Microbiota‐Dependent Involvement of Th17 Cells in Murine Models of Inflammatory Arthritis
Bibliographic record
Abstract
Objective Intestinal microbiota are associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine whether the presence of Th17 cells, beyond involvement of the cytokine interleukin‐17 ( IL ‐17), is required for arthritis development, and whether the involvement of Th17 cells in arthritis depends on the composition of the host microbiota. Methods Mucosal T cell production of IL ‐17, interferon‐γ, tumor necrosis factor α ( TNF α), IL ‐22, and granulocyte–macrophage colony‐stimulating factor ( GM ‐ CSF ) was analyzed by flow cytometry and Luminex assay before arthritis onset in mice immunized to develop collagen‐induced arthritis ( CIA ). Pathogenic features of arthritis in mice with CIA and mice with antigen‐induced arthritis were compared between Th17 cell–deficient ( CD 4‐Cre + Rorc flox/flox ) and Th17 cell–sufficient ( CD 4‐Cre − Rorc flox/flox ) mice. In addition, the impact of intestinal microbiota on the Th17 cell dependence of CIA was assessed. Results Lamina propria CD 4 T cells were activated before the onset of arthritis in mice with CIA , with marked up‐regulation of several cytokines, including IL ‐17A, TNF α, and GM ‐ CSF . CD 4‐Cre + Rorc flox/flox mice showed a specific reduction in intestinal mucosal levels of Th17 cells and partially reduced levels of IL ‐17–producing CD 8 T cells. However, total levels of IL ‐17A, mostly produced by γδ T cells and neutrophils, were unaffected. The severity of arthritis was significantly reduced in Th17 cell–deficient mice, suggesting that Th17 cells have additional, IL ‐17A–independent roles in inflammatory arthritis. Accordingly, antigen‐stimulated T cells from Th17 cell–deficient mice produced less IL ‐17A, IL ‐17F, and GM ‐ CSF . Importantly, the dependence of CIA on the involvement of Th17 cells was mitigated in the presence of an alternative microbiome. Conclusion These data from murine models suggest that activation of mucosal immunity precedes the development of arthritis, and also that Th17 cells have a microbiota‐dependent role in arthritis. Therefore, a microbiome‐guided stratification of patients might improve the efficacy of Th17‐targeted therapies.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".