Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/13/2005
Publication Date: 9/13/2005
Citation: Rasooly, R., Schuster, G.U., Gregg, J.P., Xiao, J.H., Chandraratna, R., Stephensen, C.B. 2005. RETINOID X RECEPTOR AGONISTS INCREASE BCL2A1 EXPRESSION AND DECREASE APOPTOSIS OF NAÏVE T LYMPHOCYTES. Journal of Immunology. 175:7916-7929.
Interpretive Summary: The goal of this research is to describe how vitamin A, acting through its metabolites, affect T lymphocyte function. This work is important because vitamin A deficiency is known to increase mortality from common childhood infections but how this occurs is not known. In addition, intake of vitamin A and related nutrients may decrease the severity or risk of autoimmune disease or chronic inflammatory diseases. This work will thus help in determining recommendations for dietary intake of vitamin A.
Technical Abstract: The vitamin A metabolites all-trans and 9-cis retinoic acid regulate T lymphocyte growth, survival and Th1/Th2 development. Both retinoids regulate gene expression by binding to the retinoic acid receptor (RAR), while 9-cis retinoic acid also binds to the retinoid X receptor (RXR). Naïve DO11.10 T lymphocytes expressed mRNA and protein for RAR-a, RXR-a, and RXR-b. To identify RXR-responsive genes we performed DNA microarray analysis following primary antigenic stimulation and treatment with the RXR agonist AGN194204. A total of 128 genes were differentially expressed, including 16 (15%) involved in cell growth or apoptosis. Among these was Bcl2a1, an anti-apoptotic Bcl2 family member known to protect thymocytes and naïve T lymphocytes from apoptosis during antigenic stimulation. Quantitative real-time PCR analysis confirmed this finding. The RXR agonist 9-cis retinoic acid also increased Bcl2a1 expression, although all-trans retinoic acid and ligands for other RXR partner receptors did not. Treatment with AGN194204 and 9-cis retinoic acid significantly decreased apoptosis as measured by Annexin-V staining. As expected, Bcl2a1 mRNA expression was significantly lower in apoptotic than in non-apoptotic T lymphocytes. Treatment with these retinoids did not affect expression of the other anti-apoptotic Bcl2 family members Bcl2 and Bcl-XL. Bcl2a1 promoter activity was examined using a luciferase promoter-construct. Both AGN194204 and 9-cis retinoic acid significantly increased luciferase activity using this construct, confirming that these agonists can increase Bcl2a1 transcription. In summary, RXR-a and -b are expressed in naïve T lymphocytes, Bcl2a1 expression is increased by RXR agonists, and apoptosis is decreased by the same agonists. These findings suggest that RXR agonists enhance T lymphocyte survival by increasing Bcl2a1 transcription and thereby decreasing apoptosis.