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Exploring a regulatory role for mastcells: ‘MCregs’?Barbara Frossi1*, Giorgia Gri1*, Claudio Tripodo2 and Carlo Pucillo1

1 Department of Biomedical Science and Technology, University of Udine, P. le M. Kolbe 4, 33100 Udine, Italy2 Department of Human Pathology, University of Palermo, Via del Vespro 129, 90127, Palermo, Italy

Opinion

Regulatory cells can mould the fate of the immuneresponse by direct suppression of specific subsets ofeffector cells, or by redirecting effectors against invadingpathogens and infected or neoplastic cells. These func-tions have been classically, although not exclusively,ascribed to different subsets of T cells. Recently, mastcells have been shown to regulate physiological andpathological immune responses, and thus to act at theinterface between innate and adaptive immunity assum-ing different functions and behaviors at discrete stagesof the immune response. Here, we focus on these poorlydefined, and sometimes apparently conflicting, func-tions of mast cells.

The mast complex cellThe paradigm of regulatory cells as inhibitors of immuneresponses has been reshaped by the concept of functionalplasticity, to which even the prototypic immune regulators,the regulatory T (Treg) cells, respond. In this light, a regu-latory role for mast cells (MCs) could stem from the variedbiological effects thatMCs produce in the immune response,as well as from the diverse interactions they display withother immune system effectors and regulators. Neverthe-less, under specific conditions, MCs can emerge as regulat-ory cells in the ‘classical’ meaning, i.e. as cells with anti-inflammatory properties. Under these carefully definedcriteria, we will refer to such MCs as ‘MCregs’.

MCs are widely distributed throughout the vascularizedtissues or serosal cavities, where microenvironmentalstimuli control their phenotypic profile leading to subtypedifferences in a common lineage.MCs are well-positioned tobe one of the first cell types of the immune system to interactwith environmental antigens and allergens [1]. However,their role is not limited to effector functions in infectiousdiseases and allergy, because they also have a role in localtolerance to self-antigens [2]. Indeed their functions extendto all the stages of the immune response, regulating andsupporting Treg cells in the maintenance of tolerance andshapingtheresponseagainstpathogens.MCsaccumulateattumor sites, suggesting their involvement in the regulationof tumor-associated inflammation [3]. Moreover, changes inthenumberandcytokineprofileofMCsatdifferentphasesofautoimmune diseases suggest a dual role in the inductionand regulation of autoimmune responses [2].

MCs express a broad array of molecules involved in cell–cell and cell–extracellular-matrix adhesion that mediate

Corresponding author: Pucillo, C. (carlo.pucillo@uniud.it)* B.F. and G.G. contributed equally to this study..

1471-4906/$ – see front matter � 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2009.12

the delivery of co-stimulatory signals that empower thesecells with the ability to react to multiple stimuli [4]. Thisversatility is reflected in the numerous IgE-dependent and-independent activation pathways (IgG, microbial anti-gens, complement, hormones, peptides, cytokines and che-mokines) that modulate the quality and magnitude of MCresponses and cytokine release [5]. Depending on the type,property, strength and combination of the stimuli theyreceive, MCs secrete a diverse and wide range of biologi-cally active products that can trigger, direct or suppressthe immune response [4] (Figure 1a). Thus, lymphokines,such as CCL2 (also known asMCP-1), that promote allergicinflammation are potently induced by weak stimulationfrom low antigen concentrations or low Fce receptor I(FceRI) occupancy by IgE. By contrast, mediators thatdownregulate inflammation, such as IL-10, require strongand sustained signaling through FceRI [6]. The culturemedia from weakly stimulated MCs elicit a monocyte–

macrophage chemotactic response [7]. Similarly, MC-derived exosomes induce maturation of dendritic cells(DCs) [8]. MC surface molecules and secreted productscan influence various aspects of the biology of T cells, forexample, by polarizing T-cell responses towards the Thelper 1 (Th1) or Th2 pathway, as well as of B lymphocytesby supporting their survival, proliferation, and IgA pro-duction [1,5,9].

During microbial infections, MCs help to fight patho-gens through different effector pathways: (i) by releasingpro-inflammatory cytokines, chemokines and biologicalproducts that are toxic to the pathogens; (ii) by acquiringa phagocytic function and directly eliminating pathogens;(iii) by promoting inflammation directing other immunecells such as DCs and effector T cells. MCs also supportimmunomodulatory functions that significantly reduce themagnitude and duration of the immune response throughIL-10 secretion. MC-derived IL-10 markedly limited theextent, and promoted the resolution, of innate responses tochronic low-dose UVB irradiation, and of contact hyper-sensitivity reactions induced by the hapten 2,4-dinitro-1-fluorobenzene (DNFB) [10]. IL-10 produced by MCs hasbeen shown to limit many aspects of such responses,including the number of granulocytes, macrophages, andT cells at sites of inflammation, as well as the extent of localtissue edema, epidermal hyperplasia and epidermal necro-sis and ulceration [10]. However, the precise mechanismsby which MC-derived IL-10 plays its regulatory functionsin these pathological settings are still unclear. In this light,it would be crucial to assess whether MCs and MC-derived

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Figure 1. Model of mast-cell–regulatory-T-cell or mast-cell–effector-T-cell interaction. (a) The triggering of FceRI by specific antigen on the mast cell surface results in the

influx of extracellular calcium, degranulation, and cytokine secretion. (b) When regulatory T (Treg) cells interact with mast cells (MC) through the OX40–OX40L axis, they

induce cAMP accumulation in the MC that inhibits Ca2+ influx and blocks histamine degranulation, but not cytokine secretion. (c) Primarily MC-derived IL-6, together with

OX40 engagement, switch off Treg-cell inhibition of activated T-effector (Teff)-cell proliferation and promote Teff and Treg cell expansion. (d) The cytokine milieu in the MC–

Treg–Teff system drives both Teff and Treg cells to become IL-17 producing cells.

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IL-10 could affect the number, phenotype or function ofTreg cells in the disease models in which Treg cells arethought to play important roles [11].

Interaction between MCs and Treg cellsThe wide array and fine modulation by microenvironmen-tal stimuli of cell surface receptors and the ligands MCsexpress is crucial for their interaction with differentimmune and non-immune cells. Such interactions leadto different consequences, and often to bidirectional effectson the cellular players. It has been shown that directcontact between MCs and T cells produce an increase ofMC degranulation following FceRI triggering [12], and aboost to T cell proliferation [13]. More recently, a bidirec-tional cross-talk between MCs and Treg cells has also beendescribed [14,15].

Treg cells have a crucial role in the maintenance of self-tolerance and prevention of autoimmune diseases by con-tact-dependent and cytokine-dependent mechanisms invivo [16]. They might also play a detrimental role byimpairing antitumor immune responses that are knownto be directed against autoantigens expressed on tumor

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cells [17]. Interaction between Treg cells and MCs isessential for Treg cell-dependent peripheral tolerance inskin allografting. A subset of Treg cells expressing theforkhead/winged helix transcription factor (FoxP3) andthe CD4+ and CD25+ markers, favors MC recruitmentand activation by secreting IL-9, which is a chemokineand growth factor for MCs. Indeed, neutralization of IL-9accelerates allograft rejection in tolerant mice [18]. MC-secreted IL-10, TGF-b or both cytokines are possible can-didates for mediating the suppressive effects of MCs [19].However, whether MC degranulation of proinflammatorymediators is decreased when these cells act as effectors inTreg-cell-mediated tolerance remains to be determined.

The evidence of possible interactions between MCs andTreg cells also comes from other settings [20,21]. Werecently showed that Treg cells and MCs display closespatial interactions in vivo, and investigated the con-sequences of their crosstalk on MC effector functions.The finding that the interaction of OX40-expressing Tregcells with OX40L-expressing MCs inhibited the extent ofMC degranulation in vitro and of the immediate hyper-sensitivity response in vivo [14], paved the way for the

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understanding of the reciprocal influence of MCs and Tregcells. When activated in the presence of Treg cells, MCsshowed increased cyclic adenosinemonophosphate (cAMP)concentration and reduced Ca2+ influx, independently ofphospholipase Cg (PLCg) or Ca2+ release from intracellu-lar stores (Figure 1b). Antagonism of cAMP in MCsreversed the inhibitory effects of Treg cells, thereby restor-ing normal Ca2+ release and degranulation. Direct anti-body triggering of OX40L on MCs was not possible in thisstudy because of cross-reactivity of anti-OX40L antibodieswith the Fcg receptor; therefore, the signaling and functionof OX40L on MCs remains to be elucidated.

MCs: tuning of inflammatory responses and inductionof autoimmunityThe interplay between MCs and T cells is particularlyrelevant in several T cell-mediated pathological conditions,such as neutrophilic airway inflammation and auto-immune disease of the central nervous system (CNS), inwhich MCs might influence directly the arousal of patho-genic T cell subsets. The availability of MC-deficientmousemodels has allowed a positive role to be ascribed to MCs inthe development of both allergic and neutrophilic models ofairway hyperreactivity (AHR) [22]. MC-derived TNF-a isrequired for IL-17-secreting Th17-cell development inthe lung upon ovalbumin (OVA) challenge of OTII trans-genic mice [23], an experimental system that is strictlydependent on IL-17. Indeed, Th17 cells differentiate fromuncommitted precursors after antigenic activation, co-stimulation and the concurrent delivery of suppressivesignals from TGF-b, and inflammatory stimuli from IL-6, IL-21, or both. The pathogenicity of Th17 cells is posi-tively regulated by IL-23 and negatively modulated by IL-27, which respectively hinder and promote IL-10 pro-duction by T cells [24]. Once primed in lymph nodes,pathogenic Th17 cells reach the inflamed tissue wherethey recruit granulocytes and intensify inflammation [25].

Several findings support the hypothesis that MCs arefundamentally involved in the pathogenesis of auto-immune diseases of the CNS [26]. MCs co-localize withdemyelinating plaques in the inflamed brains of humansand mice with multiple sclerosis (MS), and MC-associatedmarkers have been detected in the affected tissue [26,27].MCs could be activated directly during experimental auto-immune encephalomyelitis (EAE, the rodent model of MS)by the specific myelin peptides [28], or by locally releasedagonists, including complement, cytokines and neuropep-tides [29], or they could be stimulated indirectly via FceRIby specific IgE elicited upon Th2-cell activation [30].Through the local release of inflammatory cytokines, pro-teases, oxygen radicals and chemokines in the CNS, MCscontribute directly to myelin degradation, disruption of theblood–brain barrier, recruitment and activation of otherimmune effectors, such as T lymphocytes and granulo-cytes, in the brain parenchyma, thus exacerbating theautoimmune process. MCs may also be involved in theinitiation of autoimmunity in EAE, because they can affectDC and T-cell functions in secondary lymphoid organs [31].These findings suggest that MCs could play different rolesin the initiation, establishment and progression of auto-immune diseases. This contention is also suggested by the

puzzling notion of an increased incidence and severity ofEAE in MC-deficient KitW/W-v mice [27].

Treg cells, one of the sources of TGF-b in vitro and invivo, are endowed with immune-suppressive properties,and thus occupy a pivotal role in establishing and main-taining self-tolerance [18]. Recent findings support thenotion of Treg cell plasticity in vivo, because inflammatorystimuli can promote Treg-cell contrasuppression [32] andeven their differentiation into pathogenic Th17 cells[33,34]. MCs might directly or indirectly sustain the avail-ability of inflammatory signals that locally ‘de-program’Treg-cell suppression. The cytokine IL-6, released byinnate and adaptive cells upon activation, is known tobreak Treg-cell anergy and suppression [35], and to driveTreg cells into Th17 cell differention [36]. MCs mightprovide T cells with IL-23 or IL-27, thus tipping thebalance between pathogenicity and regulation. AmongMC-associated membrane molecules, the co-stimulatoryreceptor OX40L is known to prevent de novo differentiationof Treg cells and to switch off Treg-cell inhibition [36,37].We have demonstrated recently that, both in vivo and invitro, MCs can break Treg anergy and suppression(Figure 1c), and promote Th17 differentiation throughmechanisms that require IL-6 supply and OX40 engage-ment [15] (Figure 1d).

By these mechanisms, MCs could play a key role in thedevelopment of abnormal adaptive responses in immuno-pathologic conditions, at least in those mediated by Th17cells. Inflammatory bowel disease (IBD) is a prototypicmodel of Th17-mediated autoimmunity, in which the directpathogenic role of Th-17-associated cytokines (particularlyIL-23) has been demonstrated [38]. Under physiologicalconditions, a few scattered MCs populate the lamina pro-pria of the colonic mucosa. These MCs are round medium-sized cells, with a morphology similar to that of monocytesand suggestive of a resting state (Figure 2a,d). In IBDsamples during the florid phase of the inflammatory pro-cess, MCs increase in number and, most interestingly,display a clear shift in morphology from small roundcells to large round, stellate, or spindle-shaped cells(Figure 2b,e). Such a morphology, characteristic of anactivated state, underlines the ability of MCs to interactwith neighboring cells through cytoplasmic processes andthe release of synthesis products. In the inflammatorymilieu of IBD, activated MCs are not only mere effectors,because a significant fraction of them (which we refer to as‘MCregs’) emerge as a source of IL-10 (Figure 2g–i). Upondisease remission (or in spent phases), the number of MCsdecrease and the morphology of residual MCs switchesback to that of small round cells (Figure 2c,f). Together,these observations further support the MC functionalplasticity, which seems to be tightly dependent on theinflammatory environment, and suggest the existence ofa subpopulation of ‘MCregs’, which, under inflammatorystimuli, switches to an anti-inflammatory, regulatorystate.

MCs and tumors: one thousand functions, one cellChronic inflammation produced by immune cells is con-sidered to promote initiation and progression of tumori-genesis [39], but themechanisms of crosstalk between cells

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Figure 2. Mast cell (MC) changes in inflammatory bowel disease. (a) MCs (brown) are present in the lamina propria of the colonic mucosa under physiological conditions.

(b) The number of MCs increases significantly in the active phases of inflammatory bowel disease (IBD), and (c) decreases upon disease remission. (d) The modifications in

the number of MCs observed in IBD are paralleled by changes in MC morphology: in the active phases of IBD MCs switch from small round cells (e) to large stellate, round,

or spindle-shaped cells, suggestive of an active state, (f) whereas a ‘resting’ morphology is observed upon remission. (g) Double immunofluorescence analysis highlights

scattered IL-10-producing ‘MCregs’ (IL-10, green signal; tryptase, purple signal) in the lamina propria of the colonic mucosa under physiological conditions. (h, i) IL-10-

producing ‘MCregs’ can still be found in IBD samples, although they are outnumbered by IL-10-negative MCs, which probably act as effectors. (a)–(f) Immunohistochemistry

with anti-human mast cell tryptase and strept-ABC complex method; original magnifications: (a)–(c) � 100; (d)–(f) � 400. (g)–(i) Double immunofluorescent confocal

microscopy with FITC-conjugated anti-human IL-10 (green) and TRITC-conjugated anti-human mast cell tryptase (purple). Original magnifications: (g)–(h) � 200; (i) � 1000.

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of the innate and acquired immune system within thetumor microenvironment, and the resulting outcome ofthis interplay deserves further investigation. MCs areabundant in the tumor-associated inflammatory environ-ment in epithelial, stromal and hematological neoplasms[5]. However, the role of MCs at sites of tumor developmentand growth is as unclear as that of other immune cells,because the simple axiom that immune cells necessarilyhave an anti-cancer effect has been progressively decon-structed. Many roles can be envisaged for MCs in thetumor-associated microenvironment, from a direct anti-tumor effect to a boosting effect on the innate and adaptivebranches of the immune system against the tumor, toshaping a permissive environment for the neoplastic clone.

Many bodies of evidence support a tumorigenic role forMCs in the development and progression of cancer. MCs

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have been demonstrated recently to orchestrate a crucialtumor-promoting inflammation in the gut through theircooperation with aberrant Treg cells. These findings, indi-cating a key role of MCs in tumor initiation, highlight theimportance of a dysregulated inflammatory background[40,41]. The detrimental effects of MCs in the generation ofan aberrant immune response are not confined to themaintenance of a proinflammatory spur, but also rely onthe suppression of an effective adaptive anti-tumor immu-nity. Indeed, Hart and colleagues have provided evidencefor the contribution of the MC-derived mediators TNF-aand histamine in immune suppression associated withskin cancer [42]. MCs also have a role in tumor progressionand dissemination, because they participate in intercellu-lar matrix degradation, both by the release of proteases,and via the interaction with other immune effectors (e.g.

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granulocytes) [43]. Moreover, MCs are a major source ofmediators involved in the vascular assembly, such asvascular endothelial growth factor (VEGF) and TNF-a,and they participate in the re-modelling of the tumorvascular network [44].

However, MCs can inhibit tumor growth because theirsecretory pattern is not static [45]. MC-deficient miceundergo melanoma metastasis more rapidly than do theirwild-type littermates, possibly owing to a histamine-mediated increase of prostacyclin synthesis by endothelialcells, which has a potent antimetastatic action [46]. More-over, MC-derivedmediators, namely TNF-a, IL-1, IL-6 andIFN-g, could directly suppress melanoma cell growth[18,47], whereas the MC-derived chemokine CCL5, apotent chemoattractant for inflammatory cells, can attractmemory T cells (CD4+/CD45RO+), that might contribute toanti-tumor immunity [48]. MC heparin, as well as chon-droitinase and glycosaminoglycan lyases are even potentinhibitors of the clonogenic growth of tumor cells [49].

The findings of these contrasting functions associatedwith MCs are in agreement with studies on other humancancers, demonstrating a correlation between the numberof MCs, and either a poor prognosis, or an improvedsurvival [5]. To shed light on this issue, Huang and col-leagues have demonstrated that transplantable tumors,able to produce stem cell factor (SCF), recruit MCs withinthe tumor. Tumor-infiltrating MCs foster tumor growth bypromoting IL-6, TNF-a, VEGF, iNOS, CCL2 and IL-17mRNA expression at the tumor site. Moreover, MCs mightincrease the expression of the suppressor molecules IL-10and TGF-b and the generation of Treg cells, thus positivelyaffecting tumor growth [50]. Indeed, in many transplan-table murine models, tumor rejection is increased uponelimination of CD4+CD25+ Treg cells [51]. Some studieshave revealed the presence of CD4+CD25+ Treg cells inter-mixing with neoplastic cells in lymph nodes from patientswith breast, ovarian, lung or colon cancer, or with mela-noma [52], but the mechanisms of tumor-infiltrating Treg-cell recruitment at tumor sites, and their involvement inthe downregulation of the antitumor response still remainto be clarified. This overview of the plentiful, and some-times conflicting, functions of MCs in tumors providesfurther support for the hypothesis that MCs have a regu-latory role for in the immune system, because functionalplasticity is regarded as a key feature of cells with regu-latory properties.

ConclusionsResearch onMCs has changed dramatically our perceptionof the functions and role that MCs have in the regulation ofimmune responses. In this opinion paper, we have depictedMCs as complex and dynamic immune players claimingtheir own position in the pantheon of regulatory cells, byvirtue of the varied biological effects they have on theimmune response.

Traditionally the term of ‘‘regulatory cells’’ is attributedto particular subsets of cells that are phenotypically dis-tinguishable and display suppressive activity. However,through the selective secretion of mediators with both proand anti-inflammatory properties and through the directinteraction with Treg cells, MCs can effectively regulate

the fate and strength of the immune response. Under theseparameters, we have used and referred to such MCs as‘MCregs’. This meaning reflects the peculiarity of MCs thatshow a functional heterogeneity and the ability to samplethe microenvironment and tune the response according tothe quality and strength of the signals they perceive.Moreover, we can argue that MCs have an even moresubtle ability to play this regulatory function, adaptingtheir talent to sample and shape the response not only todiscrete stages of the immune response, but also to differ-ent tissue environments. A new perception of MCs asregulatory cells will allow a fresh perspective on the mol-ecules and signaling pathways involved in the interactionof MCs with other immune cells. This could hopefully leadto the development of different therapeutic strategiesaimed to boost or suppress specific MC functions, depend-ing on the pathological context.

AcknowledgementsThis work was supported by grants from the Italian Ministry of Health,Associazione Italiana Ricerca sul Cancro, Ministero dell’Istruzione,Universita e Ricerca (PRIN 2005), Agenzia Spaziale Italiana (ProgettoOSMA), LR.26 del Friuli Venezia Giulia.

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