Abstract
BackgroundTh2 cytokine responses are enhanced by all trans retinoic acid (ATRA), the bioavailable form of vitamin A. Retinoic acid receptor alpha (RARα) is the high affinity receptor for ATRA that mediates these pro-Th2 effects. We have previously characterized two major human Th2 subpopulations: IL-5- Th2 (IL-5-, IL-4+, IL-13+) and IL-5+ Th2 cells (IL-5+, IL-4+, IL-13+), which represent less and more highly differentiated Th2 cells, respectively. We hypothesized that the pro-Th2 effects of ATRA may differentially affect these Th2 subpopulations.MethodsSpecific cytokine producing Th2 subpopulations were identified using intracellular cytokine staining. Proliferation was measured using the Cell Trace Violet proliferation tracking dye. Apoptotic cells were identified using either annexin-V or active caspase 3 staining. Th2 gene expression was measured using quantitative polymerase chain reaction.ResultsATRA increased the output of Th2 cells from house dust mite allergen (HDM) specific short-term cell lines, and this enhancement was limited to the IL-5+ Th2 subpopulation. Conversely, the RARα antagonist Ro415253 decreased Th2 cell output from these cultures, and this effect was again limited to the IL-5+ Th2 subpopulation. ATRA and Ro415253 respectively augmented and inhibited Th2 cell proliferation, and this affect was more pronounced for the IL-5+ vs. IL-5- Th2 subpopulation. ATRA and Ro415253 respectively augmented and inhibited the expression of IL5 in a significant manner, which was not found for IL4 or IL13.ConclusionsWe report that the reciprocal regulation of Th2 cytokine expression and proliferation by RARα modulators are largely limited to modulation of IL-5 gene expression and to proliferation of the highly differentiated IL-5+ Th2 subpopulation. These results suggest that RARα antagonism is a potential means to therapeutically target allergic inflammation.Trial registrationClinicaltrials.gov identifier: NCT01212016
Highlights
Th2 cytokine responses are enhanced by all trans retinoic acid (ATRA), the bioavailable form of vitamin A
Cell Trace Violet (CTV) was used to track CD4+ house dust mite allergen (HDM)-specific memory Th2 cells, which were identified by gating on CTVlow cells that had proliferated in response to HDM antigen (Figure 1A)
The output of HDM-specific proliferated IL-5+ Th2 cells was dose-dependently enhanced by ATRA, and reciprocally suppressed by Ro41 (Figure 1C, D)
Summary
Th2 cytokine responses are enhanced by all trans retinoic acid (ATRA), the bioavailable form of vitamin A. Retinoic acid receptor alpha (RARα) is the high affinity receptor for ATRA that mediates these pro-Th2 effects. RA augments the differentiation of inducible T regulatory cells, which is abrogated both in vitro and in vivo in either vitamin A deficiency states or using retinoic acid receptor (RAR) deficient mice [5]. In vitamin A deficient mice, RA restores CD4+ T cell-mediated immunity, homeostasis, and activation [4,5]. Previous investigations suggest that retinoic acid receptor alpha (RARα) mediates these RA-induced effects on T cells [5,6,7,8]. ATRA exerts its bioactivity via binding to retinoic acid receptor ligand-activated transcription factors, and ATRA is a high-affinity ligand for retinoic acid receptor alpha (RARα). The RAR-RXR complex in turn binds to retinoic acid response elements (RARE) which are present in the promoters of RA responsive genes and result in gene activation [9]
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