Exploring a regulatory role for mast cells: 'MCregs'?

Regulatory cells can mould the fate of the immune response by direct suppression of specific subsets of effector cells, or by redirecting effectors against invading pathogens and infected or neoplastic cells. These functions have been classically, although not exclusively, ascribed to different subsets of T cells. Recently, mast cells have been shown to regulate physiological and pathological immune responses, and thus to act at the interface between innate and adaptive immunity assuming different functions and behaviors at discrete stages of the immune response. Here, we focus on these poorly defined, and sometimes apparently conflicting, functions of mast cells.

Rheostatic Functions of Mast Cells in the Control of Innate and Adaptive Immune Responses

Mast cells are evolutionarily ancient cells, endowed with a unique developmental, phenotypic, and functional plasticity. They are resident cells that participate in tissue homeostasis by constantly sampling the microenvironment. As a result of their large repertoire of receptors, they can respond to multiple stimuli and selectively release different types and amounts of mediator. Here, we present and discuss the recent mast cell literature, focusing on studies that demonstrate that mast cells are more than a switch that is turned ‘off’ when in the resting state and ‘on’ when in the degranulating state. We propose a new vision of mast cells in which, by operating in a ‘rheostatic 

Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells.

AbstractThe evidence of a tight spatial interaction between mast cells (MCs) and B lymphocytes in secondary lymphoid organs, along with the data regarding the abundance of MCs in several B-cell lymphoproliferative disorders prompted us to investigate whether MCs could affect the proliferation and differentiation of B cells. To this aim, we performed coculture assays using mouse splenic B cells and bone marrow–derived MCs. Both nonsensitized and activated MCs proved able to induce a significant inhibition of cell death and an increase in proliferation of naive B cells. Such proliferation was further enhanced in activated B cells. This effect relied on cell-cell contact and MC-derived interle…

Technical advance: Soluble OX40 molecule mimics regulatory T cell modulatory activity on FCεRI-dependent mast cell degranulation

ABSTRACT Tregs play a central role in modulating FcɛRI-dependent MC effector functions in the course of the allergic response. Cellular interaction depends on the constitutive expression of OX40 on Tregs and the OX40L counterpart on MCs. Study of OX40L signaling on MCs is hampered by the need of a highly purified molecule, which triggers OX40L specifically. We now report that sOX40 mimics the physiological activity of Treg interaction by binding to activated MCs. When treated with sOX40, activated MCs showed decreased degranulation and Ca++ influx, whereas PLC-γ2 phosphorylation remained unaffected. Once injected into experimental animals, sOX40 not only located within the endothelium but a…

Frontline Science: Mast cells regulate neutrophil homeostasis by influencing macrophage clearance activity

Abstract The receptor tyrosine kinase cKit and its ligand stem cell factor are essential for mast cells (MC) development and survival. Strains with mutations affecting the Kit gene display a profound MC deficiency in all tissues and have been extensively used to investigate the role of MC in both physiologic and pathologic conditions. However, these mice present a variety of abnormalities in other immune cell populations that can affect the interpretation of MC-related responses. C57BL/6 KitW-sh are characterized by an aberrant extramedullary myelopoiesis and systemic neutrophilia. MC deficiency in KitW-sh mice can be selectively repaired by engraftment with in vitro-differentiated MC to va…

Mast Cells and Th17 Cells Contribute to the Lymphoma-Associated Pro-Inflammatory Microenvironment of Angioimmunoblastic T-Cell Lymphoma

Reports focusing on the immunological microenvironment of peripheral T-cell lymphomas (PTCL) are rare. Here we studied the reciprocal contribution of regulatory (Treg) and interleukin-17-producing (Th17) T-cells to the composition of the lymphoma-associated microenvironment of angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified on tissue microarrays from 30 PTCLs not otherwise specified and 37 AITLs. We found that Th17 but not Treg cells were differently represented in the two lymphomas and correlated with the amount of mast cells (MCs) and granulocytes, which preferentially occurred in the cellular milieu of AITL cases. We observed that MCs directly synthesized inter…

Mast cells control the expansion and differentiation of IL-10-competent B cells

Abstract The discovery of B cell subsets with regulatory properties, dependent on IL-10 production, has expanded our view on the mechanisms that control inflammation. Regulatory B cells acquire the ability to produce IL-10 in a stepwise process: first, they become IL-10 competent, a poised state in which B cells are sensitive to trigger signals but do not actually express the Il-10 gene; then, when exposed to appropriate stimuli, they start producing IL-10. Even if the existence of IL-10–competent B cells is now well established, it is not yet known how different immune cell types cross talk with B cells and affect IL-10–competent B cell differentiation and expansion. Mast cells (MCs) contr…

Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation

Abstract The development of inflammatory diseases implies inactivation of regulatory T (Treg) cells through mechanisms that still are largely unknown. Here we showed that mast cells (MCs), an early source of inflammatory mediators, are able to counteract Treg inhibition over effector T cells. To gain insight into the molecules involved in their interplay, we set up an in vitro system in which all 3 cellular components were put in contact. Reversal of Treg suppression required T cell–derived interleukin-6 (IL-6) and the OX40/OX40L axis. In the presence of activated MCs, concomitant abundance of IL-6 and paucity of Th1/Th2 cytokines skewed Tregs and effector T cells into IL-17–producing T cel…

Chronic Spontaneous Urticaria in Patients with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a predominantly antibody deficiency and is one of the most common primary immunodeficiencies in adulthood. Replacement therapy with Ig has significantly reduced infectious complications; however, malignant, autoimmune, and inflammatory diseases are still current major causes of morbidity and mortality. In recent years, interest has increased regarding allergic manifestations that may be associated with primary immunodeficiencies; however, no data are currently available on chronic spontaneous urticaria (CSU). In this report, the authors describe CSU in patients with CVID attending their centre. Three CVID patients were affected by CSU and were unre…

Reciprocal influence of B cells and tumor macro and microenvironments in the ApcMin/+ model of colorectal cancer

One of the most fascinating aspects of the immune system is its dynamism, meant as the ability to change and readapt according to the organism needs. Following an insult, we assist to the spontaneous organization of different immune cells which cooperate, locally and at distance, to build up an appropriate response. Throughout tumor progression, adaptations within the systemic tumor environment, or macroenvironment, result in the promotion of tumor growth, tumor invasion and metastasis to distal organs, but also to dramatic changes in the activity and composition of the immune system. In this work, we show the changes of the B-cell arm of the immune system following tumor progression in the…

CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction.

T regulatory (Treg) cells play a role in the suppression of immune responses, thus serving to induce tolerance and control autoimmunity. Here, we explored whether Treg cells influence the immediate hypersensitivity response of mast cells (MCs). Treg cells directly inhibited the FcεRI-dependent MC degranulation through cell-cell contact involving OX40-OX40L interactions between Treg cells and MCs, respectively. When activated in the presence of Treg cells, MCs showed increased cyclic adenosine monophosphate (cAMP) concentrations and reduced Ca2+ influx, independently of phospholipase C (PLC)-γ2 or Ca2+ release from intracellular stores. Antagonism of cAMP in MCs reversed the inhibitory effec…

Mast cells are associated with the onset and progression of celiac disease

Background Celiac disease (CD) is an immune-mediated disorder characterized by an accumulation of immune cells in the duodenal mucosa as a consequence of both adaptive and innate immune responses to undigested gliadin peptides. Mast cells (MCs) are innate immune cells that are a major source of costimulatory signals and inflammatory mediators in the intestinal mucosa. Although MCs have previously been associated with CD, functional studies have never been performed. Objective We aimed at evaluating the role of MCs in the pathogenesis of CD. Methods Intestinal biopsy specimens of patients with CD were scored according to the Marsh classification and characterized for leukocyte infiltration a…

Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10+ phenotype

Mast cells (MCs) are innate immune cells that exert positive and negative immune modulatory functions capable to enhance or limit the intensity and/or duration of adaptive immune responses. Although MCs are crucial to regulate T cell immunity, their action in the pathogenesis of autoimmune diseases is still debated. Here we demonstrate that MCs play a crucial role in T1D pathogenesis so that their selective depletion in conditional MC knockout NOD mice protects them from the disease. MCs of diabetic NOD mice are overly inflammatory and secrete large amounts of IL-6 that favors differentiation of IL-17-secreting T cells at the site of autoimmunity. Moreover, while MCs of control mice acquire…

Efficacy of rituximab as a single-agent therapy for the treatment of granulomatous and lymphocytic interstitial lung disease in patients with common variable immunodeficiency.

Mast cells boost myeloid-derived suppressor cell activity and contribute to the development of tumor-favoring microenvironment

Abstract Inflammation plays crucial roles at different stages of tumor development and may lead to the failure of immune surveillance and immunotherapy. Myeloid-derived suppressor cells (MDSC) are one of the major components of the immune-suppressive network that favors tumor growth, and their interaction with mast cells is emerging as critical for the outcome of the tumor-associated immune response. Herein, we showed the occurrence of cell-to-cell interactions between MDSCs and mast cells in the mucosa of patients with colon carcinoma and in the colon and spleen of tumor-bearing mice. Furthermore, we demonstrated that the CT-26 colon cancer cells induced the accumulation of CD11b+Gr1+ imma…

Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma

A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein…

The aryl hydrocarbon receptor modulates acute and late mast cell responses.

Abstract The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits…

Cross-Talk between Myeloid-Derived Suppressor Cells and Mast Cells Mediates Tumor-Specific Immunosuppression in Prostate Cancer.

Abstract Immunotherapy, including the use of checkpoint inhibitors, is a potent therapeutic approach for some cancers, but has limited success with prostate tumors, in which immune suppression is instigated by the tumor. The immunosuppressive capacity of mast cells, which promote adenocarcinoma development in the prostate, prompted our investigation on whether mast cells promote tolerance to SV40 Large-T antigen, the transforming oncogene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. The incidence of adenocarcinoma was reduced in the offspring of a cross between TRAMP mice and mast cell–deficient KitWsh mice. TRAMP mice are tolerant to the SV40 Large T antigen, which is o…