G to induce Help and T cell ndependent CSR (48, 49). Our information
G to induce Help and T cell ndependent CSR (48, 49). Our data suggest that DG75 exosomes might provide a yet unknown key CSR-inducing signal (e.g., BCR crosslinking), which then synergizes with cytokine signaling to induce Aid. Additionally, hallmarks of active CSR would be the formation of circular transcripts and germline transcription (31). Germline transcripts play a central part in CSR by directing Help to a particular S region within the IgH locus, and IL-21 was shown to become a switch aspect for C1 and C3 transcripts in human B cells (50, 51). Stimulation of IgD+ B cells with DG75 exosomes induced the formation of I1/2-C circle transcripts, as well as I1/2-C1 germline transcription (Fig. 7A, 7B). Ectopic LMP1 expression inside a BJAB cell line stably transfected having a tetracycline-inducible LMP1 expression Adenosine A2B receptor (A2BR) Antagonist Compound vector was shown to induce I1/2-C1 germline transcripts (27). Nevertheless, it remains to be investigated further why the synergistic stimulation of IgD+ B cells with DG75 exosomes plus IL-21 did not increase circle transcript formation and germline transcription. In conclusion, our study demonstrates the B cell timulatory capacity of exosomes released by EBV-infected B cells. So far, numerous research have only elucidated an immunesuppressive effect of these exosomes on recipient cells, which include human T cells and DCs (15, 29). Having said that, B cells are equipped with all mandatory adaptor molecules to provide signaling for viral proteins, for example LMP1, a mimic of your B cell ctivating receptor CD40 (16). Therefore, we propose that B cell erived exosomes released from EBVinfected B cells are capable to deliver their content RSK3 Species material to B cells and, thereby, influence B cell biology. Consequently, clinical functions observed in patients with EBV-associated diseases, such asNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptJ Immunol. Author manuscript; available in PMC 2014 September 24.Gutzeit et al.Pagelymphoproliferative problems or autoimmune diseases, could be intensified by the presence and action of these exosomes. In addition, they could influence B cell improvement in healthier EBV carriers with implications, for instance, for allergy or autoimmune disease improvement.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSupplementary MaterialRefer to Net version on PubMed Central for supplementary material.AcknowledgmentsWe thank Mikael Karlsson, Lisa Westerberg, and John Andersson (Division of Medicine Solna, Karolinska Institutet and Karolinska University Hospital) for fruitful discussions. We are grateful for the fantastic technical assistance of Linda Cassis (Institut Municipal d`InvestigatiM ica, Barcelona, Spain). This operate was supported by the Swedish Study Council, the Center for Allergy Analysis Karolinska Institutet, the Hesselman Foundation by way of Junior Faculty, Karolinska Institutet, and the Swedish Cancer and Allergy Fund. N.N. is usually a recipient of a Cancer Analysis Fellowship from the Cancer Study Institute (New York)/Concern Foundation (Los Angeles).Abbreviations employed in this articleAID APRIL CLSM co CSR DC FSC FSC-A FSC-H I1-C LCL LMP1 PI SSC SSC-A activation-induced cytidine deaminase a proliferation-inducing ligand confocal laser scanning microscopy unstimulated control class-switch recombination dendritic cell forward scatter FSC area FSC height intronic 1 exon region with the H chain lymphoblastoid cell line latent membrane protein 1 propidium iodide side scatter SSC area
Valente et al. Stem Cell Resea.
