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 antigenhi (HAShi 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.
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Abbreviations
- TEC:
-
thymic epithelial cell
- DP:
-
double positive
- TCR:
-
T-cell receptor
- mTEC:
-
medullary TEC
- DED:
-
death effector domain
- DISC:
-
death-inducing signaling complex
- cFLIP:
-
cellular FLICE inhibitory protein
- IAP:
-
inhibitor of apoptosis
- AIF:
-
apoptosis-inducing factor
- SP:
-
single positive
- NOD:
-
non-obese diabetic
- FAIM:
-
Fas apoptosis inhibitory molecule
- HDAC7:
-
histone deacetylase 7
- GC:
-
glucocorticoid
- GR:
-
GC receptor
- DEX:
-
dexamethasone
- MPS:
-
methylprednisolone
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Pozzesi, N., Fierabracci, A., Liberati, A. et al. Role of caspase-8 in thymus function. Cell Death Differ 21, 226–233 (2014). https://doi.org/10.1038/cdd.2013.166
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DOI: https://doi.org/10.1038/cdd.2013.166
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