Role of caspase-8 in thymus function

Abstract

The thymus is the primary organ responsible for de novo generation of immunocompetent T cells that have a diverse repertoire of antigen recognition. During the developmental process, 98% of thymocytes die by apoptosis. Thus apoptosis is a dominant process in the thymus and occurs through either death by neglect or negative selection or through induction by stress/aging. Caspase activation is an essential part of the general apoptosis mechanism, and data suggest that caspases may have a role in negative selection; however, it seems more probable that caspase-8 activation is involved in death by neglect, particularly in glucocorticoid-induced thymocyte apoptosis. Caspase-8 is active in double-positive (DP) thymocytes in vivo and can be activated in vitro in DP thymocytes by T-cell receptor (TCR) crosslinking to induce apoptosis. Caspase-8 is a proapoptotic member of the caspase family and is considered an initiator caspase, which is activated upon stimulation of a death receptor (e.g., Fas), recruitment of the adaptor molecule FADD, and recruitment and subsequent processing of procaspase-8. The main role of caspase-8 seems to be pro-apoptotic and, in this review, we will discuss about the involvement of caspase-8 in (1) TCR-triggered thymic apoptosis; (2) death receptor-mediated thymic apoptosis; and (3) glucocorticoid-induced thymic apoptosis. Regarding TCR triggering, caspase-8 is active in medullary, semi-mature heat-stable antigen hi (HAS hi SP) thymocytes as a consequence of strong TCR stimulation. The death receptors Fas, FADD, and FLIP are involved upstream of caspase-8 activation in apoptosis; whereas, Bid and HDAC7 are involved downstream of caspase-8. Finally, caspase-8 is involved in glucocortocoid-induced thymocyte apoptosis through an activation loop with the protein GILZ. GILZ activates caspase-8, promoting GILZ sumoylation and its protection from proteasomal degradation.

CD8 + CD122 + CD49d low regulatory T cells maintain T-cell homeostasis by killing activated T cells via Fas/FasL-mediated cytotoxicity

“…Molecular mechanisms after Fas activation have been thoroughly investigated, and the signal transduction pathway has been largely elucidated (9,10). However, research on the cellular events that use the Fas/FasL system has progressed comparatively slowly.…”

Pharmacological Modulation of Caspase-8 in Thymus-Related Medical Conditions

“…Glucocorticoids (GC) are well established inducers of apoptosis in the thymus. Caspase-8 has been implicated in this process (Pozzesi et al, 2014) along with Gilz, which is upregulated by GCs in thymocytes. Recently, Gilz has been demonstrated to be involved in regulating T-helper cell differentiation (Cannarile et al, 2009) and controlling malignant transformation through inhibition of Ras-driven tumorigenesis Riccardi, 2009, 2012).…”

“…1). Additionally, thymocyte apoptosis can be triggered by exogenous molecules, such as glucocorticoids, which can lead to atrophy (Pozzesi et al, 2014).…”

“…The death receptors-Fas, FADD, Fas apoptotic inhibitory molecule (Huo et al, 2009), and FADD-like IL1b-converting enzyme inhibitory protein (FLIP)-are involved upstream of caspase-8 activation, whereas BH3 interacting domain death agonist (Bid) and HDAC7 are activated downstream. Finally, caspase-8 has been linked to the protein glucocorticoid-induced leucine zipper (Gilz) in mediating glucocorticoid-induced thymocyte apoptosis (Pozzesi et al, 2014).…”

Triptolide Protects Neurons from Endoplasmic Reticulum Stress-Mediated Apoptosis in Cerebral Ischemic Injury Rats

“…Caspases are a family of cysteine proteases and activated by apoptotic stimuli [12]. Cysteinyl aspartate specific proteinase 8 (Caspase-8) is an initiator caspase in ER stress-induced apoptosis [13,14]. The activation of caspase-8 requires its association with Fas-associated death domain (FADD) [15,16].…”