European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells Yoseph A. Mekori a,n, Alon Y. Hershko a, Barbara Frossi b, Francesca Mion b, Carlo E. Pucillo b,n a The Herbert Mast Cell Disorders Center, Department of Medicine, Meir Medical Center, Kfar Saba and the Sackler School of Medicine, Tel Aviv University, Israel b Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy

art ic l e i nf o

a b s t r a c t

Article history: Received 7 January 2015 Received in revised form 26 February 2015 Accepted 25 March 2015

A diversity of immune mechanisms have evolved to protect normal tissues from infection, but from immune damage too. Innate cells, as well as adaptive cells, are critical contributors to the correct development of the immune response and of tissue homeostasis. There is a dynamic “cross-talk” between the innate and adaptive immunomodulatory mechanisms for an integrated control of immune damage as well as the development of the immune response. Mast cells have shown a great plasticity, modifying their behavior at different stages of immune response through interaction with effector and regulatory populations of adaptive immunity. Understanding the interplays among T effectors, regulatory T cells, B cells and regulatory B cells with mast cells will be critical in the future to assist in the development of therapeutic strategies to enhance and synergize physiological immune-modulator and -suppressor elements in the innate and adaptive immune system. & 2015 Elsevier B.V. All rights reserved.

Keywords: Mast cell T reg cells T effector cells B cells B reg cells

1. Introduction Mast cells (MCs) originate in the bone marrow from lineagespecific multipotent hematopoietic progenitors, circulate as CD34 þ precursors until they migrate to tissues and mature into effector cells in proximity of blood vessels. MCs display functional diversity depending on the tissue in which they differentiate. This distribution permits them, along with dendritic cells and tissue macrophages, to be among the first cells of the immune response to interact with environmental antigens and allergens, invading pathogens or toxic compounds (Galli et al., 2011). In the intestinal tract, MCs are distributed in the lamina propria and contribute both to tolerance for food as well as to sustain the immune response against pathogens. The best known mechanism of MC activation is dependent on antigenic

Abbreviations: EAE, experimental autoimmune encephalomyelitis; EGF, epidermal growth factor; MC, mast cell; PCMC, peritoneal cell-derived mast cells; SMZL, splenic marginal zone lymphoma; Teff, effectot T cells; Tph-1, tryptophan hydroxylase-1; Treg, regulatory T cells n Corresponding authors. E-mail addresses: [email protected] (Y.A. Mekori), [email protected] (C.E. Pucillo).

stimulation through the cross-linking of immunoglobulin E (IgE)bound high affinity receptor for IgE (FcεRI). However, to sense tissue microenvironment, MCs are equipped with other receptors such TLRs and cytokines and chemokines receptors (reviewed in Gri et al. (2012) and Sibilano et al. (2012)). Moreover, the function of these receptors is finely modulated by co-stimulatory molecules (OX40, CD40L, CD80, CD86, PD-L1, PD-L2), either enhancing or inhibiting MC responses (Gri et al., 2012; Migalovich-Sheikhet et al., 2012). MCs are specialized to serve functions that can amplify or suppress innate or acquired immune responses (Galli et al., 2008; Hershko and Rivera, 2008). Such functions mainly reflect the ability of MCs to secrete a wide spectrum of preformed or newly synthesized biologically active products, many of which can potentially mediate pro-inflammatory (IL-1, IL-6, IL-8, IL-17) or immunosuppressive functions (IL-10, TGF-β) (Frossi et al., 2011; Galli et al., 2008). However, the MC can be considered a “social” cell since both positive and suppressive effects on immune responses are amplified or mediated through the interaction with different effector or regulatory immune cells. The cross-talk between MCs and effectors or regulatory T and B cells will be discussed in the present review. Additionally, physical pathways will be dissected as possible targets of immune intervention in diseases in which MCs play a role.

http://dx.doi.org/10.1016/j.ejphar.2015.03.087 0014-2999/& 2015 Elsevier B.V. All rights reserved.

Please cite this article as: Mekori, Y.A., et al., Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.03.087i

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2. Interactions between MCs and adaptive effector cells 2.1. Effector T cells activate MCs Observations such as the close physical proximity between MCs and T cells in inflamed tissues and the capability of the former to release a wide range of immunomodulatory mediators and to express surface molecules important in costimulation in both adaptive and innate immunity, have led investigators to propose a functional bidirectional relationship between these two cell populations (Mekori, 2004; Bachelet et al., 2006; Kalesnikoff and Galli, 2008; Tsai et al., 2011; Gri et al., 2012). Indeed, morphologic studies have documented an increase in the local density of MCs and their activation during T cell-mediated inflammatory processes, as observed in cutaneous delayed-type hypersensitivity, graft-versus-host reactions, sarcoidosis, Crohn's disease, rheumatoid arthritis, and psoriasis (Mekori, 2004; Bachelet et al., 2006; Kalesnikoff and Galli, 2008; Dudeck et al., 2011, Rabenhorst et al., 2012). Both in vitro and in vivo studies have demonstrated that MCs or their products are pivotal in mediating leukocyte recruitment into inflammatory sites, are capable of presenting antigens to T cells, interact directly with and affect the function of cells of the adaptive immune system, and mediate tissue remodeling (Biedermann et al., 2000; Mekori, 2004; Bachelet et al., 2006; Kalesnikoff and Galli, 2008; Dudeck et al., 2011; Tsai et al., 2011; Gri et al., 2012). However, the nature of the T cell-derived signals that lead to MC activation has not yet been fully elucidated. A wide range of soluble mediators have been regarded as triggers, but increasing evidence indicates the importance of intercellular communication involving the binding of cell surface molecules. In this regard, a direct physical contact between MCs and activated T lymphocytes was found to induce MC activation and mediator release. Both murine and human MCs could be activated to release granule-associated mediators, such as histamine and matrix metalloproteinase-9 (MMP-9); to produce several cytokines (i.e. TNF-α, IL-4, IL-6 and IL-8); and to induce MC adhesion to extracellular matrix components on physical contact with activated, but not resting, T cells (Inamura et al., 1998; Baram et al., 2001; Brill et al. 2004; Salamon et al., 2005, 2008). Furthermore, the expression and release of these mediators, were also induced when MCs were incubated with cell membranes isolated from activated T cells (Baram et al., 2001; Salamon et al., 2005, 2008; Shefler et al., 2008). Gene expression profiling validated by qRT-PCR has demonstrated the expression and production of cytokines (oncostatin M) and enzymes (MMP-9) that were specifically induced by this novel here-to-fore unknown pathway of activation (Salamon et al., 2008). Studies with murine MCs and myristate 13-acetate (PMA) – or antiCD3-activated T cells, attributed the T cell-induced MC activation to interactions of surface molecules, such as intercellular adhesion molecule-1 (ICAM-1)and lymphotoxin-β receptor (LTβR), with their respective ligands (Inamura et al., 1998; Stopfer et al., 2004). Thus, direct contact between surface molecules on activated T cells and on MCs, was found to provide the stimulatory signal in MCs necessary for degranulation and cytokine release, independent of T-cell intracellular function, and in the absence of demonstrable soluble mediators. Indeed, separation of the two cell populations by a semipermeable porous membrane prevented this pathway of MC activation (Bhattacharyya et al., 1998; Baram et al., 2001). The biological relevance of this pathway of MC activation can be envisaged from the findings with oncostatin M, a known fibrogenic cytokine. Both oncostatin M mRNA and protein were induced in human MCs specifically by means of heterotypic adhesion to activated T cells. MC-derived oncostatin was found to induce the proliferation of lung fibroblasts and its presence was demonstrated in MCs in the lungs of patients with sarcoidosis, a disease known to be mediated by T cells that culminates in fibrosis (Salamon et al., 2008). These results suggest that human MCs may

contribute to T cell-mediated fibrotic inflammatory processes by means of local release of fibrogenic cytokines (i.e., oncostatin) following direct activation by T cells. Other possible candidates of surface molecule-induced MC activation, are membrane vesicles that are secreted by T cells (Al-Nedawwi et al., 2009; Thery et al., 2009; Shefler et al., 2011). These vesicles contain cytosol and expose the extracellular side of the membrane they form from at their outer surface. Thus, membrane transfer is a mode of intercellular communication that may also involve T cellinduced MC activation within inflammatory sites in which both cell populations have been shown to be involved (Shefler et al., 2011). Indeed, T cell-derived microvesicles induced degranulation and cytokine (IL-8 and oncostatin M) release from human MCs with kinetics that resembled MC activation by activated fixed T cells or by whole membranes of the latter (Shefler et al., 2010). Thus, by releasing microvesicles, T cells might convey surface molecules similar to those involved in the activation of MCs by cellular contact. Recently, it was shown that T cell-derived microvesicles were internalized by MCs in a time-dependent manner by an active (energy dependent) process, resulting in upregulation of several proinflammatory genes that have been here-to-fore unknown to be expressed in human MCs on “classical” activation through FcεRI cross-linking. Among these, IL-24 appeared to be a hallmark of microvesicle-induced activation. MC-derived IL-24, in turn, activated keratinocytes in vitro, as manifested by STAT 3 phosphorylation, and was found to be produced by MCs in psoriatic skin lesions (Shefler et al., 2014), a T cell-mediated disease wherein keratinocyte activation and MC involvement are noticed (Rabenhorst et al., 2012). It therefore may be concluded that, through the generation of microvesicles, activated T cells may facilitate distant contactmediated activation of MCs which are not in direct contact with T cells at the inflammatory sites (Shefler et al., 2011; Mekori and Hershko, 2012).

2.1.1. Stimulation of effector T cells by MCs Stimulation of effector T cells by MCs was shown in the late 1980s in experimental autoimmune encephalomyelitis (EAE; Orr, 1988), a mouse model mimicking multiple sclerosis. In this T cell-mediated inflammatory disease MCs clearly enhanced tissue damage (Secor et al., 2000) by the induction of CD4þ and CD8þ T-cell expansion in the central nervous system (Gregory et al., 2005). The ability of MCs to be antigen presenting cells appears to underlie their capacity to enhance T-effector activity (Frandji et al., 1996). This was demonstrated in a study where exposure to LPS and IFN-γ induced expression of MHC class II by MCs (Kambayashi et al., 2009). Consequently, MHC class II-expressing MCs effectively supported activated T effectors and caused the expansion of regulatory T cells (Tregs). LPS injection increased the number of MCs in the lymph nodes of mice, and induced both the expression of MHC Class II and the positive costimulatory B7 family members CD80 and CD86 (Kambayashi et al., 2009). This observation was supported by another study (Gaudenzio et al., 2009) in which treatment of peritoneal cell-derived MCs (PCMCs) with IFN-γ and IL-4 induced expression of MHC class II molecules. This caused the activation and proliferation of effector T cells and the formation of an immunological synapse between the PCMC and the T cell (Gaudenzio et al., 2009). Notch signaling was reported to induce MHC class II and OX40L expression on MCs leading to proliferation of T cells with a Th2 phenotype (Nakano et al., 2009). Taken together, these studies indicate that upregulation of MHC class II on MCs is a pivotal factor for stimulating T effector cells. Furthermore, MHC class I-dependent cross presentation of MCs to CD8þ T cells was shown to increase CD8þ T cell proliferation and effector functions (Stelekati et al., 2009). This observation was corroborated in vivo, by EAE studies showing that MCs could regulate CD8þ T

Please cite this article as: Mekori, Y.A., et al., Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.03.087i

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cells specific priming. These data convincingly demonstrate that MCs are players in antigen-specific regulation of CD8þ T cells. It is presently accepted that MCs exert their effects on T cells by various other mechanisms as well. Following activation through FcεRI, MC produce TNF-α which can cause T cell proliferation and cytokine secretion (Nakae et al., 2005). Furthermore, while on one hand low numbers of MCs co-cultured with helper T-cells enhanced T cell proliferation, on the other hand, increased numbers suppressed T cell proliferation (Khan et al., 1986). This effect was thought to be mediated by histamine, via the H1 receptor. 2.1.2. Suppression of T effector cells There is much less data regarding the suppression of effector T cells by MCs. In a mouse model of hepatocarcinoma, stem cell factor produced by tumor cells promoted the recruitment of MCs into the tumor, as well as the release of adenosine, which, in turn, blocked the secretion of IL-2 and IFN-γ by CD4þ T cells (Huang et al., 2008). This immune suppression appears to be augmented by the increased presence of Tregs in the tumor, a process not necessarily mediated by MCs (Huang et al., 2008). This model argues that MCs contribute to tumor-mediated suppression of the immune response. Another mechanism for MC-suppression of T cell responses was elegantly demonstrated in a model of tryptophan hydroxylase-1 (Tph-1, Nowak et al., 2012) deficiency, an enzyme that causes tryptophan breakdown. This work was based on previous reports demonstrating that T cell activation is dampened by local tryptophan deprivation. In models of skin allograft tolerance, tumor growth and EAE, Tph-1 deficiency breaks allograft tolerance, induces tumor remission and intensifies neuroinflammation. MCs appear to be the major source of Tph-1 and the in vivo restoration of Tph-1 in the MC compartment compensates for the defect. We can therefore conclude that MCs may promote or suppress T effectors depending on the inflammatory setting, the involved tissue and the specific stimulatory triggers involved in the various disease processes. These variables may dictate the diverse mechanisms by which MCs modulate (enhance or suppress) T effector functions. 2.2. MCs and B cells The vision of MCs as modulators of the adaptive immune response is also due to new insights unveiling the existence of a cross-talk between MCs and B lymphocytes (Merluzzi et al., 2014). For several years the studies concerning the B/MCs interaction remained confined to the production of IgE and to the allergic context. In different settings, the CD40:CD40L crosstalk between the two cell populations, together with the release of IL-4 and IL-13 by MCs, were shown to be required for optimal B cell activation and IgE synthesis (Gauchat et al., 1993; Pawankar et al., 1997; Ryzhov et al., 2004). Only recently we have gained further insights on the role of the MC as important inducer of effector functions of B cells, in contexts not strictly related to allergy. Merluzzi et al. (2010) demonstrated that MCs are able to promote both survival and activation of naive B cells, as well as proliferation and further plasma cell differentiation of activated B cells, thanks to the constitutive expression of CD40L on their surface. Of note, these outcomes on B cell biology were observed with both non-sensitized and IgE-sensitized MCs, suggesting that the activity of MCs on B cells not necessarily requires the IgE-antigen context. Strictly dependent on MC-activation is the induction of IgA surface expression and secretion by activated B cells, which relied on MC-derived IL-6 (Merluzzi et al., 2010). Particularly relevant in terms of novel strategies for the treatment of intestinal inflammatory conditions, the authors evidenced infiltrating MCs in close contact with IgAexpressing plasma cells within specimens of inflamed mucosal

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tissues (Merluzzi et al., 2010). Initially considered a marker of diverse inflammatory conditions, IL-6 was shown to play an active role in the development of several autoimmune pathologies, including Crohn's disease (reviewed by Yao et al. (2014)). Now this cytokine is a target of therapies in autoimmune diseases (Jones et al. 2011), and more effective treatments will be developed when the role of MCs in modulating IL-6 function will be completely clear. The important role of the MC in supporting the survival and proliferation of B lymphocytes presents a downside. Indeed, an increasing body of evidence shows how MCs favor neoplastic B cell growth in several B cell malignancies. Preliminary evidence comes from a work published by Molin et al. (2001). The authors first reported that MCs are present in Hodgkin's disease and express CD30L on their surface. Furthermore, they demonstrated that, in a co-culture assay, the human mast cell line HMC-1 stimulated the growth of CD30þ Hodgkin and Reed Sternberg cells in a CD30Ldependent manner, providing evidence of their possible role in the pathogenesis of a B cell neoplasm such as Hodgkin's lymphoma. Another mechanism through which MCs were shown to directly induce malignant B cell growth is the CD40–CD40L axis. In the framework of Waldenström macroglobulinemia, MC-CD40L binds to CD40 expressed by lymphoplasmacytic cells and mediate cell proliferation and tumor colony formation (Tournilhac et al., 2006). In this regard, Santos et al. (2006) demonstrated the expression of CD52 on bone marrow MCs from patients with Waldenstrom and proposed the use of alemtuzumab, a mAb that targets CD52, to eliminate neoplastic MCs in this disease and in other pathologies in which B cells rely on MCs for growth and survival. MCs can sustain the neoplastic B cell growth also through indirect mechanisms, based on the modeling of tumor microenvironment. Since the late 1990s, there has been convincing evidence that in multiple myeloma, MCs are recruited to the tumor site where they favor angiogenesis, and therefore tumor progression, through the release of several factors such as vascular endothelial growth factor, fibroblast growth factor-2, TGF-β, TNF-α, IL-8 and angiopoietin-1 (Ribatti et al., 1999, 2001). Indirect mechanisms also include the ability of MCs to interact with cell types, other than B cells, that populate the tumor milieu. An elegant example comes from a recently published study demonstrating that the proinflammatory condition induced by the interaction between MCs and bone marrow stromal cells can favor mature B cell proliferation in splenic marginal zone lymphoma (SMZL) (Franco et al., 2014). The identification of IL-6 and TNF-α as the main factors that constitute the proinflammatory microenvironment, paves the way for new possible treatments of SMZL. In particular, targeted anti-IL-6 antibodies have been used in clinical trials for the therapy of ovarian and breast cancer, multiple myeloma, and B-lymphoproliferative disorders, with promising results (Guo et al., 2012).

3. Interactions between MCs and regulatory cells 3.1. MCs and Treg cells In a mouse model of oxazolone-induced chronic allergic dermatitis, Treg required the support of activated MCs in order to achieve optimal suppression of inflammation (Hershko et al. 2011). In this model, MCs migrated from the inflamed skin to the spleen, where they secreted IL2, a critical cytokine for Treg proliferation and function. Following this process, disease was more effectively suppressed and the proportion of Tregs in the skin increased. MC accumulation in the spleen was shown to be IgE dependent. Furthermore, inhibition of Treg activity by antiCD25 monoclonal antibodies enhanced IgE production. Elevated IgE levels, in turn, facilitated MC numbers in the spleen that counteracted this blockade by providing excess IL-2. Intriguingly, in mice that had recovered from oxazolone induced dermatitis, subsequent induction of

Please cite this article as: Mekori, Y.A., et al., Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.03.087i

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allergic asthma was actually exacerbated by MCs that had previously been anti-inflammatory (Hershko et al., 2012). This observation underscores the versatility of MC function depending on disease model. However, it remains unclear what causes production of IL-2 which is not a typical product of MCs. It is hypothesized that the microenvironment created by dermatitis provides the triggers required for this effect. Interestingly, enhancement of Treg-suppressive function by MCs was also described in a different setting. Stimulation with the EGF-like growth factor amphiregulin was shown to enhance Treg function both in vitro and in the in vivo (Zaiss et al., 2013). In this context, MCderived amphiregulin fully restored optimal Treg cell function. MCs may promote inflammation through inhibition of Treg activity. It was found that the addition of IFN-α to FcεRI-activated cord blood derived human MCs caused a shift from TNF-α production to an enhanced production of IL-10 and TGF-β along with decreased OX40L expression, thus compromising the ability of these cells to promote CD4þ T cell expansion (Fujita et al., 2006). In another study, Tregs and T effectors were mixed with MCs (Piconese et al., 2009), which counteracted the Treg suppression of effector T cells. Compromised Treg activity was mediated by OX40/OX40L interaction (the latter being expressed on MCs) and T-cell derived IL-6. Disrupted Treg suppression of effector T cells resulted in an increase in IL-17 producing T-cells (Piconese et al., 2009). In vivo investigation disclosed that some MCs could co-localize with Tregs and Th17 cells in EAE. Likewise, these three cell types were identified in the BAL fluid of OTII transgenic mice intranasally challenged with ovalbumin, implying that this tripartite regulatory mechanism might exist in this disease model (Piconese et al., 2009). Defective Treg suppressive activity has also been proposed in a mouse model of hereditary colon cancer (polyposis) (Gounaris et al., 2009), a condition where MCs are pivotal players (Gounaris et al., 2007). Progressive disease involves a shift of expanding Tregs from an IL-10 secreting to an IL-17 secreting phenotype, along with accompanying mastocytosis. These findings indicate that the presence of MCs can promote inflammation via suppression of the IL10 secreting Tregs. Inhibition of Treg suppressive activity has also been suggested by the binding of histamine to H1 receptors on Tregs (Forward et al., 2009). Exposure of Tregs to histamine, a typical MC product, caused decreased CD25 and Foxp3 expression, and this effect was counteracted by addition of the H1 antagonist loratadine. Histamine has also been suggested to act on T cells through its binding to H2 receptors. In an in vivo mouse model, cimetidine, an H2 blocker, increased the immune response to melanoma and inhibited its growth (Nordlund and Askenase, 1983), as well as reversing nonspecific suppression of contact sensitivity (Mekori et al., 1985). Histamine was also found to inhibit

T cell adhesion to extracellular matrix glycoproteins, an effect that could be reversed by pre-treatment with H2 blockers (Hershkoviz et al., 1994). In a model of hepatitis B virus vaccination, cimetidine boosted the immune response by increasing the numbers of IL-4 and IFN-γ producing CD4þ T effectors and by inhibiting IL-10 and TGF-β secretion (Wang et al., 2008), leading to reduced Treg activity. On the other hand, OX40-dependent direct interactions (physical contact) between Tregs and MCs in both murine and human cell co-cultures, resulted in inhibition of MC degranulation (Frossi et al., 2011). Taken together, these reports underscore the bidirectional interaction and the capacity of MC to modulate both Treg and Teff activity (Fig. 1). 3.2. MCs and regulatory B cells It is a relatively recent discovery that B cells, like T cells, can negatively regulate the immune response and thus exert a regulatory suppressive function in addition to their classical effector roles. Indeed, several studies have described a correlation between the absence or dysfunction of B cell populations able to produce IL-10 and exacerbated symptoms in diverse autoimmune and inflammatory disorders (Bouaziz et al., 2008). B cells that are competent to produce IL-10 are found at different anatomical sites where they produce IL-10 and exert suppressive functions after encountering an appropriate and contextspecific signal (Mion et al., 2014b; Yanaba et al., 2009). These IL-10producing B cells constitute the most widely studied functional subset of regulatory B cells and a growing body of evidence underlines how both the induction and expansion of this population is strictly related to TLRs and CD40 signaling (Mauri and Bosma, 2012). While the bidirectional cross-talk between MCs and Tregs has been deeply investigated, the study of the interplay between MCs and regulatory B cells is still in its infancy. Presently, there is no data regarding the possible effect that regulatory B cells could have on MC activation and on the consequent release of preformed or de novo-synthesized allergic mediators. Conversely, it has been recently demonstrated that MCs can affect the regulatory pool of B cells. Although not able to induce IL-10 expression and production in B lymphocytes, MCs were shown to play an important role in the expansion of the IL-10competent B cell population (Mion et al., 2014a). This fine regulation of IL-10-competent B cell expansion was proved to be particularly relevant in the context of gut microenvironment. Indeed, in the recovery phase of dextran sodium sulfate-induced intestinal inflammation, a significant up-regulation of CD19þ IL-10þ cells was observed in wild-type but not in MC-deficient mice. Both in vitro and in vivo, a relevant role was shown to be played by the CD40–

Fig. 1. Molecules involved in the interaction between Teff, Treg and B with MCs and induced effects.

Please cite this article as: Mekori, Y.A., et al., Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.03.087i

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CD40L axis since the MC-induced IL-10-competent B cell expansion was impaired in the presence of an anti-CD40L blocking Ab or of Cd40l  / MCs (Mion et al., 2014a). This last point must be kept in mind when CD40L-specific blocking mAbs (i.e., aglycosyl ruplizumab) or peptides are used to revert the adverse effects of CD40 signaling in the context of autoimmune diseases. As elegantly reviewed by Peters et al. (2009), signaling through CD40, which is fundamental for normal adaptive immunity, can contribute to the pathogenesis of autoimmunity and therefore several strategies blocking the damaging effects of CD40 are under investigation. However, these drugs could negatively affect the expansion of regulatory B cells induced by CD40Lþ MCs and, presumably, by other CD40L-expressing cells, further exacerbating the autoimmune and inflammatory condition. Notably, it has been shown that MCs provide important signals for IL-10-competent B cell expansion also through the release of exosomes (Mion et al., 2014a), small membrane vesicles of 30–100 nm in diameter, that are gaining increasing relevancy in the context of intercellular communication (Gyorgy et al., 2011). MC-exosomes were already known to support B cell proliferation and activation (Skokos et al., 2001a, 2001b; Tkaczyk et al., 1996) but the finding that they also affect the regulatory B cell population may acquire great relevance in terms of new perspectives in translational medicine. Similarly to dendritic cell-derived exosomes, that are currently tested for their therapeutic potential in cancer (Pitt et al., 2014), MC-exosomes could open a new frontier in the resolution of smoldering inflammation through the induction of IL-10-competent B cells.

4. Concluding remarks Research on MCs has changed dramatically our perception of the functions and roles that MCs exert in the regulation of immune responses. This function is mainly dependent on the physical interaction and the continuous cross-talk that the MCs have with almost all the immune cells. Depending on the context, the cell involved, the soluble and membrane bound molecules and the composition of the microenvironment, MCs can suppress, amplify or modulate the immune response and contribute to the development or suppression of inflammatory as well as autoimmune reactions. In this review, we have depicted MCs as complex and dynamic immune players, claiming their own position in the pantheon of regulatory cells, by virtue of the varied biological effects they have on the immune response.

Acknowledgments This study was supported by the COST Action BM1007 “Mast cells and Basophils: targets for innovative therapies.”, Italian Ministry of Health, the (no. 15561 and 11843), Ministero dell'Istruzione, Università e Ricerca (PRIN 2009), and the ASIMAS (ASsociazione Italiana MAStocitosi).YAM is the incumbent of the Argentina Chair of Allergic Diseases, Tel Aviv University. This work was also supported in part by a Grant from the Tel Aviv University to YAM and AYH, from Allergists for Israel to AYH and from the Israel Science Foundation to YAM (no. 1061/09). References Al-Nedawwi, K., Meehan, B., Rak, J., 2009. Microvesicles. Cell Cycle 8, 2014–2018. Bachelet, I., Levi-Schaffer, F., Mekori, Y.A., 2006. Mast cells, not only in allergy. Immunol. Allergy Clin. N. Am. 26, 407–426. Baram, D., Vaday, G.G., Salamon, P., Drucker, I., Hershkovis, R., Mekori, Y.A., 2001. Human mast cells release metalloproteinase-9 on contact with activated T cells: Juxtacrine regulation by TNF-α. J. Immunol. 167, 4008–4016. Bhattacharyya, S.P., Drucker, I., Reshef, T., Kirshenbaum, A.S., Metcalfe, D.D., Mekori, Y. A., 1998. Activated lymphocytes induce degranulation and cytokine production by human mast cells following cell to cell contact. J. Leukoc. Biol. 63, 337–341.

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Biedermann, T., Kneilling, M., Mailhammer, R., Maier, K., Sander, C.A., Kollias, G., Kunkel, S.L., Hultner, L., Rocken, M., 2000. Mast cells control neutrophil recruitment during T cell mediated delayed-type hypersensitivity. J. Exp. Med. 192, 1441–1452. Bouaziz, J.D., Yanaba, K., Tedder, T.F., 2008. Regulatory B cells as inhibitors of immune responses and inflammation. Immunol. Rev. 224, 201–214. Brill, A., Baram, D., Sela, U., Salamon, P., Mekori, Y.A., Hershkoviz, R., 2004. Induction of mast cell interactions with blood vessel wall components by direct contact with intact T cells or T cell membranes in vitro. Clin. Exp. Allergy 34, 1725–1731. Dudeck, A., Dudeck, J., Scholten, J., Petzold, A., Surianarayanan, S., Kohler, A., Peshcke, K., Vohringer, D., Wascow, C., Krieg, T., Muller, W., Waismann, A., Hartmann, K., Gunzer, M., Roers, A., 2011. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 34, 973–984. Forward, N.A., Furlong, S.J., Yang, Y., Lin, T.J., Hoskin, D.W., 2009. Mast cells downregulate CD4 þ CD25þ T regulatory cell suppressor function via histamine H1 receptor interaction. J. Immunol. 183, 3014–3022. Franco, G., Guarnotta, C., Frossi, B., Piccaluga, P.P., Boveri, E., Gulino, A., Fuligni, F., Rigoni, A., Porcasi, R., Buffa, S., Betto, E., Florena, A.M., Franco, V., Iannitto, E., Arcaini, L., Pileri, S.A., Pucillo, C., Colombo, M.P., Sangaletti, S., Tripodo, C., 2014. Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma. Blood 123, 1836–1849. Frandji, P., Tkaczyk, C., Oskeritzian, C., David, B., Desaymard, C., Mecheri, S., 1996. Exogenous and endogenous antigens are differentially presented by mast cells to CD4 þ T lymphocytes. Eur. J. Immunol. 26, 2517–2528. Frossi, B., D’Inca, F., Crivellato, E., Sibilano, R., Gri, G., Mongillo, M., Danelli, L., Maggi, L., Pucillo, C.E., 2011. Single cell dynamics of mast cell – CD4þ CD25þ regulatory T cell interaction. Eur. J. Immunol. 41, 1872–1882. Fujita, T., Kambe, N., Uchiyama, T., Hori, T., 2006. Type I interferons attenuate T cell activating functions of human mast cells by decreasing TNF-α production and OX40 ligand expression while increasing IL-10 production. J. Clin. Immunol. 26, 512–518. Galli, S.J., Borregaard, N., Wynn, T.A., 2011. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat. Immunol. 12, 1035–1044. Galli, S.J., Grimbaldeston, M., Tsai, M., 2008. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat. Rev. Immunol. 8, 478–486. Gauchat, J.F., Henchoz, S., Mazzei, G., Aubry, J.P., Brunner, T., Blasey, H., Life, P., Talabot, D., Flores-Romo, L., Thompson, J., et al., 1993. Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 365, 340–343. Gaudenzio, N., Espagnole, N., Mars, L.T., Liblau, R., Valitutti, S., Espinosa, E., 2009. Cell–cell cooperation at the T helper cell/mast cell immunological synapse. Blood 114, 4979–4988. Gounaris, E., Blatner, N.R., Dennis, K., Magnusson, F., Gurish, M.F., Strom, T.B., Beckhove, P., Gounari, F., Khazaie, K., 2009. T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting pro-inflammatory phenotype in polyposis. Cancer Res. 69, 5490–5497. Gounaris, E., Erdman, S.E., Restaino, C., Gurish, M.F., Friend, D.S., Gounari, F., Lee, D.M., Zhang, G., Glickman, J.N., Shin, K., Rao, V.P., Poutahidis, T., Weissleder, R., McNagny, K.M., Khazaie, K., 2007. Mast cells are an essential hematopoietic component for polyp development. Proc. Natl. Acad. Sci. USA 104, 19977–19982. Gregory, G.D., Robbie-Ryan, M., Secor, V.H., Sabatino Jr., J.J., Brown, M.A., 2005. Mast cells are required for optimal autoreactive T cell responses in a murine model of multiple sclerosis. Eur. J. Immunol. 35, 3478–3486. Guo, Y., Xu, F., Lu, T., Duan, Z., Zhang, Z., 2012. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat. Rev. 38, 904–910. Gri, G., Frossi, B., D’Inca, F., Danielli, L., Betto, B., Mion, F., Sibilano, R., Pucillo, C., 2012. Mast cells: an emerging partner in immune interaction. Front. Immunol. 3, 120. Gyorgy, B., Szabo, T.G., Pasztoi, M., Pal, Z., Misjak, P., Aradi, B., Laszlo, V., Pallinger, E., Pap, E., Kittel, A., Nagy, G., Falus, A., Buzas, E.I., 2011. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell. Mol. Life Sci. 68, 2667–2688. Hershko, A.Y., Rivera, J., 2010. Mast cell and T cell communication; amplification and control of adaptive immunity. Immunol. Lett. 128, 98–104. Hershko, A.Y., Suzuki, R., Charles, N., Alvarez-Errico, D., Sargent, J., Laurence, A., Rivera, J., 2011. Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis. Immunity 35, 562–571. Hershko, A.Y., Charles, N., Olivera, A., Alvarez-Errico, D., Rivera, J., 2012. Cutting edge: persistence of increased mast cell numbers in tissues links dermatitis to enhanced airway disease in a mouse model of atopy. J. Immunol. 188, 531–535. Hershkoviz, R., Lider, O., Baram, D., Reshef, T., Miron, S., Mekori, Y.A., 1994. Inhibition of T cell adhesion to extracellular matrix glycoproteins by histamine: a role for mast cell degranulation products. J. Leukoc. Biol. 56, 495–501. Huang, B., Lei, Z., Zhang, G.M., Li, D., Song, C., Li, B., Liu, Y., Yuan, Y., Unkeless, J., Xiong, H., Feng, Z.H., 2008. SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood 112, 1269–1279. Inamura, N., Mekori, Y.A., Bhattacaryya, S.P., Bianchine, P.J., Metcalfe, D.D., 1998. Induction and enhancement of FC(epsilon)RI-dependent mast cell degranulation following coculture with activated T cells: dependency on ICAM-1 and leukocyte function-associated antigen (LFA)-1-mediated heterotypic aggregation. J. Immunol. 160, 4026–4033.

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Jones, S.A., Scheller, J., Rose-John, S., 2011. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Investig. 121, 3375–3383. Kalesnikoff, J., Galli, S.J., 2008. New developments in mast cell biology. Nat. Immunol. 9, 1215–1223. Kambayashi, T., Allenspach, E.J., Chang, J.T., Zou, T., Shoag, J.E., Reiner, S.L., Caton, A.J., Koretzky, G.A., 2009. Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation. J. Immunol. 182, 4686–4695. Khan, M.M., Strober, S., Melmon, K.L., 1986. Regulatory effects of mast cells on lymphoid cells: the role of histamine type 1 receptors in the interaction between mast cells, helper T cells and natural suppressor cells. Cell. Immunol. 103, 41–53. Mauri, C., Bosma, A., 2012. Immune regulatory function of B cells. Annu. Rev. Immunol. 30, 221–241. Mekori, Y.A., Bender, E.M., Zapata, R., Hansbrough, J.F., Claman, H.N., 1985. The effect of histamine receptor antagonists on specific and nonspecific suppression of experimental contact sensitivity. J. Allergy Clin. Immunol. 76, 90–96. Mekori, Y.A., 2004. The mastocyte: the “other” inflammatory cell in immunopathogenesis. J. Allergy Clin. Immunol. 114, 52–57. Mekori, Y.A., Hershko, A.Y., 2012. T cell modulation of mast cell function. Heterotypic adhesion-induced stimulatory or inhibitory effects. Front. Immunol. 3, 6–10. Merluzzi, S., Betto, E., Ceccaroni, A.A., Magris, R., Giunta, M., Mion, F., 2014. Mast cells, basophils and B cell connection network. Mol. Immunol. 63, 94–103. Merluzzi, S., Frossi, B., Gri, G., Parusso, S., Tripodo, C., Pucillo, C., 2010. Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells. Blood 115, 2810–2817. Migalovich-Sheikhet, H., Friedman, S., Mankuta, D., Levi-Schaffer, F., 2012. Novel identified receptors on mast cells. Front. Immunol. 3, 238. Mion, F., D’Inca, F., Danelli, L., Toffoletto, B., Guarnotta, C., Frossi, B., Burocchi, A., Rigoni, A., Gerdes, N., Lutgens, E., Tripodo, C., Colombo, M.P., Rivera, J., Vitale, G., Pucillo, C.E., 2014a. Mast cells control the expansion and differentiation of IL10-competent B cells. J. Immunol. 193, 4568–4579. Mion, F., Tonon, S., Toffoletto, B., Cesselli, D., Pucillo, C.E., Vitale, G., 2014b. IL-10 production by B cells is differentially regulated by immune-mediated and infectious stimuli and requires p38 activation. Mol. Immunol. 62, 266–276. Molin, D., Fischer, M., Xiang, Z., Larsson, U., Harvima, I., Venge, P., Nilsson, K., Sundstrom, C., Enblad, G., Nilsson, G., 2001. Mast cells express functional CD30 ligand and are the predominant CD30L-positive cells in Hodgkin's disease. Br. J. Haematol. 114, 616–623. Nakae, S., Suto, H., Kakurai, M., Sedgwick, J.D., Tsai, M., Galli, S.J., 2005. Mast cells enhance T cell activation: importance of mast cell-derived TNF. Proc. Natl. Acad. Sci. USA 102, 6467–6472. Nakano, N., Nishiyama, C., Yagita, H., Koyanagi, A., Akiba, H., Chiba, S., Ogawa, H., Okumura, K., 2009. Notch signaling confers antigen-presenting cell functions on mast cells. J. Allergy Clin. Immunol. 123, 74–81. Nordlund, J.J., Askenase, P.W., 1983. The effect of histamine, antihistamines, and a mast cell stabilizer on the growth of cloudman melanoma cells in DBA/2 mice. J. Investig. Dermatol. 81, 28–31. Nowak, E.C., de Vries, V.C., Wasiuk, A., Ahonen, C., Bennett, K.A., Le Mercier, I., Ha, D. G., Noelle, R.J., 2012. Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J. Exp. Med. 209, 2127–2135. Orr, E.L., 1988. Presence and distribution of nervous system-associated mast cells that may modulate experimental autoimmune encephalomyelitis. Ann. N. Y. Acad. Sci. 540, 723–726. Pawankar, R., Okuda, M., Yssel, H., Okumura, K., Ra, C., 1997. Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the Fc epsilonRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J. Clin. Investig. 99, 1492–1499. Peters, A.L., Stunz, L.L., Bishop, G.A., 2009. CD40 and autoimmunity: the dark side of a great activator. Semin. Immunol. 21, 293–300. Piconese, S., Gri, G., Tripodo, C., Musio, S., Gorzanelli, A., Frossi, B., Pedotti, R., Pucillo, C.E., Colombo, M.P., 2009. Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood 114, 2639–2648. Pitt, J.M., Charrier, M., Viaud, S., Andre, F., Besse, B., Chaput, N., Zitvogel, L., 2014. Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J. Immunol. 193, 1006–1011. Rabenhorst, A., Schlaak, M., Heukamp, L.C., Förster, A., Theurich, S., von BergweltBaildon, M., Butner, R., Kurschat, P., Mauch, C., Roers, A., Hartmann, K., 2012. Mast cells play a protumorigenic role in cutaneous lymphoma. Blood 120, 2042–2054. Ribatti, D., Vacca, A., Nico, B., Quondamatteo, F., Ria, R., Minischetti, M., Marzullo, A., Herken, R., Roncali, L., Dammacco, F., 1999. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br. J. Cancer 79, 451–455.

Ribatti, D., Vacca, A., Nico, B., Crivellato, E., Roncali, L., Dammacco, F., 2001. The role of mast cells in tumour angiogenesis. Br. J. Haematol. 115, 514–521. Ryzhov, S., Goldstein, A.E., Matafonov, A., Zeng, D., Biaggioni, I., Feoktistov, I., 2004. Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2Bmediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma. J. Immunol. 172, 7726–7733. Salamon, P., Shoham, N.G., Gavrieli, R., Wolach, B., Mekori, Y.A., 2005. Human mast cells release Interleukin-8 and induce neutrophil chemotaxis on contact with activated T cells. Allergy 60, 1316–1319. Salamon, P., Shoham, N.G., Puxeddu, I., Paitan, Y., Levi-schaffer, F., Mekori, Y.A., 2008. Human mast cells release oncostatin M on contact with activated T cells: possible biologic relevance. J. Allergy Clin. Immunol. 121, 448–455. Santos, D.D., Hatjiharissi, E., Tournilhac, O., Chemaly, M.Z., Leleu, X., Xu, L., Patterson, C., Branagan, A.R., Manning, R.J., Ho, A.W., Hunter, Z.R., Dimmock, E.A., Kutok, J.L., Churchill, W.H., Castells, M.C., Tai, Y.T., Anderson, K.C., Treon, S.P., 2006. CD52 is expressed on human mast cells and is a potential therapeutic target in Waldenstrom's macroglobulinemia and mast cell disorders. Clin. Lymphoma Myeloma 6, 478–483. Secor, V.H., Secor, W.E., Gutekunst, C.A., Brown, M.A., 2000. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191, 813–822. Shefler, I., Mekori, Y.A., Mor, A., 2008. Stimulation of human mast cells by activated T cells leads to N-Ras activation through Ras guanine nucleotide releasing protein 1. J. Allergy Clin. Immunol. 122, 1222–1225. Shefler, I., Salamon, P., Mor, A., Mekori, Y.A., 2010. T cell induced mast cell activation: a role for microparticles released from activated T cells. J. Immunol. 185, 4206–4212. Shefler, I., Salamon, P., Hershko, A., Mekori, Y.A., 2011. Mast cells as sources and targets of membrane microvesicles. Curr. Pharm. Des. 17, 3797–3804. Shefler, I., Pasmanik, M., Kidron, D., Mekori, Y.A., Hershko, A.Y., 2014. T cell-derived microvesicles induce mast cell production of IL-24: relevance to inflammatory skin diseases. J. Allergy Clin. Immunol. 133, 217–224. Sibilano, R., Frossi, B., Calvaruso, M., Danelli, L., Betto, E., Dall’Agnese, A., et al., 2012. The aryl hydrocarbon receptor modulates acute and late mast cell responses. J. Immunol. 189, 120–127. Skokos, D., Le Panse, S., Villa, I., Rousselle, J.C., Peronet, R., David, B., Namane, A., Mecheri, S., 2001a. Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes. J. Immunol. 166, 868–876. Skokos, D., Le Panse, S., Villa, I., Rousselle, J.C., Peronet, R., Namane, A., David, B., Mecheri, S., 2001b. Nonspecific B and T cell-stimulatory activity mediated by mast cells is associated with exosomes. Int. Arch. Allergy Immunol. 124, 133–136. Stelekati, E., Bahri, R., D’Orlando, O., Orinska, Z., Mittrucker, H.W., Langenhaun, R., Glatzel, M., Bollinger, A., Paus, R., Bulfone-Paus, S., 2009. Mast cell mediated antigen presentation regulates CD8 þ T cell effector functions. Immunity 31, 665–676. Stopfer, P., Mannel, D.N., Hehlgans, T., 2004. Lymphotoxin-beta receptor activation by T cells induces cytokine release from mouse bone marrow-derived mast cells. J. Immunol. 172, 7459–7465. Thery, C., Ostrowski, M., Segura, E., 2009. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9, 581–593. Tkaczyk, C., Frandji, P., Botros, H.G., Poncet, P., Lapeyre, J., Peronet, R., David, B., Mecheri, S., 1996. Mouse bone marrow-derived mast cells and mast cell lines constitutively produce B cell growth and differentiation activities. J. Immunol. 157, 1720–1728. Tournilhac, O., Santos, D.D., Xu, L., Kutok, J., Tai, Y.T., Le Gouill, S., Catley, L., Hunter, Z., Branagan, A.R., Boyce, J.A., Munshi, N., Anderson, K.C., Treon, S.P., 2006. Mast cells in Waldenstrom's macroglobulinemia support lymphoplasmacytic cell growth through CD154/CD40 signaling. Ann. Oncol. 17, 1275–1282. Tsai, M., Grimbaldeston, M., Galli, S.J., 2011. Mast cells and immunoregulation/ immunomodulation. Adv. Exp. Med. Biol. 716, 186–211. Yanaba, K., Bouaziz, J.D., Matsushita, T., Tsubata, T., Tedder, T.F., 2009. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J. Immunol. 182, 7459–7472. Yao, X., Huang, J., Zhong, H., Shen, N., Faggioni, R., Fung, M., Yao, Y., 2014. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol. Ther. 141, 125–139. Wang, J., Su, B., Ding, Z., Du, X., Wang, B., 2008. Cimetidine enhances immune response of HBV DNA vaccination via impairment of the regulatory function of regulatory T cells. Biochem. Biophys. Res. Commun. 372, 491–496. Zaiss, D.M.W., van Loosdregt, J., Gorlani, A., Bekker, C.P.J., Grone, A., Sibilia, A., van Bergen en Heneqouwen, P.M.P., Roovers, R.C., Coffer, P.J., Sijts, A.J.A.M., 2013. Amphiregulin enhances regulatory T cell suppressive function via the epidermal growth factor receptor. Immunity 38, 275–284.

Please cite this article as: Mekori, Y.A., et al., Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.03.087i