Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis.
Cell death is an important mechanism to limit uncontrolled T-cell expansion during immune responses. Given the role of death-receptor adapter protein Fas-associated death domain (FADD) in apoptosis, it is intriguing that T-cell receptor (TCR)-induced proliferation is blocked in FADD-defective T cells. Necroptosis is an alternate form of death that can be induced by death receptors and is linked to autophagy. It requires the death domain-containing kinase RIP1 and, in certain instances, RIP3. FADD and its apoptotic partner, Caspase-8, have also been implicated in necroptosis. To accurately assess the role of FADD in mature T-cell proliferation and death, we generated a conditional T-cell-specific FADD knockout mouse strain. The T cells of these mice develop normally, but lack FADD at the mature stage. FADD-deficient T cells respond poorly to TCR triggering, exhibit slow cell cycle entry, and fail to expand over time. We find that programmed necrosis occurs during the late stage of normal T-cell proliferation and that this process is greatly amplified in FADD-deficient T cells. Inhibition of necroptosis using an inhibitor of RIP1 kinase activity rescues the FADD knockout proliferative defect. However, TCR-induced necroptosis did not appear to require autophagy or involve RIP3. Consistent with their defective CD8 T-cell response, these mice succumb to Toxoplasma gondii infection more readily than wild-type mice. We conclude that FADD constitutes a mechanism to keep TCR-induced programmed necrotic signaling in check during early phases of T-cell clonal expansion.
Osborn
Stephanie L
SL
Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Diehl
Gretchen
G
Han
Seong-Ji
SJ
Xue
Ling
L
Kurd
Nadia
N
Hsieh
Kristina
K
Cado
Dragana
D
Robey
Ellen A
EA
Winoto
Astar
A
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001343:Autophagy; D053181:Caspase 8 / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D004198:Disease Susceptibility; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D009336:Necrosis / Q000276:immunology*; D010641:Phenotype; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000276:immunology / Q000469:parasitology
D053200:Fas-Associated Death Domain Protein; D011948:Receptors, Antigen, T-Cell; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; D053181:Caspase 8