9���cis Retinoic acid and 1.25���dihydroxyvitamin D 3 drive differentiation into IgA + secreting plasmablasts in human na��ve 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 na��ve B cell differentiation and to which extent VDR/RXR and RAR/RXR signaling interferes. Calcitriol and 9cRA mediated activation of purified na��ve 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 ��-germline transcription (GLT). Induction of ��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-�� promoter thus inducing TGF-�� 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 na��ve B cells. The balance between both ligands may be an important factor in channeling humoral immune responses toward a protective direction.