Activation-induced apoptosis and cell surface expression of Fas (CD95) ligand are reciprocally regulated by retinoic acid receptor alpha and gamma and involve nur77 in T cells

It has been previously shown that CD4(+) T cells enter the apoptotic suicid e program via the Fas ligand (FasL)/Fas-mediated pathway upon T cell recept or (TCR) stimulation. In Jurkat cells TCR stimulation regulates the de novo synthesis of Fast, while in the influenza hemagglutinin-specific CD4(+) mu rine T cell hybridoma (IP-12-7) the cell surface appearance of a preformed Fast is initiated. Both processes are dependent on new mRNA and protein syn thesis, involve up-regulation of nur77, and can be inhibited by retinoic ac ids (RA). Two groups of nuclear receptors for RA have been identified: reti noic acid receptors (RAR) and retinoid X receptors (RXR). In this study var ious synthetic retinoids were used to define which receptors regulate TCR-m ediated apoptosis. It is demonstrated that the inhibition is mediated via R AR alpha, while RAR gamma enhances TCR-mediated apoptosis, and when both re ceptors are stimulated, the costimulation by RXR will promote the effect of RARa. Evidence is presented that these receptors affect the transcriptiona l activity of nur77 and consequently the expression of Fast. Our data sugge st a complex interaction between the various isoforms of retinoid receptors in regulating T cell death and demonstrate that the target through which r etinoids regulate TCR-mediated apoptosis is nur77.