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 suicide program via the Fas ligand (FasL) Fas-mediated pathway upon T cell receptor (TCR) stimulation. In Jurkat cells TCR stimulation regulates the de novo synthesis of Fast, while in the influenza hemagglutinin-specific CD4(+) murine 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 synthesis, involve up-regulation of nur77, and can be inhibited by retinoic acids (RA). Two groups of nuclear receptors for RA have been identified: retinoic acid receptors (RAR) and retinoid X receptors (RXR). In this study various synthetic retinoids were used to define which receptors regulate TCR-mediated apoptosis. It is demonstrated that the inhibition is mediated via RAR alpha, while RAR gamma enhances TCR-mediated apoptosis, and when both receptors are stimulated, the costimulation by RXR will promote the effect of RARa. Evidence is presented that these receptors affect the transcriptional activity of nur77 and consequently the expression of Fast. Our data suggest a complex interaction between the various isoforms of retinoid receptors in regulating T cell death and demonstrate that the target through which retinoids regulate TCR-mediated apoptosis is nur77.It has been previously shown that CD4(+) T cells enter the apoptotic suicide program via the Fas ligand (FasL) Fas-mediated pathway upon T cell receptor (TCR) stimulation. In Jurkat cells TCR stimulation regulates the de novo synthesis of Fast, while in the influenza hemagglutinin-specific CD4(+) murine 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 synthesis, involve up-regulation of nur77, and can be inhibited by retinoic acids (RA). Two groups of nuclear receptors for RA have been identified: retinoic acid receptors (RAR) and retinoid X receptors (RXR). In this study various synthetic retinoids were used to define which receptors regulate TCR-mediated apoptosis. It is demonstrated that the inhibition is mediated via RAR alpha, while RAR gamma enhances TCR-mediated apoptosis, and when both receptors are stimulated, the costimulation by RXR will promote the effect of RARa. Evidence is presented that these receptors affect the transcriptional activity of nur77 and consequently the expression of Fast. Our data suggest a complex interaction between the various isoforms of retinoid receptors in regulating T cell death and demonstrate that the target through which retinoids regulate TCR-mediated apoptosis is nur77.