Cell-extrinsic mechanism of CTLA4-mediated regulation of dendritic cell maturation depends on STAT3 (P1202)
Bibliographic record
Abstract
Abstract The role of cytotoxic T lymphocyte antigen 4 (CTLA4) in hampering immune responses has been well documented; however, the exact mechanism by which CTLA4 exerts its effect is still under debate. Here, we investigated whether CTLA4 signal alone is sufficient to inhibit dendrtic cell (DC) maturation, stimulatory function, and the molecular mechanisms involved. We demonstrate that stimulation of DCs with CTLA4, either expressed by inducible regulatory T cells (iTregs) or by cross-linking with CTLA4Fc fusion protein, is sufficient to inhibit LPS-induced maturation of both mouse and human DCs. The CTLA4 signaling significantly decreased DC CD80 and CD86 expression as determined by flow cytometry, real-time PCR and Western blot analyses. Importantly, CTLA4Fc-treated DCs had reduced ability to stimulate T cell proliferation and cytokine production in both syngeneic and allogeneic settings. Furthermore, we identified a novel reverse signaling pathway that is dependent on direct activation of STAT3 in DCs and subsequent suppression of NFκB activity. Our data demonstrate, for the first time, that a reverse signal induced by CTLA4 is sufficient to suppress LPS-induced DC maturation and function. This work opens new windows for generation of tolerogenic DCs that could ultimately be used for treating autoimmune diseases and transplant rejection.
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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) | 0.002 | 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".