G to induce Help and T cell ndependent CSR (48, 49). Our information
G to induce Aid and T cell ndependent CSR (48, 49). Our information recommend that DG75 exosomes could provide a yet unknown major CSR-inducing signal (e.g., BCR crosslinking), which then synergizes with cytokine signaling to induce Help. Furthermore, hallmarks of active CSR are the formation of circular transcripts and germline transcription (31). Germline transcripts play a Adenosine A3 receptor (A3R) Agonist Storage & Stability central role in CSR by directing Aid to a distinct S region within the IgH locus, and IL-21 was shown to be 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, at the same time as I1/2-C1 germline transcription (Fig. 7A, 7B). Ectopic LMP1 expression within a BJAB cell line stably transfected with a tetracycline-inducible LMP1 expression vector was shown to induce I1/2-C1 germline transcripts (27). Nonetheless, it remains to become investigated further why the synergistic stimulation of IgD+ B cells with DG75 exosomes plus IL-21 did not enhance 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, different studies have only elucidated an immunesuppressive effect of these exosomes on recipient cells, like human T cells and DCs (15, 29). Nevertheless, B cells are equipped with all mandatory adaptor molecules to MMP Compound supply signaling for viral proteins, which include LMP1, a mimic of your B cell ctivating receptor CD40 (16). Hence, we propose that B cell erived exosomes released from EBVinfected B cells are capable to provide their content to B cells and, thereby, influence B cell biology. Consequently, clinical attributes observed in patients with EBV-associated illnesses, such asNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptJ Immunol. Author manuscript; out there in PMC 2014 September 24.Gutzeit et al.Pagelymphoproliferative issues or autoimmune illnesses, might be intensified by the presence and action of these exosomes. In addition, they might influence B cell development in wholesome EBV carriers with implications, for instance, for allergy or autoimmune disease development.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 outstanding technical help of Linda Cassis (Institut Municipal d`InvestigatiM ica, Barcelona, Spain). This work was supported by the Swedish Analysis Council, the Center for Allergy Research Karolinska Institutet, the Hesselman Foundation by means of Junior Faculty, Karolinska Institutet, and the Swedish Cancer and Allergy Fund. N.N. can be a recipient of a Cancer Research Fellowship from the Cancer Research 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 manage class-switch recombination dendritic cell forward scatter FSC area FSC height intronic 1 exon region on the H chain lymphoblastoid cell line latent membrane protein 1 propidium iodide side scatter SSC region
Valente et al. Stem Cell Resea.
