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 data suggest that DG75 exosomes may possibly provide a but unknown major CSR-inducing signal (e.g., BCR crosslinking), which then synergizes with cytokine signaling to induce Help. In addition, hallmarks of active CSR are the formation of circular transcripts and Germline transcription (31). Germline transcripts play a central part in CSR by directing Help to a distinct S region within the IgH locus, and IL-21 was shown to be a switch factor for C1 and C3 transcripts in human B cells (50, 51). p70S6K Formulation 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 within a BJAB cell line stably transfected with a tetracycline-inducible LMP1 expression vector was shown to induce I1/2-C1 germline transcripts (27). Nevertheless, it remains to become investigated further why the synergistic stimulation of IgD+ B cells with DG75 exosomes plus IL-21 did not improve 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, various studies have only elucidated an immunesuppressive effect of those exosomes on recipient cells, such as human T cells and DCs (15, 29). On the other hand, B cells are equipped with all mandatory adaptor molecules to supply signaling for viral proteins, like LMP1, a mimic of the B cell ctivating receptor CD40 (16). Therefore, we propose that B cell erived exosomes released from EBVinfected B cells are able to deliver their content to B cells and, thereby, influence B cell biology. For that reason, clinical attributes observed in patients with EBV-associated SSTR1 MedChemExpress ailments, 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 problems or autoimmune ailments, could possibly be intensified by the presence and action of these exosomes. Additionally, they may well influence B cell improvement in healthy EBV carriers with implications, as an example, for allergy or autoimmune disease development.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSupplementary MaterialRefer to Web version on PubMed Central for supplementary material.AcknowledgmentsWe thank Mikael Karlsson, Lisa Westerberg, and John Andersson (Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital) for fruitful discussions. We are grateful for the great technical assistance of Linda Cassis (Institut Municipal d`InvestigatiM ica, Barcelona, Spain). This perform was supported by the Swedish Investigation Council, the Center for Allergy Analysis Karolinska Institutet, the Hesselman Foundation by way of Junior Faculty, Karolinska Institutet, and also the Swedish Cancer and Allergy Fund. N.N. is really a recipient of a Cancer Analysis Fellowship in the Cancer Investigation 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 location FSC height intronic 1 exon area on the H chain lymphoblastoid cell line latent membrane protein 1 propidium iodide side scatter SSC area
Valente et al. Stem Cell Resea.
