Retinoic acid and α-galactosylceramide regulate the expression of costimulatory receptors and transcription factors responsible for B cell activation and differentiation

Abstract

Mature naïve B cells possess a number of BCR coreceptors and other antigen receptors, including the MHC class I-like molecule CD1d, but little is known of the response of B cells to stimulation by the CD1d ligand, α-galactosylceramide (αGalCer). Previously, we showed that all-trans-retinoic acid (RA) increases the expression of CD1d and the magnitude of CD1d-mediated antibody production in vivo. Potential mechanisms could include changes in the expression of costimulatory molecules and transcription factors that regulate plasma cell formation. In the present study, we have used isolated purified B cells and in vivo studies to demonstrate that αGalCer and RA initiate a regulated expression of several genes essential for B cell activation and differentiation, such as Pax-5, Blimp-1, IRF-4 and activation-induced cytidine deaminase (Aid). Moreover, whereas αGalCer mainly increased the expression of Pax-5, CD40 and CD86 that are critical for B cell activation, RA predominantly increased CD138⁺ and Fas⁺-PNA⁺ B cells, which represent more advanced B cell differentiation. It is also noteworthy that αGalCer enriched a CD19hi subset of B cells, which represent B cells with more differentiated phenotype and higher potential for antibody production. In vivo, treatment with αGalCer enriched the CD19hi population, which, after sorting, produced more anti-TT IgG by ELISPOT assay. Together, our data demonstrate that RA and αGalCer can regulate B cell activation and differentiation at multiple levels in a complementary manner, facilitating the progress of B cells towards antibody secreting cells.

Keywords: AID; CD138; CD19; CD40; CD86; GC; IRF; Pax-5; RA; TT; activation induced deaminase; all-trans-retinoic acid; germinal center; interferon regulatory factor; tetanus toxoid; α-galactosylceramide; αGalCer.