Inhibition of activation-induced apoptosis of thymocytes by all-trans- and 9-cis-retinoic acid is mediated via retinoic acid receptor α

Abstract

Thymocytes can be induced to undergo apoptotic cell death by activation through the T-cell receptor (TCR). This process requires macromolecular synthesis and has been shown to be inhibited by retinoic acids (RAs). Two groups of nuclear receptors for RAs have been identified: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). All-trans-RA is the high-affinity ligand for RARs, and 9-cis-RA additionally binds to RXRs with high affinity. Because 9-cis-RA is much more potent in inhibiting TCR-mediated death than all-trans-RA, it was suggested that RXRs participate in the process. In the present study various synthetic retinoid analogues were used to address this question further. The results presented suggest that the inhibitory effect of RAs on activation-induced death of thymocytes is mediated via RARalpha, because (1) it can be reproduced by various RARalpha analogues both in vitro and in vivo, (2) the effect of RAs can be inhibited by the addition of an RARalpha antagonist, (3) CD4+CD8+thymocytes, which die on TCR stimulation, express RARalpha. Stimulation of RARgamma, in contrast, enhances the activation-induced death of thymocytes and inhibits its prevention by RARalpha stimulation. RXR co-stimulation suspends this inhibitory effect of RARgamma and permits the preventive function of RARalpha on activation-induced death. Our results suggest a complex interaction between the various isoforms of retinoid receptors and demonstrate that low (physiological) concentrations of all-trans-RA do not affect the activation-induced death of thymocytes because the RARalpha-mediated inhibitory and the RARgamma-mediated enhancing pathways are in balance, whereas if 9-cis-RA is formed, additional stimulation of RXRs permits the inhibitory action of RARalpha.

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

“…First, retinoids are known to regulate apoptosis in T lymphocytes, thymocytes, and T lymphoma cells (7,21,44). Second, in addition to promoting Th2 development, treatment with the RXR agonist AGN194204 during primary antigenic stimulation reproducibly caused a greater accumulation of viable cells after 1 wk of culture than did treatment with the vehicle control.…”

Retinoids induce Fas(CD95) ligand cell surface expression via RARγ and nur77 in T cells

“…Selective ligation of RAR § , on the other hand, inhibited negative selection [15,27] or activationinduced apoptosis of T cell hybridomas [13] and T lymphocytes from HIV-infected individuals [14,28]. It was also demonstrated that selective ligation of RAR § and RAR + affects the function and the expression of the nur77 transcription factor, an apoptosis-linked protein, respectively [13,15].…”

“…After the discovery of nuclear retinoid receptors and their ligands, and the demonstration of the expression of RAR § and RAR + in T cells [12,24], suggestions have been made that the active metabolites of vitamin A that mediate its effects on the immune system are the RA, including all-trans RA and 9-cis RA [25]. Indeed, RA were shown to promote T cell proliferation [24], and to affect apoptosis of T cells at various stages of their differentiation [12][13][14][15][26][27][28].…”

Depletion of lymphocytes, but not neutrophils, via apoptosis in a murine model of Vibrio vulnificus infection

“…DNA fragmentation was analysed as described previously with some modification (Szondy et al, 1998). Briefly, thymus and spleen tissues from the mice were gently glassground to dissociate the cells, and then suspended in cold Hanks' balanced salt solution (HBSS), which was then gently passed through a stainless steel mesh to obtain single-cell suspensions (thymocytes and splenocytes).…”