Inflammation-Driven Reprogramming of CD4+Foxp3+ Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo
Bibliographic record
Abstract
While natural CD4(+)Foxp3(+) regulatory T (nT(REG)) cells have long been viewed as a stable and distinct lineage that is committed to suppressive functions in vivo, recent evidence supporting this notion remains highly controversial. We sought to determine whether Foxp3 expression and the nT(REG) cell phenotype are stable in vivo and modulated by the inflammatory microenvironment. Here, we show that Foxp3(+) nT(REG) cells from thymic or peripheral lymphoid organs reveal extensive functional plasticity in vivo. We show that nT(REG) cells readily lose Foxp3 expression, destabilizing their phenotype, in turn, enabling them to reprogram into Th1 and Th17 effector cells. nT(REG) cell reprogramming is a characteristic of the entire Foxp3(+) nT(REG) population and the stable Foxp3(NEG) T(REG) cell phenotype is associated with a methylated foxp3 promoter. The extent of nT(REG) cell reprogramming is modulated by the presence of effector T cell-mediated signals, and occurs independently of variation in IL-2 production in vivo. Moreover, the gut microenvironment or parasitic infection favours the reprogramming of Foxp3(+) T(REG) cells into effector T cells and promotes host immunity. IL-17 is predominantly produced by reprogrammed Foxp3(+) nT(REG) cells, and precedes Foxp3 down-regulation, a process accentuated in mesenteric sites. Lastly, mTOR inhibition with the immunosuppressive drug, rapamycin, stabilizes Foxp3 expression in T(REG) cells and strongly inhibits IL-17 but not RORγt expression in reprogrammed Foxp3(-) T(REG) cells. Overall, inflammatory signals modulate mTOR signalling and influence the stability of the Foxp3(+) nT(REG) cell phenotype.
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) | 0.001 | 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) | 0.001 | 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".