title: 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.
authors.affiliation: Section of Pharmacology, Toxicology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Pozzesi
authors.affiliation: Research Laboratories, Ospedale Pediatrico Bambino Gesù, Research Institute (IRCCS), Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Fierabracci
authors.affiliation: Section of Onco-Hematology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Liberati
authors.affiliation: Section of Hematology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: M P
authors.initials: MP
authors.lastname: Martelli
authors.affiliation: Section of Pharmacology, Toxicology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ayroldi
authors.affiliation: Section of Pharmacology, Toxicology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Riccardi
authors.affiliation: Section of Pharmacology, Toxicology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: D V
authors.initials: DV
authors.lastname: Delfino
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000378:metabolism*; D006801:Humans; D013950:Thymus Gland / Q000201:enzymology* / Q000502:physiology*
chemical_list: D053181:Caspase 8