TLR9 Signaling Failure Renders Peyer’s Patch Regulatory B Cells Unresponsive to Stimulation with CpG Oligodeoxynucleotides
Why this work is in the frame
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Bibliographic record
Abstract
Intestinal Peyer's patch (PP) regulatory CD21+ B cells (B(regs)) suppress TLR9-induced innate immune responses. However, it is not known whether TLR9 activation is regulated in PP B(regs). Here, we investigated the responses of PP B(regs) to stimulation with the TLR9 agonist CpG oligodeoxynucleotides (ODN). We observed that PP CD21+ B(regs) express high levels of TLR9 mRNA, but fail to proliferate when stimulated with CpG ODN. Furthermore, unlike CD21+ B cells from blood, PP CD21+ B(regs) do not secrete IgM or IL-12 following CpG ODN stimulation. We hypothesized that the unresponsiveness of PP B(regs) to CpG stimulation was due to an inability of the TLR9 agonist to activate the TLR9 signaling pathway in these cells. This was confirmed by kinome analysis which demonstrated dynamic patterns of phosphorylation of key TLR adaptor proteins such as IRAK1, TAK1, IKK and NF-kappaB-p65 in CpG-stimulated blood CD21+ B cells, consistent with activation of the TLR9 pathway. In contrast, stimulation of PP CD21+ B(regs) with CpG ODN resulted in phosphorylation patterns of these adaptor proteins suggestive of inactivation of the TLR9 pathway. The absence of apparent TLR9 signaling events immediately following stimulation indicated that signaling is blocked close to the receptor. Our observations suggest a novel mechanism by which the host regulates TLR responses in TLR-expressing cells with regulatory functions.
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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 | 0.002 | 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) | 0.000 | 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 it