RETINOIC ACIDS REGULATE APOPTOSIS OF T-LYMPHOCYTES THROUGH AN INTERPLAY BETWEEN RAR AND RXR RECEPTORS

Vitamin A deficiency has been known for a long time to be accompanied with immune deficiency and susceptibility to a wide range of infectiou s diseases. Increasing evidence suggests that retinoic acids derived f rom vitamin A are involved in the functional regulation of the immune system. Of the two groups of retinoid receptors, retinoic acid recepto rs (RARs) and retinoid X receptors (RXRs) all-trans and 9-cis retinoic acids are high affinity ligands for RARs and 9-cis retinoic acid addi tionally binds to RXRs. In cells, at high concentrations, all-trans re tinoic acid can be converted to 9-cis retinoic acid by unknown mechani sms. Apoptosis plays a major role in shaping the T cell repertoire and one way in which retinoids may affect immune functions is to influenc e the various apoptosis pathways, Indeed, it has been shown that retin oic acids can induce apoptosis, increase the rate of dexamethasone-ind uced death and inhibit activation-induced death of thymocytes and T ly mphocytes. Therefore, retinoids together with glucocorticoids may be i nvolved in regulating positive and negative selection of T lymphocytes . Here we demonstrate that retinoids can induce apoptosis of T cells t hrough the stimulation of RAR gamma. Specific stimulation of RAR alpha , on the other hand, prevents both RAR gamma-dependent and TCR-mediate d cell death. In all these functions 9-cis retinoic acid proved to be more effective than all trans retinoic acid suggesting the involvement of RXRs, Based on these results a possible mechanism through which co stimulation of RARs and RXRs might affect spontaneous and activation-i nduced death of T lymphocytes is proposed.