Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors

The vitamin A metabolite, retinoic acid (RA), affects T(h)1 and T(h)2 development. The effect is partly exerted through the modulation of antigen-presenting cell functions, but it remains unclear whether RA directly exerts its effect on T cells to influence T(h)1/T(h)2 development. To clarify this problem, we used two experimental systems with isolated T cells in vitro. In one system, isolated CD4(+)CD8(+) thymocytes differentiated into T(h)1 and T(h)2 by two transient stimulations with defined combinations of ionomycin and phorbol myristate acetate followed by treatment with IL-2 and IL-4 and/or IL-12. In the second system, functional differentiation was induced in purified naive CD4 T cells from DO-11.10 TCR-transgenic and RAG-2-deficient mice with cytokines and antibodies to CD3 and CD28. In both systems, all-trans-RA at greater than or equal to1 nM concentrations suppressed T(h)1 development, but enhanced T(h)2 development. 9-cis-RA elicited similar effects. The optimal enhancement of T(h)2 development in the second system, however, was achieved with a delayed addition of RA. The presence of RA during the initial stimulation period often suppressed T(h)2 development. The RA receptor (RAR) antagonists, LE540 and LE135, but not the retinoic X receptor (RXR) antagonist, PA452, inhibited the effect of RA on T(h)1/T(h)2 development. Accordingly, the RAR agonists, Am80 and Tp80, but not the RXR agonists, HX600 and TZ335, mimicked the effect of RA. The RXR agonists enhanced the effect of the RAR agonists only slightly, if at all. These results indicate that, via RAR, RA directly suppresses T(h)1 development and directly enhances T(h)2 development with its timely addition.