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 antigen-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 non-obese diabetic (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 MyD88-dependent pathways, 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-gamma-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 diabetes-resistant NOR 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.

Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro

“…Exosomes from the Min6 mouse insulinoma cell-line have been shown to contain antigens that trigger autoimmunity in NOD mice. 10 In preliminary mouse experiments, we did not detect an in vivo immune effect in BALB/c mice after injection of EVs purified from leukoreduced RBC units from C57BL/6 mice (supplemental Figure 3), potentially due to limitations of the mouse model in recapitulating the human system. Of note, in our human experiments, the immune effect did not appear to be antigen specific, as EV stimulatory capacity did not differ when EVs were derived from autologous vs allogeneic cells.…”

“…6 However, exosomes bearing autoimmune antigens are immunostimulatory in a NOD mouse model of diabetes, leading to production of proinflammatory cytokines and proliferation of T cells. 10 In this article we examine the role of EVs in potentially mediating an immune modulatory effect associated with blood transfusion. It is believed that transfusion of fresh blood may carry less risk of adverse reactions compared with old blood, attributed to a red blood cell (RBC) "storage lesion," which has been described as physical and chemical changes of RBCs during the time of storage.…”

The Effect of Glucose on the Release and Bioactivity of Exosomes From First Trimester Trophoblast Cells

“…Exosomes isolated from mouse insulinoma induce the secretion of inflammatory cytokines including IL-6 and TNF-␣ in splenocytes cultured from nonobese diabetic mice (34). Studies using microvascular endothelial cells (HMEC-1) as an exosome source demonstrated that stress conditions (such as hypoxia, glucose, and TNF-␣) can alter exosomal protein and mRNA composition (35).…”

Stem cell-derived exosomes: a novel vector for tissue repair and diabetic therapy

“…The transfer of miRNAs and siRNAs can also alter protein expression in target cells by binding to complementary mRNA in the cytoplasm, inhibiting translation (Guay et al 2015, Lee et al 2015b. Intercellular transfer of exosomal cargo has been implicated in immunomodulation, initiation of cellular proliferation, angiogenesis, regulation of apoptosis, platelet activation and other phenotypic alterations in targeted cells (Rak 2010, Sheng et al 2011, Corrado et al 2013, Tomasoni et al 2013, Rahman et al 2014, Shabbir et al 2015. Such alterations have been associated with both healthy and pathogenic cellular behaviors (BenitoMartin et al 2015, Ciardiello et al 2016.…”