Role of USP7 in the regulation of tolerogenic dendritic cell function in type 1 diabetes
Bibliographic record
Abstract
BACKGROUND: Tolerogenic dendritic cells (toDCs) are critical for maintaining immune homeostasis and preventing autoimmune disease development, such as type 1 diabetes (T1D). We have previously shown that DCs of non-obese diabetic (NOD) mice expressing active Stat5b (Stat5b-CA.DCs) acquire toDCs signature and protect against diabetes. However, the mechanisms involved in reprogramming DCs to adopt tolerogenic or immunogenic signatures are not fully known. This study investigates for the first time the role of USP7 in DC-mediated immune regulation in T1D using a transgenic NOD mouse model expressing an active form of Stat5b (NOD.Stat5b-CA). METHODS: Splenic DCs were purified from diabetes-prone NOD mice and diabetes-resistant NOD.Stat5b-CA transgenic mice and their tolerogenic and immunogenic phenotypes were analyzed by FACS. Their pro-and anti-inflammatory cytokine patterns, IRF4, IRF8, de-ubiquitin ligase USP7, and methyltransferase Ezh2 expression were assessed by FACS and Western blot. Moreover, the impact of USP7 inhibition in DCs on Th1/Th2/Th17 and Treg and diabetes onset was assessed using an in vivo DC-based transfer model. RESULTS: In this study, we found that splenic Stat5b-CA.DCs expressed high levels of USP7, Ezh2, and PD-L-1/2 and contained a higher proportion of tolerogenic conventional DC2 (cDC2) subsets than immunogenic cDC1 compared to NOD mice DCs. We also found that the USP7 blockade increased Stat5b-CA.DCs maturation and proinflammatory cytokines production while decreasing anti-inflammatory cytokines and PD-L1 and PD-L2 expressions. Mechanistically, USP7 blockade in Stat5-CA.DCs promoted cDC1 over cDC2 subsets by increasing IRF8 expression in an Ezh2-dependent manner and decreasing IRF4 expression independently of Ezh2. USP7 blockade also increased Stat5b-CA.DC capacity to promote Th17 and to restrain Th2 and Treg cells. Importantly, the capacity of Stat5b-CA.DCs to protect NOD mice from diabetes were lost when treated with USP7 inhibitor. CONCLUSIONS: Our findings underscore the role of the USP7/Ezh2 axis in maintaining tolerogenic DC functions that are required to tailor adaptive immune response and diabetes protection in NOD mice.
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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 | 0.000 | 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 | 0.000 |
| 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".