ORIGINAL ARTICLE Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis Maryam Azimi 1 & Mojdeh Ghabaee 2 & Abdorreza Naser Moghadasi 3 & Farshid Noorbakhsh 1 & Maryam Izad 1,3 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Multiple sclerosis (MS) is an autoimmune disease which is characterized by neuroaxonal degeneration in the central nervous system. Impaired function of regulatory T cells (Tregs) is believed to be an underlying pathogenic mechanism in MS. Tregs is able to release exosomes, which contain a considerable amount of protein and RNA. Exosomes are capable of transporting their content to other cells where the released content exerts biological functions. Here, we investigated whether Tregs exosomes of RRMS patients or healthy controls might regulate the proliferation or survival of T lymphocytes. Regulatory T cells derived from MS patients or healthy controls were cultured for 3 days and exosomes were purified from supernatants. Treg-derived exosomes were co-cultured with conventional T cells (Tconv). The percentages of Tconv proliferation and apoptosis were measured. Our findings showed that the percentage of proliferation suppression induced by exosomes in patients compared to healthy controls was 8.04 ± 1.17 and 12.5 ± 1.22, respectively, p value = 0.035. Moreover, the rate of Tconv apoptosis induced by exosome of MS patient was less than healthy controls (0.68 ± 0.12 vs. 1.29 ± 0.13; p value = 0.015). Overall, Treg-derived exosomes from MS patients and healthy controls suppressed the proliferation and induced apoptosis in Tconv. However, the effect of MS-derived exosomes was significantly less than healthy controls. Our results point to an alternative Treg inhibitory mechanism which might be important in immunopathogenesis of MS. Although, the cause of the exosomal defect in MS patients is unclear, manipulation of patients’ Treg-derived exosomes to restore their suppressive activity might be considered as a potential therapeutic approach. Keywords Multiple sclerosis . T lymphocytes . Regulatory T cell . Exosome . Treg-derived exosomes Introduction Multiple sclerosis (MS) is a multifactorial autoimmune dis- ease, in which chronic inflammation of the central nervous system (CNS) leads to demyelination and neural cell injury in both white and gray matter [1–3]. Different clinical patterns have been reported for MS with relapsing-remitting MS (RRMS) being the most common clinical form of the disease with several periods of relapses and remissions [4, 5]. Numerous studies performed on MS patients or its animal models have pointed to CD4 + and CD8 + T cells as crucial players in the pathogenesis of disease [6, 7]. It is known that infiltration of CNS with myelin-reactive T cells with either a Th1 or Th17 phenotype is one of the determining pathogenic events in RRMS [1, 8, 9]. Various mechanisms have been proposed to explain this pathogenic activation and infiltration of autoreactive T cells. One of the proposed explanations which have considerable empirical evidence is insufficient control and suppression of autoreactive T cells due to defec- tive functioning of CD4 + CD25 High regulatory T cells [10, 11]. Indeed, some immunomodulatory drugs that are used for the treatment of MS are known to be able to restore or enhance Treg function [12, 13]. Regulatory T cells have been shown to exert their suppres- sive activity by a variety of molecular mechanisms such as production of immunomodulatory cytokines, expression of inhibitory receptors, and direct cytotoxic killing of target cells * Maryam Izad izadm@sina.tums.ac.ir 1 Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Poorsina St., 16 Azar St., Enghelab Ave., Tehran, Iran 2 Department of Neurology, Iranian Center of Neurological Research, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran 3 MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran Immunologic Research https://doi.org/10.1007/s12026-018-9008-5