Essential pro-survival role for caspase-8 during T-cell activation and embryonic development through inhibition of RIPK3-dependent necrosis (159.9)
Bibliographic record
Abstract
Abstract Caspase-8 is required for initiation of death receptor-mediated apoptosis, but counterintuitively is also required for normal T-cell proliferation and embryonic development. Recent work demonstrated that upon activation, caspase-8-deficient T cells fail to proliferate due to high rates of necroptosis, an alternative form of programmed cell death. To investigate these seemingly contradictory functions, we bred caspase-8 knockouts, which are embryonic lethal at E10.5, with necroptosis deficient RIPK3-/- animals. Unlike Casp8-/- animals, Casp8-/- RIPK3-/- double knockout (DKO) animals were generated at expected Mendelian frequencies and appeared grossly normal. DKO thymocytes responded normally to stimuli inducing intrinsic cell death, but resisted death induced by ligation of CD95. DKO animals, but not their normal littermates, were resistant to liver damage and death induced by injection of agonistic anti-Fas Ab Jo2. In contrast to casp8-/- T cells, DKO T cells proliferated normally in response to TCR ligation and displayed normal expansion and subsequent peripheral deletion in vivo when challenged with SEB. Interestingly, DKO animals display lymphoaccumulation of an aberrant B220+CD3+ population similar to that seen in gld or lpr mice. The survival of Casp8-/- RIPK3-/- mice and the normal proliferation of T cells from these animals point to an essential role for caspase-8 in limiting RIP3-dependent necrosis both during development and immune cell activation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".