Killer B Lymphocytes and Their Fas Ligand Positive Exosomes as Inducers of Immune Tolerance

Abstract

Induction of immune tolerance is a key process by which the immune system is educated to modulate reactions against benign stimuli such as self-antigens and commensal microbes. Understanding and harnessing the natural mechanisms of immune tolerance may become an increasingly useful strategy for treating many types of allergic and autoimmune diseases, as well as for improving the acceptance of solid organ transplants. Our laboratory and others have been interested in the natural ability of some B lymphocytes to express the death-inducing molecule Fas ligand (FasL), and their ability to kill T helper (TH) lymphocytes. We have recently shown that experimental transformation of human B cells by a non-replicative variant of Epstein-Barr virus (EBV) consistently resulted in high expression of functional FasL protein. The production and release of FasL+ exosomes that co-expressed major histocompatibility complex (MHC) class II molecules and had the capacity to kill antigen-specific TH cells was also observed. Several lines of evidence indicate that FasL+ B cells and FasL+MHCII+ exosomes have important roles in natural immune tolerance and have a great deal of therapeutic potential. Taken together, these findings suggest that EBV-immortalized human B lymphoblastoid cell lines could be used as cellular factories for FasL+ exosomes, which would be employed to therapeutically establish and/or regain immune tolerance toward specific antigens. The goals of this review are to summarize current knowledge of the roles of FasL+ B cells and exosomes in immune regulation, and to suggest methods of manipulating killer B cells and FasL+ exosomes for clinical purposes.

Endotoxemia contributes to CD27+ memory B-cell apoptosis via enhanced sensitivity to Fas ligation in patients with Cirrhosis

“…In addition to enhanced expression of mFasL on CD4 + T-cells in cirrhosis, sFasL serum levels were markedly elevated and we speculate that sFasL may participate in B-cell apoptosis in vivo in cirrhosis. sFasL has been reported to be secreted in exosomes by EBV-transformed B-cells in vitro 27 with cytotoxic effects; however, we found no cytotoxic effect of exosomes separated from cirrhotic plasma except at extreme concentrations and that removal of exosomes enhanced apoptosis suggesting exosomes may harbor anti-apoptotic signals that require further exploration.…”

“…These findings appear to contradict findings in other systems in which sFasL in vitro fails to activate apoptosis due to lack of crosslinking of Fas receptors242526. Removal of exosomes, a putative source of circulating mFasL27, increased CD27 + B-cell apoptosis suggesting that exosomes do not contribute to B-cell Fas-mediated apoptosis in vivo and may actually provide pro-survival signals (Fig. 4C).…”

Plasma exosome profiles from dairy cows with divergent fertility phenotypes

“…The immune system and the various immunomodulatory pathways and products are critical in establishing pregnancy and, hence, enhancing fertility (Stenqvist et al, 2013;Lundy et al, 2015). We are exploring differences in these pathways, again considering that utilization of this information may derive potential biomarkers of fertility to support genetic gain in fertil-ity.…”

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis

“…80,81 The major EBV oncoprotein LMP-1 can be detected in EBV exosomes and may inhibit both T-cell and natural killer cell responses in vitro through the strong immunosuppressive properties of a conserved region within the first transmembrane domain of LMP-1. 82 EBV-infected B cells were also shown to produce and release FasL1 exosomes that have the capacity to kill antigen-specific T cells, 83,84 an effect that could contribute to keep immune effectors away from tumor cells. EBV exosomes also contain deoxyuridine triphosphate nucleotidohydrolase (dUTPase), a protein encoded by the BLLF3 EBV gene expressed during abortive or lytic replication, which may interfere with both innate and adaptive immune responses.…”