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Title: Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes

Author
item Dawson, Harry
item COLLINS, GARY - GRC,NIA,NIH,BALTIMORE MD
item PYLE, ROBERT - GRC,NIA,NIH,BALTIMORE MD
item KEY, MICHAEL - GRC,NIA,NIH,BALTIMRORE MD
item WEERARATNA, ASHANI - GRC,NIA,NIH,BALTIMORE MD
item DEEP-DIXIT, VISHWA - GRC,NIA,NIH,BALTIMORE MD
item NADAL, CELESTE - COLLEGE OF MED,U OF FL
item TAUB, DENNIS - GRC,NIA,NIH,BALTIMORE, MD

Submitted to: BMC Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/21/2006
Publication Date: 11/21/2006
Citation: Dawson, H.D., Collins, G., Pyle, R., Key, M., Weeraratna, A., Deep-Dixit, V., Nadal, C.N., Taub, D.D. 2006. Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes. BioMed Central (BMC) Immunology. 7:27.

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, and the inhibition of a Th1-related cytokine IFN-g upon treatment of human T cells with either all trans retinoic acid (ATRA) or 9-cis-RA. In addition, we refined the description of immune signaling and cytokine requirements for these cells. 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: Vitamin A (VA) deficiency induces a type 1 cytokine response and exogenously provided retinoids can induce a type 2 cytokine response both in vitro and in vivo. The precise mechanism(s) involved in this phenotypic switch are inconsistent and have been poorly characterized in humans. In an effort to determine if retinoids are capable of inducing Th2 cytokine responses in human T cell cultures, we stimulated human PBMC with immobilized anti-CD3 mAb in the presence or absence of all-trans retinoic acid (ATRA) or 9-cis-RA. Stimulation of PBMC, T cells and T cell subsets with ATRA and 9-cis-RA increased mRNA and protein levels of IL-4, IL-5, and IL-13 and decreased levels of IFN-g, IL-2, IL-12p70 and TNF-a upon activation with anti-CD3 and/or anti-CD28 mAbs. These effects were dose-dependent and evident as early as 12 hr post stimulation. In the absence of anti-CD28-costimulation, ATRA exhibited little to no effect on T cell-derived IFN-g synthesis; however, increased levels of IL-4 and IL-5 were still observed. Moreover, retinoid-induced changes in Th1 and Th2 cytokine production persisted in secondary cultures and T cell clones previously skewed toward type 1 or 2 responses. Real time RT-PCR analysis revealed a dampened expression of the Th1-associated gene, T-bet, and a time-dependent increase in the mRNA for the Th2-associated genes, GATA-3, c-MAF and STAT6, upon treatment with ATRA. Besides Th1 and Th2 cytokines, a number of additional pro inflammatory and regulatory cytokines including several chemokines were also differentially regulated by ATRA treatment. These data provide strong evidence for multiple inductive roles for retinoids in the development of human type-2 cytokine responses.