Coordinate regulation of autophagy and apoptosis in T cells by death effectors: FADD or foundation.
During an immune response, specific recognition of microbial and tumor antigens leads to the rapid proliferation of lymphocytes. Once the immunological challenge is eliminated, the vast majority of these lymphocytes must be removed via apoptosis. Cell death is also vital for the deletion of autoreactive or chronically activated lymphocytes to prevent the development of autoimmunity in the host. Such processes are highly dependent on death receptors (DRs), molecules of the TNF receptor family. While these DRs promote apoptosis, interference with DR signaling paradoxically interferes with rapid lymphocyte proliferation. Recently, we discovered that T cells lacking Fas-Associated protein with Death Domain (FADD) or caspase-8 (casp8) function, both essential for DR-induced apoptosis, succumb to hyperactivation of autophagy and die through a nonapoptotic form of cell death rather than proliferating after mitogen stimulation. We observed recruitment of FADD, casp8 and serine/threonine kinase RIPK1 to complexes containing Atg5, Atg12 and Atg16L, suggesting that the generation of early autophagosomes leads to the assembly of complexes that activate casp8. Because blockade of RIPK1 or interference with autophagic signaling inhibited this alternative death process, we propose that hyperactive autophagy induced in the absence of caspase activity leads to a necrosis-like form of death that depends on RIPK1 enzymatic function. Herein, we summarize these findings and speculate on the significance and means by which autophagy is normally activated in proliferating lymphocytes.
Bell
Bryan D
BD
Center for Immunology, Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, California 92697-3900, USA.
Walsh
Craig M
CM
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*
D053200:Fas-Associated Death Domain Protein; D011948:Receptors, Antigen, T-Cell