N, Sugimoto N, Kambe N, Hori T, Miyachi Y et al (2006) IgE-activated mast cells in combination with pro-inflammatory factors induce Th2-promoting dendritic cells. Int Immunol 18:1789–1799
Jawdat DM, Albert EJ, Rowden G, Haidl ID, Marshall JS (2004) IgE-mediated mast cell activation induces Langerhans cell migration in vivo. J Immunol 173:5275–5282
Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2006) Mast cell-associated TNF promotes dendritic cell migration. J Immunol 176:4102–4112
Dudeck A, Suender CA, Kostka SL, von Stebut E, Maurer M (2011) Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function. Eur J Immunol 41:1883–1893
Dawicki W, Jawdat DW, Xu N, Marshall JS (2010) Mast cells, histamine, and IL-6 regulate the selective influx of dendritic cell subsets into an inflamed lymph node. J Immunol 184:2116–2123
Kabashima K, Narumiya S (2003) The DP receptor, allergic inflammation and asthma. Prostaglandins Leukot Essent Fatty Acids 69:187–194
Hammad H, de Heer HJ, Soullie T, Hoogsteden HC, Trottein F, Lambrecht BN (2003) Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1. J Immunol 171:3936–3940
Otsuka A, Nakajima S, Kubo M, Egawa G, Honda T, Kitoh A et al (2013) Basophils are required for the induction of Th2 immunity to haptens and peptide antigens. Nat Commun 4:1739
Askenase PW, Van Loveren H, Kraeuter-Kops S, Ron Y, Meade R, Theoharides TC et al (1983) Defective elicitation of delayed-type hypersensitivity in W/Wv and SI/SId mast cell-deficient mice. J Immunol 131:2687–2694
Biedermann T, Kneilling M, Mailhammer R, Maier K, Sander CA, Kollias G et al (2000) Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J Exp Med 192:1441–1452
Galli SJ, Hammel I (1984) Unequivocal delayed hypersensitivity in mast cell-deficient and beige mice. Science 226:710–713
Mekori YA, Galli SJ (1985) Undiminished immunologic tolerance to contact sensitivity in mast cell-deficient W/Wv and Sl/Sld mice. J Immunol 135:879–885
Swope VB, Sauder DN, McKenzie RC, Sramkoski RM, Krug KA, Babcock GF et al (1994) Synthesis of interleukin-1 alpha and beta by normal human melanocytes. J Invest Dermatol 102:749–753
Yu N, Zhang S, Zuo F, Kang K, Guan M, Xiang L (2009) Cultured human melanocytes express functional toll-like receptors 2–4, 7 and 9. J Dermatol Sci 56:113–120
Piliponsky AM, Chen CC, Grimbaldeston MA, Burns-Guydish SM, Hardy J, Kalesnikoff J et al (2010) Mast cell-derived TNF can exacerbate mortality during severe bacterial infections in C57BL/6-KitW-sh/W-sh mice. Am J Pathol 176:926–938
Dudeck J, Ghouse SM, Lehmann CH, Hoppe A, Schubert N, Nedospasov SA et al (2015) Mast-cell-derived TNF Amplifies CD8(+) dendritic cell functionality and CD8(+) T cell priming. Cell Rep 13:399–411
Perrigoue JG, Saenz SA, Siracusa MC, Allenspach EJ, Taylor BC, Giacomin PR et al (2009) MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity. Nat Immunol 10:697–705
Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R (2009) Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol 10:713–720
Yoshimoto T, Yasuda K, Tanaka H, Nakahira M, Imai Y, Fujimori Y et al (2009) Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat Immunol 10:706–712
Nakajima S, Igyarto BZ, Honda T, Egawa G, Otsuka A, Hara-Chikuma M et al (2012) Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J Allergy Clin Immunol 129:1048–1055, e6
Kumamoto Y, Linehan M, Weinstein JS, Laidlaw BJ, Craft JE, Iwasaki A (2013) CD301b(+) dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39:733–743
Gao Y, Nish SA, Jiang R, Hou L, Licona-Limon P, Weinstein JS et al (2013) Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 39:722–732
Connor LM, Tang SC, Camberis M, Le Gros G, Ronchese F (2014) Helminth-conditioned dendritic cells prime CD4+ T cells to IL-4 production in vivo. J Immunol 193:2709–2717
Otsuka A, Nakajima S, Kubo M, Egawa G, Honda T, Kitoh A et al (2013) Basophils are required for the induction of Th2 immunity to haptens and peptide antigens. Nat Commun 4:1738
Tang H, Cao W, Kasturi SP, Ravindran R, Nakaya HI, Kundu K et al (2010) The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol 11:608–617
Poulsen BC, Poulsen LK, Jensen BM (2012) Detection of MHC class II expression on human basophils is dependent on antibody specificity but independent of atopic disposition. J Immunol Methods 381:66–69
Voskamp AL, Prickett SR, Mackay F, Rolland JM, O’Hehir RE (2013) MHC class II expression in human basophils: induction and lack of functional significance. PLoS One 8:e81777
Kitzmuller C, Nagl B, Deifl S, Walterskirchen C, Jahn-Schmid B, Zlabinger GJ et al (2012) Human blood basophils do not act as antigen-presenting cells for the major birch pollen allergen Bet v 1. Allergy 67:593–600
Eckl-Dorna J, Ellinger A, Blatt K, Ghanim V, Steiner I, Pavelka M et al (2012) Basophils are not the key antigen-presenting cells in allergic patients. Allergy 67:601–608
Sharma M, Hegde P, Aimanianda V, Beau R, Maddur MS, Senechal H et al (2013) Circulating human basophils lack the features of professional antigen presenting cells. Sci Rep 3:1188
Annunziato F, Romagnani C, Romagnani S (2015) The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol 135:626–635
Roediger B, Weninger W (2015) Group 2 innate lymphoid cells in the regulation of immune responses. Adv Immunol 125:111–154
Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H et al (2010) Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature 463:540–544
Licona-Limon P, Kim LK, Palm NW, Flavell RA (2013) TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 14:536–542
Mjosberg J, Bernink J, Golebski K, Karrich JJ, Peters CP, Blom B et al (2012) The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37:649–659
Hung LY, Lewkowich IP, Dawson LA, Downey J, Yang Y, Smith DE et al (2013) IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms. Proc Natl Acad Sci U S A 110:282–287
McKenzie AN, Spits H, Eberl G (2014) Innate lymphoid cells in inflammation and immunity. Immunity 41:366–374
Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med 2013; 5:170ra16.
Nakashima C, Otsuka A, Kitoh A, Honda T, Egawa G, Nakajima S et al (2014) Basophils regulate the recruitment of eosinophils in a murine model of irritant contact dermatitis. J Allergy Clin Immunol 134:100–107
Liang HE, Reinhardt RL, Bando JK, Sullivan BM, Ho IC, Locksley RM (2012) Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol 13:58–66
Imai Y, Yasuda K, Sakaguchi Y, Haneda T, Mizutani H, Yoshimoto T et al (2013) Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A 110:13921–13926
Matsuba-Kitamura S, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Taki Y, Muto T et al (2010) Contribution of IL-33 to induction and augmentation of experimental allergic conjunctivitis. Int Immunol 22:479–489
Motomura Y, Morita H, Moro K, Nakae S, Artis D, Endo TA et al (2014) Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity 40:758–771
Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A et al (2010) IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci U S A 107:18581–18586
Halim TY, Krauss RH, Sun AC, Takei F (2012) Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36:451–463
Chang YJ, Kim HY, Albacker LA, Baumgarth N, McKenzie AN, Smith DE et al (2011) Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12:631–638
Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B et al (2011) Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 12:1055–1062
Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA et al (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol 12:1045–1054
Roediger B, Kyle R, Yip KH, Sumaria N, Guy TV, Kim BS et al (2013) Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol 14:564–573
Gervais FG, Cruz RP, Chateauneuf A, Gale S, Sawyer N, Nantel F et al (2001) Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. J Allergy Clin Immunol 108:982–988
Satoh T, Moroi R, Aritake K, Urade Y, Kanai Y, Sumi K et al (2006) Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor. J Immunol 177:2621–2629
Xue L, Salimi M, Panse I, Mjosberg JM, McKenzie AN, Spits H et al (2014) Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J Allergy Clin Immunol 133:1184–1194
Brandt EB, Strait RT, Hershko D, Wang Q, Muntel EE, Scribner TA et al (2003) Mast cells are required for experimental oral allergen-induced diarrhea. J Clin Invest 112:1666–1677
Lee JB, Chen CY, Liu B, Mugge L, Angkasekwinai P, Facchinetti V, et al. IL-25 and CD4 T2 cells enhance type 2 innate lymphoid cell-derived IL-13 production, which promotes IgE-mediated experimental food allergy. J Allergy Clin Immunol 2015.
Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002
Hart PH, Grimbaldeston MA, Swift GJ, Jaksic A, Noonan FP, Finlay-Jones JJ (1998) Dermal mast cells determine susceptibility to ultraviolet B-induced systemic suppression of contact hypersensitivity responses in mice. J Exp Med 187:2045–2053
Grimbaldeston MA, Nakae S, Kalesnikoff J, Tsai M, Galli SJ (2007) Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat Immunol 8:1095–1104
Hershko AY, Suzuki R, Charles N, Alvarez-Errico D, Sargent JL, Laurence A et al (2011) Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis. Immunity 35:562–571
Morita H, Arae K, Unno H, Miyauchi K, Toyama S, Nambu A et al (2015) An Interleukin-33-Mast cell-interleukin-2 axis suppresses papain-induced allergic inflammation by promoting regulatory T cell numbers. Immunity 43:175–186
Acknowledgments
This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare of Japan.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is a contribution to the special issue on Basophils and Mast Cells in Immunity and Inflammation - Guest Editor: Hajime Karasuyama
Rights and permissions
About this article
Cite this article
Otsuka, A., Nonomura, Y. & Kabashima, K. Roles of basophils and mast cells in cutaneous inflammation. Semin Immunopathol 38, 563–570 (2016). https://doi.org/10.1007/s00281-016-0570-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-016-0570-4