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Sullivan, Jeremy A.; Tomita, Yusuke; Jankowska-Gan, Ewa; Lema, Diego A.; Arvedson, Matt P.; Nair, Ashita; Bracamonte-Baran, William; Zhou, Ying; Meyer, Kristy K.; Zhong, Weixiong; Sawant, Deepali V.; Szymczak-Workman, Andrea L.; Zhang, Qianxia; Workman, Creg J.; Hong, Seungpyo; Vignali, Dario A.A.; Burlingham, William J.
Cell reports (Cambridge), 01/2020, Letnik: 30, Številka: 4Journal Article
Interleukin-35 (IL-35) is an immunosuppressive cytokine composed of Epstein-Barr-virus-induced protein 3 (Ebi3) and IL-12α chain (p35) subunits, yet the forms that IL-35 assume and its role in peripheral tolerance remain elusive. We induce CBA-specific, IL-35-producing T regulatory (Treg) cells in TregEbi3WT C57BL/6 reporter mice and identify IL-35 producers by expression of Ebi3TdTom gene reporter plus Ebi3 and p35 proteins. Curiously, both subunits of IL-35 are displayed on the surface of tolerogen-specific Foxp3+ and Foxp3neg (iTr35) T cells. Furthermore, IL-35 producers, although rare, secrete Ebi3 and p35 on extracellular vesicles (EVs) targeting a 25- to 100-fold higher number of T and B lymphocytes, causing them to acquire surface IL-35. This surface IL-35 is absent when EV production is inhibited or if Ebi3 is genetically deleted in Treg cells. The unique ability of EVs to coat bystander lymphocytes with IL-35, promoting exhaustion in, and secondary suppression by, non-Treg cells identifies a novel mechanism of infectious tolerance. Display omitted •IL-35 subunits Ebi3 and p35 are secreted as components of CD81+ EVs•IL-35+ EVs secreted by a small number of Treg cells target a higher number of lymphocytes•EV coating of bystander lymphocytes with IL-35 promotes infectious tolerance Sullivan et al. show that while many factors and cytokines contribute to primary immunosuppression, EV-associated IL-35 uniquely promotes “infectious” tolerance not only by inducing IL-35 production in non-Treg cells but also by causing an immunosuppressive phenotype in EV-acquiring T and B cells, leading to secondary suppression of immune responses.
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in: SICRIS
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