Accumulation of Major Histocompatibility Complex Class II Molecules in Mast Cell Secretory Granules and Their Release upon Degranulation

Abstract

To investigate the relationship between major histocompatibility complex (MHC) class II compartments, secretory granules, and secretory lysosomes, we analyzed the localization and fate of MHC class II molecules in mast cells. In bone marrow-derived mast cells, the bulk of MHC class II molecules is contained in two distinct compartments, with features of both lysosomal compartments and secretory granules defined by their protein content and their accessibility to endocytic tracers. Type I granules display internal membrane vesicles and are accessed by exogenous molecules after a time lag of 20 min; type II granules are reached by the endocytic tracer later and possess a serotonin-rich electron-dense core surrounded by a multivesicular domain. In these type I and type II granules, MHC class II molecules, mannose-6-phosphate receptors and lysosomal membrane proteins (lamp1 and lamp2) localize to small intralumenal vesicles. These 60-80-nm vesicles are released along with inflammatory mediators during mast cell degranulation triggered by IgE-antigen complexes. These observations emphasize the intimate connection between the endocytic and secretory pathways in cells of the hematopoietic lineage which allows regulated secretion of the contents of secretory lysosomes, including membrane proteins associated with small vesicles.

Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects

“…These 'exosomes' appeared to play a central role in communication between lymphocytes and dendritic cells, mediating the development of cellular responses or suppressing excessive activation, as in AICD. The phenomena of shedding 'exosomes' have also been demonstrated with other haematopoietic cells, such as mast cells and platelets, and it is thought to play important roles mediating their actions (Raposo et al, 1997). Recent studies have isolated 'exosomes' from tumour cells in vivo and in vitro and have demonstrated the presence of tumourassociated antigens and class I MHC antigens (Wolfers et al, 2001;André et al, 2002a, b;Chaput et al, 2004).…”

Mast Cell-Derived Exosomes Induce Phenotypic and Functional Maturation of Dendritic Cells and Elicit Specific Immune Responses In Vivo

“…During exocytosis, in addition to soluble proteins and mediators, vesicles heterogeneous in size and shape, termed exosomes, are released from the lumen of multivesicular bodies in the extracellular environment (3,4).…”

“…Ag presentation by bone marrow-derived MCs (BMMC) is strictly controlled by cytokines: IL-4 and GM-CSF are potent inducers of the Ag-presenting capacity, whereas IFN-␥ completely abrogate this function. Thus, MCs synthesize MHC class II molecules, which accumulate in the internal membrane vesicles of multivesicular organelles called secretory granules (4). It has been recently shown that IL-4-treated BMMC and untreated MC lines P815 and MC/9 induce in vitro and in vivo B and T lymphocyte proliferation and cytokine production (17).…”

Exosomes: A new delivery system for tumor antigens in cancer immunotherapy

“…14,20,21 It has been shown that various types of eukaryotic cells, including hematopoietic cells and more recently tumor cells, secrete exosomelike vesicles. [5][6][7][8][9][10][11][12][13] Exosomes have diverse functions on the basis of their origins. In particular, exosomes from B lymphocytes were found to stimulate CD4ϩ T cells in vitro and exosomes from tumor-peptide-pulsed dendritic cells could activate cytolytic T cells in vivo and induce an antitumor activity.…”

“…[1][2][3][4] These extracellular vesicles are also produced by various kinds of hematopoietic cells, including mast cells, platelets, T lymphocytes, B lymphocytes and dendritic cells (DCs), as well as by intestinal epithelial cells. [5][6][7][8][9][10][11][12][13] Exosomes are known to originate from the inward budding of limiting membrane of multivesicular bodies (MVBs), and these internal vesicles of MVBs are released into the extracellular space by fusion of MVBs with the plasma membrane. 14 Proteomic analysis of DC-or B-cell-derived exosomes revealed selective enrichment of a subset of cellular proteins, including antigen-presenting proteins such as MHC class I and II molecules, heat shock proteins (HSPs), targeting-related MFG-E8 and tetraspanins such as CD9, CD63, CD81 and CD82.…”