A37 DEFECTS IN INTESTINAL MUCUS DISRUPTS THE REPERTOIRE OF DEVELOPING T CELLS IN THE THYMUS
Bibliographic record
Abstract
Severe, chronic inflammation of the intestinal tract is a defining hallmark of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease. IBD is postulated to result from a complex combination of environmental and genetic factors that lead to excessive bacterial stimulation of the mucosal immune system. An overlying layer of mucus functions to segregate contents of the intestinal lumen from the intestinal epithelium and the underlying immune system. Importantly, decreased mucus production and impaired mucus function have been associated with UC pathogenesis. MUC2 is the primary intestinal mucin and acts as a structural scaffold for mucus formation - forming a physical barrier to shield the intestinal wall. However, recent work suggests that mucus may also function to maintain immunological tolerance towards luminal antigens by promoting the regulatory activity of intestinal antigen-presenting cells. Currently, it is unclear what role mucus plays in influencing the T cell repertoire and modulating T cell immunity both at local and distal sites. We hypothesize that mucus is essential for maintaining T cell tolerance towards intestinal luminal antigens and preventing disease caused by constitutive T cell activation. To investigate whether peripheral T cells become highly activated in young, mildly colitic Muc2-/- mice following oral antigen gavage. To test our hypothesis, young (6–10 week old) wild type and MUC2-deficient (Muc2-/-) mice were gavaged with the model antigen ovalbumin (OVA) and the elicited OVA-specific T cell responses monitored at various time points post-treatment. We found that oral administration of OVA resulted in the antigen rapidly escaping the gut and disseminating throughout the blood and lymphoid tissues of Muc2-/- but not wild type mice. Given the systemic spread of antigen in the Muc2-/- mice, we next sought to investigate whether the selection of developing T cells in the thymus of Muc2-/- mice was impacted by dietary antigens. Remarkably, we found that gavage of Muc2-/- mice led to presentation of OVA by thymic dendritic cells and the deletion of OVA-specific thymocytes whereas T cell development in wild type mice appeared unaffected. Based on our results, we concluded that oral antigens are rapidly disseminated throughout Muc2-/- mice. The heightened concentration of oral antigens induced rapid depletion of oral antigen-specific double positive (DP) thymocytes, and altered the T cell repertoire. Future studies will explore whether IBD patients suffering from impaired gut mucus structure/function also suffer defects in their T cell repertoires. CIHR
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".