Activated Notch1 Redirects CD4-Fated CD4 <sup>+</sup> CD8 <sup>+</sup> Precursors to the CD8 Lineage During Thymocyte Selection Without Causing T Cell Leukemia
Bibliographic record
Abstract
ABSTRACT Positive selection of CD4/CD8 double-positive (DP) thymocytes generates helper and cytotoxic T lineages whose CD4 or CD8 co-receptor expression matches their αβ T cell receptor (TCRαβ) specificity MHCII or MHCI, respectively. Notch1 signaling is critical for early T cell development and was suggested to regulate CD4/CD8 lineage determination during DP thymocyte selection. However, early studies expressing activated Notch1 in pre-DP progenitors did not resolve this question. Here we showed that CD4-Cre-mediated activation of canonical Rbpj -dependent Notch1 signalling potently skews DP selection to the CD8 lineage. We used a tamoxifen-inducible “time-stamp” model coupled with phenotypic staging to show that that activated Notch1 decreases generation of Gata3 + CD4 + CD8 lo selection intermediates during the earliest stages of DP selection, thereby preventing ThPOK induction and emergence of CD4 lineage cells. Finally, activated Notch1 efficiently re-directed DP thymocytes expressing MHCII-specific TCRαβ into the CD8 lineage. These studies show that activated Notch1 acts early during DP selection to skew selection of CD4-fated, MHCII-specific DP precursors to the CD8 lineage.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.002 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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; both teacher heads agree on what is shown here.
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".