ICOS, CD40 and lymphotoxin-beta receptors signal sequentially and interdependently to initiate a germinal centre reaction
Bibliographic record
Abstract
Studies using gene-targeted mice have identified ICOS, a costimulatory molecule expressed on activated T cells, as an important molecule in the development of Germinal Centres (GCs). In the absence of ICOS, humoral immune responses are impaired and GC formation is defective. Although it is known that ICOS stimulation has multiple downstream consequences such as cytokine production, expression of CD40L on Th cells, and differentiation of CD4 + T cells into CXCR5+ follicular Th cells, the reasons for a defect in the architectural microenvironment of the GC itself remains obscure. Given that the Lymphotoxin (LT) pathway plays an essential role in maintaining GC niches and that both ICOS-/- and LTbeta-/- mice have similar GC defects, we investigated if the LT pathway is activated downstream of ICOS in order to induce the formation of a GC microenvironment. Here, we show that GC-B cells from ICOS-/- mice express lower levels of LTalphabeta compared with WT GC-B cells in vivo, and stimulation of ICOS on T cells induces LTalphabeta expression on B cells in vitro. Enforced signaling through the LTbetaR was unable to restore the GC response in ICOS-/- mice, suggesting that additional input from another pathway is involved for optimal GC generation. In contrast, treatment with agonistic anti-CD40 Ab in vivo recovered GC networks and restored LTalphabeta expression on GC-B cells in ICOS-/- mice. Recovery of GC networks by anti-CD40 Ab treatment however, can be annulled by simultaneous treatment with an LT-pathway inhibitor, LTbetaR-Ig, demonstrating that rescue of the GC microenvironment in ICOS-/- mice not only depends on CD40 signaling but also on LTbetaR signaling. Collectively, these data show signaling by both LTbetaR and CD40 downstream of ICOS activation promotes GC formation.
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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 | 0.000 | 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".