The role of Notch signaling during alphabeta and gammadelta T cell lineage commitment and differentiation
Bibliographic record
Abstract
The requirement for thymus-derived factors in supporting thymocyte differentiation are increasingly being appreciated, however, their precise role and mechanism of action remain to be elucidated. Notch receptor-ligand interactions are indispensable for T lineage specification, yet the requirement for Notch signals at later stages in T cell development are still under investigation. In this work, the role of Notch-ligand interactions during alphabeta and gammadelta T cell lineage commitment is delineated. This is accomplished by employing an in vitro T cell differentiation system in which the availability of Notch ligand Delta-like 1 (Dll1) and the precise timing of T cell receptor (TCR) expression (pre-TCR or gammadeltaTCR) and thus, developmental transition, are controlled. Expression of the pre-TCR defines a critical developmental checkpoint termed beta-selection. This work uncovers an obligatory cooperation between Notch and pre-TCR-mediated signals for the functional outcomes of beta-selection including proliferation, rescue from apoptosis, and developmental progression. The necessity for Notch signals at this checkpoint reflects, in part, its role in promoting pre-TCR-independent pre-T cell survival through the maintenance of glucose metabolism. In this regard, the trophic effects of Notch signaling are mediated by the phosphatidylinositol-3-kinase/Akt pathway, such that the expression of active Akt substitutes for Notch during beta-selection. This role for Notch likely anticipates the bioenergetic demands associated with pre-TCR-triggered proliferation and differentiation. Notably, whereas Notch-ligand interaction is indispensable for alphabeta development, irrespective of the inductive TCR complex, gammadelta T cell differentiation can occur effectively in the absence of Notch signals from T lineage committed progenitors once gammadeltaTCR expression is attained. The work in this Thesis also provides insight into the role of Notch signals during alphabeta versus gammadelta T cell lineage decision, which has remained controversial. Employing progenitor frequency analysis encompassing clonal assays, it is now clear that Notch-Dll1 interactions do not mediate a binary fate decision. Moreover, this work positions the alphabeta/gammadelta lineage bifurcation to the DN3 stage and underscores the central role of TCR complex formation in T cell lineage commitment. Collectively, this Thesis elucidates the role of Notch signals at a critical checkpoint in T cell development where commitment to the alphabeta and gammadelta lineages occurs.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 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 | 0.001 | 0.000 |
| 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; a candidate call from one teacher head, 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".