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      Role of Exosomes in the Regulation of T-Cell Mediated Immune Responses and in Autoimmune Disease

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          Abstract

          T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention or development of autoimmune disease. The expression of membrane-bound death ligands on the surface of exosomes during AICD or the more recently described transfer of miRNA or even DNA inside T-cell exosomes is a molecular mechanism that will be analyzed.

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          Most cited references83

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes.

            Dendritic cells (DCs) secrete vesicles of endosomal origin, called exosomes, that bear major histocompatibility complex (MHC) and T cell costimulatory molecules. Here, we found that injection of antigen- or peptide-bearing exosomes induced antigen-specific naïve CD4+ T cell activation in vivo. In vitro, exosomes did not induce antigen-dependent T cell stimulation unless mature CD8alpha- DCs were also present in the cultures. These mature DCs could be MHC class II-negative, but had to bear CD80 and CD86. Therefore, in addition to carrying antigen, exosomes promote the exchange of functional peptide-MHC complexes between DCs. Such a mechanism may increase the number of DCs bearing a particular peptide, thus amplifying the initiation of primary adaptive immune responses.
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              Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.

              Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim, that share only the BH3 domain with this family. Gene targeting in mice revealed important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T cell development was perturbed, and most older mice accumulated plasma cells and succumbed to autoimmune kidney disease. Lymphocytes were refractory to apoptotic stimuli such as cytokine deprivation, calcium ion flux, and microtubule perturbation but not to others. Thus, Bim is required for hematopoietic homeostasis and as a barrier to autoimmunity. Moreover, particular death stimuli appear to activate apoptosis through distinct BH3-only proteins.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                12 February 2019
                February 2019
                : 8
                : 2
                : 154
                Affiliations
                [1 ]Immunity, Cancer & Stem Cells Group, Department of Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain; jnaval@ 123456unizar.es
                [2 ]Department of Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Campus San Francisco Sq., University of Zaragoza and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain; annaiss89@ 123456hotmail.com
                [3 ]Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, Gower St, Bloomsbury, London WC1E 6BT, UK; diego_demiguel@ 123456hotmail.com
                [4 ]Immunology Department, Lozano Blesa Clinical Hospital, and Aragón Health Research Institute (IIS Aragón), E-50009 Zaragoza, Spain; lmartinezlos@ 123456salud.aragon.es
                Author notes
                [* ]Correspondence: anel@ 123456unizar.es ; Tel.: +34-976-761279
                Author information
                https://orcid.org/0000-0002-5175-8394
                Article
                cells-08-00154
                10.3390/cells8020154
                6406439
                30759880
                4d142a09-ad9f-4bcb-8d17-723f4085b38c
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 December 2018
                : 11 February 2019
                Categories
                Review

                exosomes,extracellular vesicles,immune regulation,autoimmunity

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