Glucocorticoids inhibit activation-induced cell death (AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer

Abstract

Glucocorticoids (GCs IntroductionUpon triggering of their T-cell receptor (TCR), resting naive T lymphocytes are activated to elicit an immune response. In contrast, preactivated T cells undergo activation-induced cell death (AICD) in response to the same signal. [1][2][3] Apoptosis by AICD is an important mechanism to down-regulate the number of reactive T cells and to terminate the immune response. 4 The main apoptotic pathway of AICD is mediated by the CD95 (apoptosis antigen-1 [APO-1]/Fas) death receptor system since cell death by TCR restimulation can be blocked almost completely in the presence of reagents that inhibit CD95/CD95L interaction. 1-3 CD95 ligand (CD95L, CD178) is induced upon TCR/CD3 cross-linking and triggers CD95 signaling and subsequently apoptosis. 5 Deregulation of CD95L expression results in several diseases, such as autoimmunity and uncontrolled lymphoproliferation. [6][7][8] The transcriptional regulation of the CD95L promoter upon TCR/CD3 stimulation has been studied extensively. Various transcription factors and regulatory elements have been identified, such as several binding sites for nuclear factor of activated T cells (NF-AT), nuclear factor B (NF-B), activator protein 1 (AP-1), early growth response (Egr) protein, and interferon regulatory factor 1 (IRF-1). 9 The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that acts as a major modulator of the immune system due to its anti-inflammatory and immunosuppressive activities, thus serving a function that is frequently put to use in the treatment of autoimmune disorders, inflammatory diseases, and allergy. In the absence of ligand, the receptor is retained in the cytoplasm in an inactive state forming a large complex that includes chaperones. 10 Upon hormone binding, the GR dissociates from the cytoplasmic complex and translocates into the nucleus. Within the nucleus it acts as a transcriptional activator by binding as a homodimer with high affinity to glucocorticoid responsive DNA elements (GREs). In addition to enhancing the rate of transcription, the GR can also act as a transcriptional repressor by binding to different DNA sequences called negative GREs (nGREs). 11,12 Besides direct DNA binding, the GR can also modulate transcription as a monomer via protein-protein interactions as documented by repressive effects on AP-1 and NF-B 13-15 and activation of signal transducer and activator of transcription 5 (Stat-5). 16 Glucocorticoid (GC) hormones exert their potent antiinflammatory action mainly by inhibition of cytokine gene expression, and hence effectively block the activation of the immune system. 15,17,18 In addition, GCs are potent inducers of apoptosis in thymocytes and in some T-cell hybridomas by DNA bindingdependent transcriptional regulation, whereas peripheral T cells are only weakly sensitive toward GC-induced cell death. Although both GC and TCR stimulation can induce apoptosis in T-cell hybridomas, surprisingly, cell death is strongly reduced when both stimuli are provided simultaneously. 19...

Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death

“…This was notable because adult human T cells take 5 to 6 days to reach a plateau of CD95 expression (data not shown). However, murine T cells were also sensitized toward CD95L faster than adult T cells after TCR stimulation, 24 which suggests that naive human cord blood T cells share similarities with murine T cells. Simultaneous FACS analysis of memory cell markers during the in vitro stimulation of cord blood T regs revealed that CD45RO increased more gradually than CD95 ( Figure 5B) and that CD45RA and CD31 were gradually lost until day 6 (data not shown).…”

Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

“…Glucocorticoids have been hypothesized to have multiple roles from directing selection processes in T-cell maturation 1 and molding the T-cell repertoire 2 to regulating thymocyte apoptosis following polyclonal T-cell activation. 29 However, the central requirement for de novo gene expression in glucocorticoidmediated apoptosis of thymocytes is clearly established. 4,5 Using DNA microarrays, we identified genes upregulated in primary thymocytes on exposure to the glucocorticoid, dexamethasone.…”

Involvement of the intrinsic and extrinsic cell‐death pathways in the induction of apoptosis of mature lymphocytes by the Escherichia coli heat‐labile enterotoxin

“…In fact, the activation-induced T-cell apoptosis, a phenomenon mediated by Fas/FasL interaction [17], is known to be inhibited in vitro by glucocorticoids through the downregulation of FasL expression in T cells [18,19]. This effect is controlled by the binding of ligand-bound glucocorticoid receptor to a negative glucocorticoid regulatory element within the fasL promoter [20,21]. This site overlaps with a NFkBbinding site, establishing a competition between ligand-bound glucocorticoid receptor and NFkB for the regulation of FasL expression [21].…”