title: Insulinoma-released exosomes or microparticles are immunostimulatory and can activate autoreactive T cells spontaneously developed in nonobese diabetic mice.
abstract: Exosomes (EXO) are secreted intracellular microparticles that can trigger inflammation and induce Ag-specific immune responses. To test possible roles of EXO in autoimmunity, we isolated small microparticles, mainly EXO, from mouse insulinoma and examined their activities to stimulate the autoimmune responses in NOD mice, a model for human type 1 diabetes. We demonstrate that the EXO contains strong innate stimuli and expresses candidate diabetes autoantigens. They can induce secretion of inflammatory cytokines through a MyD88-dependent pathway, and activate purified APC and result in T cell proliferation. To address whether EXO or the secreted microparticles are possible autoimmune targets causing islet-specific inflammation, we monitored the T cell responses spontaneously developed in prediabetic NOD mice for their reactivity to the EXO, and compared this reactivity between diabetes-susceptible and -resistant congenic mouse strains. We found that older NOD females, which have advanced islet destruction, accumulated more EXO-reactive, IFN-γ-producing lymphocytes than younger females or age-matched males, and that pancreatic lymph nodes from the prediabetic NOD, but not from the resistant mice, were also enriched with EXO-reactive Th1 cells. In vivo, immunization with the EXO accelerates insulitis development in nonobese diabetes-resistant mice. Thus, EXO or small microparticles can be recognized by the diabetes-associated autoreactive T cells, supporting that EXO might be a possible autoimmune target and/or insulitis trigger in NOD or congenic mouse strains.
authors: Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
authors: Huiming
authors: H
authors: Sheng
authors: Saleema
authors: S
authors: Hassanali
authors: Courtney
authors: C
authors: Nugent
authors: Li
authors: L
authors: Wen
authors: Emma
authors: E
authors: Hamilton-Williams
authors: Peter
authors: P
authors: Dias
authors: Yang D
authors: YD
authors: Dai
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000276:immunology* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D055354:Exosomes / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D007340:Insulinoma / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D012727:Sex Characteristics; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88