Cellular retinoic acid binding protein 2 (CRABP2) serves as a critical regulator in immune regulation and inflammation

Abstract Retinoic acid (RA) is a metabolite of Vitamin A, which plays anti-inflammatory roles by ligating and transactivating nuclear RA receptors that control gene expression and cell differentiation. Cellular retinoic acid binding protein 2 (CRABP2) binds to and transports RA from the cytoplasm to the nucleus. Because of its direct interaction with RARs bound to retinoic acid responsive elements (RARE) in the promoters of RA target genes, CRABP2 specifically channels RA to chromatin-bound nuclear receptors, which then mediate transcriptional activation and expression of RA target genes. CRABP2 is not expressed in naïve T cells, but strongly induced in response to T cell receptor (TCR) signaling. Consequently, activated T cells from CRABP2 KO animals show reduced RARE-luciferase reporter activity, indicating that TCR-induced CRABP2 controls gene transcription and expression in activated T cells. In CD4 T cells we showed before that RA promotes the generation of Foxp3 Tregs and reciprocally suppresses the generation of Th17 cells. Consistent with that, CRABP2 KO mice show a marked reduction of Tregs in the periphery. In the absence of RA, CRABP2 remains in the cytoplasm where it functions in a non-genomic fashion and enhances expression of inflammatory cytokines. In biopsies from patients with various autoimmune diseases, inflammatory CD4 T cells with enhanced expression of CRABP2 accumulate whereas expression of RA target gene is reduced. These findings point at genomic versus non-genomic CRABP2 as an important regulator of the reciprocal generation of Tregs versus inflammatory Th17 cells. Defects in the regulation by activation-induced CRABP2 may form an important underlying cause in autoimmune and other inflammatory diseases.