The relation of ontogeny between IL-10?LAG-3+CD138hi cells from na?ve mice and IL-10+LAG-3+CD138hi cells from infected mice was corroborated by the similitude of their BCR repertoire and DNA methylome, which differed from your ones of LAG-3?CD138hi and IL-10?CD138hi ASC. under the control of the BCR into LAG-3+CD138hi natural regulatory plasma cells (bottom part). Damaged cells (including reddish blood cells) might contribute to the generation of these cells. Upon challenge with brokers that for instance provide abundant TLR agonists, these cells can upregulate IL-10 expression while remaining in a nondividing state. The light green quadrant (left) indicates what is happening before BMS-777607 any immune challenge. The orange quadrant (right) indicates what is happening after activation of an appropriate immune response. Open in a separate windows Abstract B cells can generate several types of antibody-secreting cells, including plasmablasts that divide and are short Cxcl12 lived, as well as plasma cells that do not proliferate and can persist for extended time periods. Here, we discuss the identification of a novel subset of non-dividing plasma cells specialized in the production of interleukin(IL)-10. These cells develop at constant state, including in germ-free mice, via a mechanism dependent on the B cell receptor for antigen and possibly involving the acknowledgement of damaged cells. They are characterized by the expression of the inhibitory receptor LAG-3, and also express CD200, PD-L1, as well as PD-L2. Their specialized epigenome allows them to produce IL-10 within hours after activation, which altogether qualify these cells as natural regulatory plasma cells. Current Opinion in Immunology 2018, 55:62C66 This review comes from a themed issue on Autoimmunity Edited by Daniel Stetson BMS-777607 For any complete overview see the Issue and the Editorial Available online 4th October 2018 https://doi.org/10.1016/j.coi.2018.09.012 0952-7915/? 2018 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction Antibodies provide an essential line of defense against infectious diseases. The incidence and severity of infectious diseases are markedly increased in patients suffering from genetic deficiencies impairing antibody production . The differentiation of antibody-secreting cells (ASC) is usually linked to B cell proliferation, epigenome remodeling, and the expression of transcription factors driving the functional plasma cell state . Different ASC subtypes can be distinguished depending on their lifespan and degree of differentiation. Plasmablasts are less mature, proliferative, and short-lived, while plasma cells are more differentiated, do not divide, and can persist for a lifetime in dedicated niches . In this review, we use the term plasmocyte as a general descriptor for ASC, including both plasmablasts and plasma cells. The durability of some non-dividing plasma cells might explain the amazing persistence of serum antibody titers towards vaccine antigens, which for instance can reach half-lives up to 3014 years for measles . It has long been considered BMS-777607 that the unique function of plasmocytes (including plasmablasts and plasma cells) was to produce antibodies. However, recent studies exhibited that some plasmocytes could produce cytokines with either pro- or anti-inflammatory functions including interleukin(IL)-10 [5,6]. The loss of suppressive plasmocytes might explain why some patients with immune-deficiencies also often present with an increased incidence of immune-mediated diseases. For instance, patients with common variable immune deficiencies (CVID) have an increased incidence of autoimmune manifestations including autoimmune cytopenia . The exploration of this possibility requires the better characterization of anti-inflammatory plasmocytes. This review discusses the identification of a novel subset of regulatory plasma cells in mice. The role of plasmocytes as mediators of immune suppression B BMS-777607 cells necessitate stimulatory signals to acquire immune suppressive activities, including activation via the B cell receptor for antigen (BCR), CD40, Toll-like receptors (TLR), and receptors for cytokines [8??,9, 10, 11,12?]. Their suppressive effect also depends on their expression of the transcription factors IRF4 and BLIMP-1 transcription. For instance, IRF4 binds to the conserved noncoding sequence (CNS) 9 located upstream of the transcription start [13??], and is important for the induction of IL-10 in B cells stimulated by the M2 protein of the murine gammaherpes computer virus 68 . These transcription factors are well-known for their crucial role in ASC formation , and no B cell has been described so far that expresses elevated levels of BLIMP-1 and IRF4 that is not a plasmocyte. This establishes a molecular link between expression and plasmocyte differentiation. Accordingly, plasmocytes were identified as the major BMS-777607 source of B cell-derived IL-10 in autoimmune, malignant, and infectious diseases [8??,13??,15, 16, 17]. The suppressive function of.