Mast Cell-Dependent B and T Lymphocyte Activation Is Mediated by the Secretion of Immunologically Active Exosomes

Abstract

Mitogenic activity of bone marrow-derived mouse mast cells and mast cell lines P815 and MC/9 on B and T lymphocytes is present in their culture supernatants. To identify this activity, mast cells were incubated in serum-free medium and the supernatant was subjected to differential centrifugation, which resulted in two fractions, the hypodense and dense fraction (pellet). When analyzed for their mitogenic activity on spleen cells, all activity was found to be associated with the dense fraction. Electron microscopy studies revealed the presence in this fraction of small vesicles called exosomes with a heterogeneous size from 60 to 100 nm of diameter. When cocultured with spleen cells, purified exosomes induced blast formation, proliferation, as well as IL-2 and IFN-γ production, but no detectable IL-4. Similar data were obtained by injecting exosomes into naive mice. In contrast to mast cell lines, a pretreatment with IL-4 is required for bone marrow-derived mast cells to secrete active exosomes. Structurally, exosomes were found to harbor immunologically relevant molecules such as MHC class II, CD86, LFA-1, and ICAM-1. These findings indicate that mast cells can represent a critical component of the immunoregulatory network through secreted exosomes that display mitogenic activity on B and T lymphocytes both in vitro and in vivo.

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Mast cells express MHC class I and II molecules, and have been reported to process and present antigen in vitro (reviewed in REFS 13,[43][44][45] ). Mast cells also can enhance antigen presentation in vitro by internalizing antigen bound to high-affinity Fc receptor for IgE (FcεRI)-associated IgE; this mechanism is independent of mast-cell MHC class II expression, but requires mastcell apoptosis and phagocytosis by other antigen-presenting cells, which then present the antigen 45 .…”

“…Mast cells represent potential sources of many mediators that can enhance or suppress the development, survival, proliferation, migration, maturation, or function of immune cells (reviewed in REFS [1][2][3][5][6][7][8]13,[16][17][18]21,30,31,43,44,[46][47][48][49][50][51][52][53][54][55][56]. Some individual mediators, such as histamine, can have both positive and negative immunomodulatory effects.…”

Exosomes as intercellular signalosomes and pharmacological effectors

“…Mast cell exosomes also participate in the immune response since they have the capacity to stimulate B and T cell proliferation and cytokines production such as IL-2 and IFN [91]. It was shown that peptide-loaded exosomes from mast cells elicit an efficient antibodies production in-vivo following a subcutaneous injection in mice.…”

“…Opposite to the potent immune stimulatory properties of exosomes issued from immunocompetent cells, many studies have demonstrated that tumor cell-derived exosomes display detrimental effects on immune response against tumors, leading to suppressive pathways hampering immune defenses in patients [91]. Consequently, tumor exosomes may contribute to tumor growth and to participate in tumor evasion.…”

HIV Type 1 Can Act as an APC upon Acquisition from the Host Cell of Peptide-Loaded HLA-DR and CD86 Molecules

“…Exosomes are small MHC-II-bearing vesicles (50 -90 nm) that originate from late endosomes and are secreted by a broad array of hemopoietic and epithelial cells (62)(63)(64)(65). The molecular characterization of dendritic cell-derived exosomes highlighted the presence, among others, of HSP hsc73 and CD86.…”