9-cis retinoic acid and 1,25-dihydroxyvitamin D3 interfere with the migration and survival of in vitro generated human plasmablasts and activated B cells ; 9-cis-Retinsäure und 1,25-Dihydroxyvitamin D3 beeinträchtigen die Migration und das Überleben von in vitro erzeugten menschlichen Plasmablasten und aktivierten B-Zellen

9-cis retinoic acid (9cRA) and 1,25-dihydroxyvitamin D3 (calcitriol) are the biological active forms of vitamin A and vitamin D respectively. Their mode of action is the direct activation of their nuclear hormone receptors – retinoic acid receptor (RAR) and vitamin D receptor (VDR). Activated RAR and VDR heterodimerize with retinoic X receptor (RXR), migrate into nucleus and bind as transcription factors to promoters of downstream response elements. Besides many homeostatic functions they have been identified to alter B cell development and function. Previous studies from M. Worm’s research group have revealed through transcriptome analysis of activated naïve B cells that 9cRA and calcitriol modulate the expression of genes involved in B cell homing and survival. The aim of this study was to gain a better understanding of how 9cRA and/or calcitriol in culture systems modulate the migration and survival of in vitro generated human plasmablasts (PBs) and activated B cells (aB cells). For this purpose, human naïve B cells were isolated by magnetic sorting and cultured in vitro with or without 9cRA ± calcitriol for differentiation into PBs and aB cells. RNA-sequencing revealed 9cRA + calcitriol primed PBs and aB cells from the PB culture exhibited enhanced expression of pro-survival genes. Consistent with previous studies, mass cytometry analysis revealed that 9cRA and calcitriol added to PB cultures directs the differentiation of naive B cells towards IgA+ PBs. With the help of in vitro migration assays, in vitro generated PBs and aB cells migrated towards BM abundant C-X-C motif chemokine ligand 12 (CXCL12) and gut abundant C-C motif chemokine ligand 25 (CCL25) in a dose-dependent manner. The cell migration towards CXCL12 was attributed to CXCR4 as incubation of cells with CXCR4 antagonist- AMD3100 (prior to migration assays) resulted in reduced migration. Cells from PB culture + 9cRA, demonstrated increased cell migration towards CXCL12 and CCL25, calcitriol addition individually to PB cultures did not impact PB ...