Submitted to: BioMed Central (BMC) Immunology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 4/16/2008
Publication Date: 4/16/2008
Citation: Dawson, H.D., Collins, G., Pyle, R., Key, M., Taub, D. 2008. The retinoic acid receptor-a mediates human T-cell activation and Th2 cytokine production. BioMed Central (BMC) Immunology. 169(4):16-30. Interpretive Summary: The CD4+ T cell represents a population of lymphocytes that regulate acquired immunity in mammals. These cells differentiate into sub-populations (Th1 cells and Th2 cells) and express a particular pattern of cytokines that orchestrate appropriate protective responses to intracellular and extra cellular pathogens, respectively. A skewing of the immune response toward a Th1 phenotype has been consistently observed in vitamin A (VA) deficient mice. Conversely, a skewing of the immune response toward a Th2 phenotype accompanies VA or retinoic acid (RA) administration to mice; however data describing potential mechanisms for these phenomena are often contradictory. Furthermore, species differences limit extrapolation of data on experimental interaction between nutrition and immunology from mice to humans. In the current study, we have described induction of the expression of the Th2-related cytokines, IL-4, IL-5, and IL-13, increased expression of the T cell activation markers CD69 and CD38 and the inhibition of the Th1-related cytokine IFN-g upon treatment of human T cells or peripheral blood mononuclear cells with either all trans retinoic acid (ATRA), 9-cis-RA or a synthetic compound, Am-580 that binds to one of six receptors for retinoic acids, RAR-a. These effects were not observed to the same extent for 13-cis-RA or another synthetic compound, 4-HPR, that binds to different retinoic acid receptors (RAR-b or RAR-g). Furthermore, an antagonist for the RAR-a receptor partially blocked the effects of ATRA on these parameters. A better understanding of the mechanisms involved in the human Th2-related cytokine promoting activity of ATRA and 9-cis-RA is likely to provide information on how vitamin A is able to maintain protective responses to pathogens, modify vaccine efficacy to certain antigens ,or influence various types of pro-inflammatory and autoimmune pathologies.
Technical Abstract: We have recently demonstrated that all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cis RA) promote IL-4, IL-5 and IL-13 synthesis, while decreasing IFN-g and TNF-a expression by activated human T cells and reducing the synthesis of IL-12p70 from accessory cells. Here, we have demonstrated that the observed effects using ATRA and 9-cis RA are shared with the clinically useful RAR ligand, 13-cis retinoic acid (13-cis RA), and the retinoic acid receptor-a (RAR-a)-selective agonist, AM580, but not with the RAR-b/g ligand, 4-hydroxyphenylretinamide (4-HPR). The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers, CD69 and CD38. The RAR-a-selective agonist, AM580, recapitulated all of the T cell activation and type 2 cytokine-inducing effects of ATRA and 9-cis-RA, while the RAR-a-selective antagonist, RO 41-5253, inhibited these retinoid effects. These results strongly support a role for RAR-a engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production.