9-cis Retinoic acid and 1.25-dihydroxyvitamin D3 drive differentiation into IgA+ secreting plasmablasts in human naive B cells

Calcitriol and 9-cis retinoic acid (9cRA) play a fundamental role in shaping the adaptive immune response by altering the Ig profile and the differentiation of B cells, controlled by their corresponding nuclear receptors, VDR and RAR. Herein, after the establishment of a plasmablast differentiation culture, we investigated how both ligands modulate human naive B cell differentiation and to which extent VDR/RXR and RAR/RXR signaling interferes. Calcitriol and 9cRA mediated activation of purified naive B cells resulted in a strong differentiation of CD27(+) CD38(+) plasmablasts and antibody secretion. The significant IgA response was preceded by a strong induction of alpha-germline transcription (GLT). Induction of alpha GLT and consecutively IgA secretion driven by calcitriol is a novel observation and we show by magnetic chromatin IP that this was mediated by recruitment of the VDR to the TGF-beta promoter thus inducing TGF-beta expression. Finally, as revealed by transcriptomic profiling calcitriol and 9cRA modulate several signals required for differentiation and isotype switching in a noncompeting but rather additive manner. Calcitriol and 9cRA participate in the control of the IgA response in human activated naive B cells. The balance between both ligands may be an important factor in channeling humoral immune responses toward a protective direction.